Item 1. Business
Overview
We are a forward-thinking women's healthcare company dedicated to fulfilling the unmet health needs of today's women. Our current product
candidates are designed to provide women with contraceptive options that offer greater convenience and facilitate compliance. Our lead product candidate, Twirla®, also known as AG200-15,
is a once-weekly prescription combination
hormonal contraceptive patch that is at the end of Phase 3 clinical development. We completed the third of three Phase 3 clinical trials for Twirla in December 2016 and expect to
resubmit our new drug application, or NDA, in the first half of 2017. Our short-term goal is to establish a market-leading franchise in the U.S. hormonal contraceptive market, which had total market
sales of approximately $5.5 billion in 2016. Over half of those sales were generated by branded products. Currently, there is only one other contraceptive patch available in the United States
and we believe it has limitations due to its dose and physical characteristics. Twirla is designed to address these limitations. We have developed a proprietary transdermal patch technology, called
Skinfusion®, which is designed to provide advantages over the currently available patch and is intended to optimize patch adhesion and patient wearability. We believe there is an unmet
market need for a low-dose contraceptive patch that is designed to address the limitations of the existing patch, while increasing patient convenience and compliance in a non-invasive fashion.
Twirla
is a combined hormonal contraceptive, or CHC, patch that contains the active ingredients ethinyl estradiol, or EE, which is a synthetic estrogen, and levonorgestrel, or LNG, which
is a type of progestin, a synthetic steroid hormone, both of which have an established history of efficacy and safety in currently marketed combination low-dose, oral contraceptives. Twirla is
designed using our proprietary Skinfusion technology to consistently deliver both hormones over a seven-day period at levels comparable to currently marketed low-dose oral contraceptives. By
delivering these active ingredients over seven days, in a comfortable, convenient and easy-to-use weekly patch, Twirla is designed to promote ease of use and enhanced patient compliance. The patch is
applied once weekly for three weeks, followed by a week without a patch. If approved, Twirla will be packaged with three patches per carton to provide for one 28-day cycle of therapy.
We
have conducted a comprehensive clinical program, with completed Phase 1, Phase 2, and Phase 3 trials enrolling over 4,100 women, over 3,500 of whom received
Twirla. Most recently, in December 2016, we completed a Phase 3 trial, the SECURE trial, in which we enrolled over 2,000 women for up to one year of treatment. In the Phase 1 and
Phase 2 clinical trials, we demonstrated that Twirla delivers levels of both EE and LNG to the blood stream that are consistent with current low-dose oral contraceptives. Prior to the SECURE
trial, we completed two Phase 3 clinical trials that enrolled over 1,900 women in the aggregate for up to 12 months, and we demonstrated that Twirla generally had comparable efficacy and
tolerability to an approved low-dose oral contraceptive. In the SECURE trial, we observed positive evidence of efficacy for Twirla based on use for up to one year. In our completed Phase 3
trials to date, over 1000 women have received Twirla for 12 months. Across all completed clinical trials, Twirla was generally well tolerated and had a favorable safety profile.
We
have filed a Section 505(b)(2) NDA, for approval of Twirla by the U.S. Food and Drug Administration, or FDA, which is required before marketing a new drug in the United States.
Our 505(b)(2) NDA relies in part on clinical trials that we conducted and in part on the FDA's findings of safety and efficacy from investigations for approved products containing the active
ingredients and published scientific literature for which we have not obtained a right of reference. The FDA has indicated in a Complete Response Letter, or CRL, that our NDA was not sufficient for
approval as originally submitted. After multiple communications with the FDA, we have received significant guidance as to what additional clinical development and other activities need to be completed
prior to approval. In accordance with the FDA's advice and comments, we conducted an additional Phase 3
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clinical
trial, the SECURE trial, which was initiated in 2014 and completed in December 2016. We announced the top-line results for the SECURE trial in January 2017. Based on the guidance that we
received from the FDA in connection with our discussions on clinical trial design, we believe that the results from the SECURE trial will address all of the clinical issues raised in the CRL. We
expect to respond to the CRL and supplement our NDA with the results of the trial in the first half of 2017, along with additional information relating to the manufacture of Twirla.
We
intend to commercialize Twirla in the United States, if approved, through a direct sales force. Obstetricians and gynecologists, or ObGyns, contribute 43% of the U.S. contraception
prescription volume, and Nurse Practitioners and Physician Assistants, or NP/PAs, who are often affiliated with an ObGyn practice, contribute an additional 29% of the U.S. prescriptions. We anticipate
that a targeted sales force focused initially on ObGyns, NPs, PAs and primary care providers who comprise the top prescribers of contraceptives will be highly effective. We believe that we can address
this market with a specialty sales force of approximately 70 to 100 representatives. We also intend to augment our sales force through digital marketing and other techniques to market directly to
patients. We will require additional capital for the commercial launch of Twirla, if approved.
Our
Skinfusion technology makes Twirla the first patch capable of delivering a contraceptive dose of LNG across the skin, allowing weekly application using a patch that is soft and
flexible and is designed to adhere well with low levels of skin irritation. We, along with Corium International, Inc., or Corium, our manufacturing partner, have made a significant investment
in a proprietary process to manufacture Twirla. We believe we have developed a robust process to reliably manufacture Twirla on a commercial scale. The materials produced for our clinical trials were
manufactured using the same process that we expect will be used for our commercial-scale manufacturing, and we have made a significant investment in equipment for commercial-scale manufacturing if
Twirla is approved. We believe that the technical challenges and know-how involved in manufacturing, including proprietary chemistry, production to scale and use of custom equipment and
reproducibility, present significant barriers to entry for other pharmaceutical companies who might potentially want to replicate our Skinfusion technology.
Our
intellectual property represents an additional barrier to potential competitors. We have thirteen issued U.S. patents, eight of which cover Twirla and that we intend to list in the
Orange Book, the last of which expires in 2028, and five that provide additional coverage for other product candidates in our pipeline. The Orange Book lists drug products, including related patent
and exclusivity information, approved by the FDA under the Federal Food, Drug, and Cosmetic Act. If a patent is listed in the Orange Book, potential competitors seeking approval of drug products under
an Abbreviated New Drug Application, which provides for the marketing of a generic drug product that has the same active ingredients, dosage form, strength, route of administration, labeling,
performance characteristics and intended use, among other things, of a previously approved product, or a 505(b)(2) application, for which the listed drug is a reference product, must provide a patent
certification in their application stating either that (1) no patent information on the drug product has been submitted to the FDA; (2) such patent has expired; (3) the date on
which such patent expires; or (4) such patent is invalid or will not be infringed upon by the manufacture, use or sale of the drug product for which the application is submitted. In addition,
we continue to prosecute additional patent applications relating to Twirla, as
well as our other product candidates, both in the United States and internationally. The intellectual property behind all of our product candidates in the pipeline and our Skinfusion technology
consists of patent families developed and wholly-owned by us. There are no royalties or payments owed to third parties on our Skinfusion technology or any of our product candidates.
In
addition to Twirla, we plan to develop a pipeline of other new transdermal contraceptive products, including AG200-ER, which is a regimen designed to allow a woman to extend the
length of her cycle, AG200-SP, which is a regimen designed to provide shorter lighter periods, AG200-ER (SmP), which is a regimen designed to allow a woman to extend the length of her cycle and
experience shorter,
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lighter
periods, and AG890, which is a progestin-only contraceptive patch intended for use by women who are unable or unwilling to take estrogen. Substantially all of our resources are currently
dedicated to developing and seeking regulatory approval for Twirla. We will require additional capital to advance the development of our other product candidates.
Background
Hormonal Contraception Overview
A woman is biologically capable of pregnancy from the time of her first menstrual cycle, at the average age of 12.6 years, to natural
menopause, at the average age of 51.3 years. This is nearly half of a typical woman's lifespan and, for the typical woman, the majority of this time frame is spent trying to avoid pregnancy or
is characterized by no desire to become pregnant. Nearly half of the pregnancies that occur each year in the United States are unplanned. The United States was the first country to approve a hormonal
contraceptive, with the approval of the first contraceptive pill in 1960. The latest data from 2011 to 2013 from the Centers for Disease Control, or CDC, indicate that approximately 28% of women aged
15 to 44 use some form of hormonal contraception, which amounts to approximately 17 million U.S. women.
Hormonal
contraceptives are composed of synthetic estrogens and progestins. Contraceptives containing both estrogen and a progestin are referred to as CHCs, and contraceptives containing
only progestin are referred to as P-only. There are three synthetic estrogens approved in the United States for use in contraceptive products: EE, mestranol and estradiol valerate. EE has been
available for over 40 years and is the estrogen component in nearly all CHCs today. There are 10 different progestins that have been used in contraceptives sold in the United States. The
progestin component provides most of the contraceptive effect, while the estrogen component primarily provides cycle control, for example, minimizing bleeding or spotting between cycles. The progestin
exerts its contraceptive effect by inhibiting ovulation, or release of an egg from the ovary, and by thickening cervical mucus. Thickening cervical mucus helps to prevent sperm entry into the upper
genital tract. The estrogen component, in addition to providing cycle control, makes a small contribution to contraception by decreasing the maturation of the egg in the ovary.
Hormonal
contraceptives are generally well-tolerated and are generally safer than pregnancy. A risk associated with hormonal contraceptives is a rare but serious adverse event called
venous thromboembolism, or VTE, which involves the formation of a blood clot in a vein. VTEs can be life-threatening, and typically present as either deep vein thrombosis or pulmonary embolism.
Evidence supports that the increased risk of VTE in CHC users is dependent upon the estrogen dose and duration of use. Estrogen increases formation of clotting factors in the liver and decreases
production of elements that promote breakdown of blood clots. Most experts believe that progestins on their own have minimal to no impact on the clotting system, but some progestins, when combined
with estrogen, can increase estrogen's effect on the clotting system.
The
likelihood of a woman spontaneously developing a VTE is extremely low and the use of combination oral contraceptives, or COCs, increases the incidence only slightly, and less than
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pregnancy.
Epidemiologic studies evaluated by the FDA have demonstrated the incidence of VTE in women based on pregnancy or use of COCs as follows:
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Incidence of VTE Based on Pregnancy Status or use of COCs
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Population
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VTE incidence
(cases per 10,000
woman years*)
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Non-pregnant woman who does not use a COC
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1 to 5
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COC users
|
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3 to 12
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Pregnant women
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5 to 20
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Postpartum women (in the 12 weeks following delivery)
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40 to 65
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*
-
One
woman year is one woman using a contraceptive for one year, which is either 12 months or 13 cycles
The
available progestins are commonly categorized into generations, based on their history of introduction in the United States. The first and second generation progestins, including
LNG, have been available in contraceptive formulations in the United States for over 25 years. The third and fourth generation progestins, for example desogestrel and drospirenone,
respectively, were introduced to reduce androgenic side effects, such as oily skin and acne. Epidemiologic data suggest that CHCs containing third and fourth generation progestins are associated with
an increased risk of VTE as compared to those containing the second generation progestin, LNG.
Effectiveness of Hormonal Contraceptives
For the purpose of FDA approval, contraceptive effectiveness is measured by a calculation called the Pearl Index, or PI and its associated 95%
confidence interval (CI). The PI is a measure of the rate of pregnancies over a specific period of time in a clinical trial, and is expressed as the number of pregnancies per 100 woman years, or WY,
of use. Each cycle lasts 28 days, so there are approximately 13 cycles in one year. According to recent FDA guidance, the PI calculation typically includes all pregnancies for which conception
is estimated to have occurred while the subject was using the drug (i.e., on-treatment pregnancies), but only includes cycles where the woman indicates that she engaged in sexual activity and
did not use backup contraception, such as a condom, and where she has completed a study diary. The PI values from clinical trials are affected by several factors, including differences in study
design, increased sensitivity of early pregnancy tests, weight and body mass index, or BMI, of the study population, user experience and inconsistent or incorrect use of the contraceptive method. In
addition, there has been an observable trend in PIs for approved combined hormonal contraceptives demonstrating an increase in the PIs over time, believed to be related to changes in study design and
study populations. The FDA has not established any regulatory guidance on specific parameters for an acceptable PI or CI to support approval.
The
contraceptive failure rates observed in clinical trials are generally lower than those seen once a CHC is approved and in use by a broad population, referred to as typical use,
without the close monitoring of a clinical trial setting. There is a large difference in pregnancy rates under conditions of perfect use, where the method is used following the directions exactly, and
typical use. For example, for CHCs, including oral contraceptives, the vaginal ring and the transdermal patch, the percent of women experiencing an unintended pregnancy during the first year of use is
0.3% for perfect use and 9.0% for typical use.
U.S. Hormonal Contraceptive Market Background
Contraceptive methods, other than sterilization, can be divided into non-hormonal and hormonal alternatives. Examples of non-hormonal products
available in the United States include the diaphragm,
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male
condom and female condom. There are several categories of hormonal contraception products available in the United States, including:
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oral contraceptive;
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vaginal ring;
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transdermal patch;
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intrauterine contraceptive device, or IUD;
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subcutaneous implant; and
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injectable.
The
U.S. hormonal contraceptive market recorded annual sales in 2016 of approximately $5.5 billion, according to IMS Health. The CHC portion of the market, consisting of pills, a
transdermal patch and a vaginal ring, generates significantly greater prescription volume and sales compared to the P-only portion of the market, consisting of IUDs, injectables, implants, and P-only
pills. In 2016, IMS Health reported total U.S. sales of $3.9 billion for the CHC market and $1.6 billion for the P-only market. Twirla is a CHC and, if approved, we believe it will
compete primarily with products in the CHC market.
The
U.S. hormonal contraceptive market is a mature market, with many branded and generic products available. In the past 10 years, the market growth was flat to declining as
measured by prescription volume, with the exception of a 4.8% increase in 2013 compared to 2012. The average annual growth rate in dollar sales for the five years ended December 31, 2016 was
1.0% for the total hormonal contraceptive market and 0.7% for the CHC market. Market growth in gross sales is primarily due to price increases amongst branded products.
We
believe there are two possible factors primarily affecting prescription volume growth in the contraceptive market. First, according to U.S. Census Bureau data and projections, the
population of women aged 15 to 44 years has been growing at a rate of approximately 0.4% to 0.5% per year since 2011, increasing this population by 250,000 to 300,000 women per year.
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Contraceptive Population
(Total women aged 15-44 yrs)
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Source:
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U.S.
Census Bureau, National projections released 2008 based on 2000 census data.
Second,
in 2010, the Patient Protection and Affordable Care Act, as amended by the Healthcare and Education Reconciliation Act, or collectively, the ACA, was signed into law, which,
among other things, requires all health plans, with limited exceptions, to cover certain preventive services for women with no cost-sharing, which means no deductible, no co-insurance and no
co-payments by the patient, effective August 1, 2012. These services include those set forth in the Guidelines for Women's Preventive Services, or HRSA Guidelines, and adopted by the U.S.
Department of Health and Human Services Health Resources and Services Administration. Contraceptive methods and counseling, including all FDA approved contraceptive methods as prescribed, are included
in the HRSA Guidelines. Since these new ACA provisions went into effect in August 2012, quarterly prescription volume growth for the CHC market rose from negative growth year-on-year to positive
growth between 4.0% and 5.0% for each of the six quarters following implementation. However, this appears to be a one-time phenomenon, as the market volume growth fell to 0.8% in 2014 and
0.9% in 2015.
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Effect of ACA on Market Growth
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Source:
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IMS
National Prescription Audit, IMS Health
During
the period following enactment of the ACA, generic oral contraceptives have shown the greatest growth, primarily at the expense of branded oral contraceptives. This is likely due
to the policies that were implemented by many managed care plans, which generally only provided generic oral contraceptives with no cost-sharing to the patient. The effect on non-oral products is less
clear, but prescription volume for the vaginal ring showed a 5.1% decline from 2013 to 2015, while the prescription volume for the patch increased by 15.0% over the same time period. In May 2015,
several government agencies, such as the U.S. Department of Health and Human Services, or HHS, the Department of Labor, or DOL, and the U.S. Department of Treasury, or Treasury, issued a clarification
in the form of an FAQ which clarified the requirements for coverage of contraceptives under the ACA. The FAQ states that plans and issuers must cover without cost-sharing at least one form of
contraception in each of the 18 current methods that the FDA has identified for women in its current Birth Control Guide. The patch is identified as a specific method in the FDA Birth Control Guide,
and therefore insurers must cover at least one patch product with no cost-sharing to the patient. Because this clarifying guidance is applied for plan years (or in the individual market, policy years)
beginning on or after 60 days from the date of publication of the FAQs, patients did not have the benefit of this clarification until their new plan year, which generally started in January
2016.
In
March 2017, the U.S. Congress proposed legislation, which, if signed into law by the new administration, would repeal certain aspects of the ACA. Further, on January 20, 2017,
the new administration signed an Executive Order directing federal agencies with authorities and responsibilities under the ACA to waive, defer, grant exemptions from, or delay the implementation of
any provision of the ACA that would impose a fiscal or regulatory burden on states, individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices, among
others. Congress also could consider subsequent legislation to repeal and replace elements of the ACA that are repealed. Therefore, it is difficult to determine the full effect of the ACA or any other
healthcare reform efforts on our business. We will continue to monitor the healthcare reform efforts. We believe the CHC market will maintain a long-term neutral to slightly positive annual growth
rate in line with contraceptive population growth.
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In spite of the availability of generic contraceptives for over 25 years, branded products have maintained a significant share of the CHC market, with 55%
of dollar sales and 17% of prescriptions for 2016. Branded contraceptives in the CHC market have driven significant increases in the value of branded total prescriptions, or TRx. In the five years
ended December 2016, the average annual price increase among the top branded products was 10.6%. The average price per cycle, referred to as the wholesale acquisition cost, or WAC, for a single 28-day
cycle of the top branded products was $41.53 in 2006 and rose to $131.40 by December 2016. As of October 2014, the branded CHC transdermal patch (Ortho Evra) has been discontinued, and the generic CHC
transdermal patch (Xulane) is currently priced at $105.92 per cycle. The other non-oral form of CHC, the vaginal ring, is currently priced at $128.21 per cycle. We cannot predict whether the
manufacturers of branded products will continue to increase prices going forward, but we believe we will be able to set a WAC price for Twirla, if approved, that is comparable to other branded CHC
products at the time of launch. Based on IMS Health data, we estimate that each percentage point of market share of CHC total prescriptions in the United States currently represents approximately
$166 million of annual gross sales potential for Twirla, if approved.
Contraceptive Pills
Based on data from the CDC, of women who choose to use a hormonal contraceptive, approximately 64% use the contraceptive pill, vaginal ring or
patch, the majority of which use the contraceptive pill. Based on this information, we believe that contraceptive pills are the most popular choice because:
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patients and physicians are familiar with pills;
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pills were the first to market and have been aggressively promoted for a long period of time;
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historically, pills have been a covered benefit with good reimbursement in private and public healthcare plans; and
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pills are a non-invasive option.
However,
compliance remains a significant draw-back with pills. Published studies have shown that the average woman who uses oral contraceptives misses approximately two to four pills
per month, which increases the potential for unintended pregnancies. We believe that a patch can offer greater convenience than a pill, as it does not require daily administration and, for certain
women, could lead to greater compliance and ease of use.
Contraceptive Patch Market Experience
The Ortho Evra® contraceptive patch, or Evra, was introduced in early 2002 and was the first FDA-approved contraceptive patch. The
initial approved labeling for Evra indicated that it delivered a daily EE dose of 20 micrograms. Evra had rapid uptake in the contraceptive market, and achieved a 10% share of the CHC market by
September 2003. Following FDA approval of Evra, users of Evra began to report thrombotic and thromboembolic events to the FDA. Johnson & Johnson, the manufacturer of Evra, revised the Evra
labeling in November 2005 to include information that EE exposure with Evra is 60% higher than that of an oral contraceptive containing EE of 35 micrograms, based on area under the curve, a
commonly-used metric for measuring EE exposure in contraceptives. This information was ultimately included in a black box warning and bolded warnings unique to the Evra label. The Evra market share
declined rapidly following the labeling changes, from a peak share of 11% in 2005, to 4% by the end of 2006, to 1.4% by the end of 2013, where it stabilized, with a 1.5% share of the market based on
combined prescriptions for Evra and its generic equivalent in 2014. In the past two years, the patch share of the CHC market grew slightly, with a 1.6% TRx share in 2015 and 1.7% TRx share in 2016.
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In
April 2014, Mylan Inc. announced the launch of Xulane, a generic version of Evra. Generic pharmaceutical products are the chemical and pharmaceutical equivalents
of the brand or a reference listed drug, or RLD. Generic drugs are bioequivalent to their reference brand name counterparts. Bioequivalence studies compare the bioavailability of the proposed drug
product with that of the RLD product containing the same active ingredients. Bioavailability is a measure of the rate and extent to which the active ingredient is absorbed from a drug product and
becomes available at the site of action. Under pharmacy dispensing rules governed by state law, depending on the state, if an automatic generic substitute is introduced, the pharmacist may dispense
either the prescribed product, or they may replace it with an equivalent generic without being required to inform the patient or healthcare professional. In addition, the FDA offers a 180-day
exclusivity period for generic products in specific cases. The first generic applicants to submit a substantially complete Abbreviated New Drug Application containing a paragraph IV
certification to a listed patent are protected from competition from other generic versions of the same drug for the 180 days. As of December 2016, no other generic equivalents to Evra have
been introduced.
The
FDA has maintained, in spite of the wording in the labeling for Evra and its approved generic, that none of the epidemiologic studies to date provides a definitive answer regarding
the relative risk of VTE with Evra compared to combined oral contraceptive use or whether the increased risk that some studies demonstrated is directly attributable to Evra. An advisory committee for
the FDA stated that the benefits of Evra outweigh the risks. In its denial of a Citizen's Petition calling for the withdrawal of Evra, the FDA followed the committee's recommendations stating that the
increased VTE risk does not
warrant removal from the market, and that the labeling revisions to the Evra label provide a sufficient update and guidance on the interpretation of the epidemiologic data about the risk of VTE with
Evra. In spite of the labeling changes, and Johnson & Johnson ceasing promotion of Evra in 2007, Evra and its generic equivalent generated $211 million in gross sales in 2016.
We
believe that the rapid uptake and acceptance of Evra upon its introduction demonstrates that there is an unmet market need for a transdermal patch as a contraceptive option. Also, the
epidemiologic data on VTE risk suggest that there is a need for a contraceptive patch that delivers both a low dose of EE similar to oral contraceptives and a first or second generation progestin.
Our Product Candidates
Each of our product candidates utilizes our proprietary Skinfusion technology, which is designed to provide advantages over the currently
available patch. Skinfusion is designed to deliver contraceptive levels of hormones to the blood stream through the skin over a seven-day period. It is also designed to optimize patch adhesion and
patient wearability. Our lead product candidate is Twirla, a prescription CHC patch which contains both EE and LNG and is designed to deliver a low dose of EE and LNG comparable to the total dose
delivered with low-dose oral contraceptives. In addition to Twirla, we plan to develop a pipeline of other new transdermal contraceptive products, including AG200-SP, which is a regimen designed to
provide shorter, lighter periods; AG200-ER, which is a regimen designed to allow a woman to extend the length of her cycle; AG200-ER (SmP), which is a regimen designed to allow a woman to extend the
length of her cycle and experience shorter, lighter periods; and AG890, which is a progestin-only contraceptive patch intended for use by women who are unable or unwilling to take estrogen. AG200-SP,
AG200-ER, and AG200-ER (SmP) are intended to be Twirla line extensions that would expand the use of Twirla beyond its initial, approved use. In July 2016, we began preparations for an initial
Phase 2 clinical trial examining the use of AG200-SP along with a smaller lower-dose combination ethinyl estradiol/levonorgestrel patch (SmP) in the fourth week of the woman's cycle. The
Phase 2 clinical trial is aimed at identifying the optimal dose of the SmP, and will evaluate bleeding profiles, pharmacokinetic parameters, ovulation inhibition and safety over three cycles of
treatment with AG200-SP (SmP). We have decided to postpone the trial and will continue to evaluate the timing for
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initiating
dosing of subjects for this Phase 2 clinical trial, which is dependent on financial and other capital resources.
The
National Institutes of Health, through a clinical trial agreement with us, conducted a Phase 1/2 trial with AG890. The Phase
1
/
2
study was a multicenter study
to evaluate the pharmacokinetics, safety and mechanisms of potential contraceptive efficacy of AG890. The trial is complete and we continue to evaluate the findings. After we complete our evaluation,
we may need to perform additional patch development work to determine the optimal formulation and dose to advance to Phase 3. Based upon a number of factors, including, but not limited to, our
available capital resources and feedback from the FDA, we continue to review the clinical path and budgetary requirements for each of AG200-SP, AG200-ER and AG890.
Our
current product candidate pipeline is summarized in the graphic below:
Substantially
all of our resources are currently dedicated to developing and seeking regulatory approval for Twirla. We will require additional capital to advance the development of our
other product candidates.
Twirla Product Overview
Twirla is a CHC patch which contains both EE and LNG. Twirla is designed to address an unmet medical need for increased compliance and improved
ease of use as compared to oral contraceptives. A single Twirla patch delivers the active ingredients LNG and EE over a seven-day dosing interval, and thereby eliminates the need to take a daily pill
as is necessary with an oral contraceptive. Twirla uses a traditional 28-day contraceptive regimen, where one patch is applied weekly for three consecutive weeks and then there is a fourth, patch-free
week in each 28-day time period. Twirla may be applied to the buttock, abdomen or upper torso, but not the breast. In clinical trials reported to date, women most frequently chose the buttock and
abdomen for patch placement. The exact patch location needs to be rotated with each patch change. Twirla has demonstrated a therapeutically equivalent pharmacokinetic profile when worn on the buttock,
abdomen or upper torso. A drug's pharmacokinetic
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profile
refers to the specific way in which a given drug is handled by the body over time, reflecting the particular patterns of absorption, distribution and elimination of the drug in the body.
Twirla
is designed to be highly appealing to patients as a method of contraception. The patch is round and made of a soft, flexible, silky fabric, designed to flex with the movement of a
woman's body. Twirla is a matrix patch consisting of several layers of material that contain the active ingredients EE and LNG, as well as the inactive ingredients Dimethylsulfoxide, Ethyl Lactate,
Capric Acid and Lauryl Lactate, which are ingredients to assist in the transport of EE and LNG across the skin, and adhesives that enable adherence to the skin. The final top layer is the one seen on
the skin, and consists of a thin, silky material consisting of only adhesive. There is a barrier formed between the inner portion of the patch, which contains the active ingredients, and the outer
portion of the patch, which only contains the adhesive. This barrier is intended to prevent the active and inactive ingredients from migrating to the peripheral portion of the patch, and from breaking
down the adhesive in that portion of the patch. Twirla is also designed to help prevent seepage of the adhesives from around the edge of the patch where it could collect dirt and leave a sticky black
ring on the skin. The six layers of the patch are integrated to create a patch which has a slim profile, and is unobtrusive when applied. The results of multiple clinical trials suggest that Twirla
delivers the active ingredients needed for contraception over a
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seven-day
period and that it remains adhered to the skin of most subjects for the full seven-day period, even under conditions of heat, humidity, showering, exposure to water and vigorous exercise.
Twirla Patch Profile
The following table compares Twirla with the Evra product and its generic equivalent, Xulane, as stated in their labels, based upon
publicly-available information regarding the products and the characteristics of Twirla and other Twirla attributes observed in our completed Phase 3 clinical trials. We have not performed a
head-to-head comparison of Twirla to Evra.
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Characteristic
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Twirla
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Ortho Evra*/Xulane
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Form of product
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Transdermal patch Round, approximately 28 square centimeters Soft, silky, stretchy fabric
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Transdermal patch Square, Evra approximately 20 square centimeters; Xulane approximately 14 square centimeters Smooth, plastic film
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Active ingredients
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EE, LNG
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EE, norelgestromin
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Pharmacokinetic profile of EE per day
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~30 micrograms
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60% higher than that of an oral contraceptive containing 35 micrograms (~56 micrograms)**
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Regimen
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One patch weekly 21 days active / 7 days patch-free
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Same as Twirla;
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Package configurations
|
|
1 box of 3 patches = 1 cycle 1 box with 1 patch = replacement
|
|
Evra is same as Twirla; Xulane is 1 box of 3 patches only
|
Top four adverse events/reactions in clinical trials completed prior to SECURE
|
|
Nausea 3.0% Application site irritation 2.4% Breast tenderness 2.1% Headache 2.0%***
|
|
Breast symptoms 22.4% Headache 21.0% Application site disorders 17.1% Nausea 16.6%
|
-
*
-
Source
of Ortho Evra and Xulane data are U.S. prescribing information or package inserts.
-
**
-
The
Ortho Evra and Xulane package inserts indicate a strength of 35 micrograms of EE per day.
-
***
-
Adverse
events deemed definitely, probably or possibly related to Twirla in Phase 3 clinical trials completed prior to SECURE.
14
Table of Contents
|
|
|
Twirla
|
|
Evra
|
|
|
|
Twirla
employs our Skinfusion patch technology, resulting in a unique appearance and feel of the patch. Evra/Xulane does not utilize our Skinfusion technology; its active ingredients and
adhesives are dispersed to its edges. One frequent complaint about patches that do not utilize Skinfusion is that they collect dirt and lint and may leave a sticky black ring of residue on the skin
which can be difficult to remove. We do not have any direct comparison of the appearance of the patch on the skin at the end of seven days between Twirla and Evra/Xulane, but we believe, based on
anecdotal feedback from our clinical trial investigators, as well as based upon the differences in the design of the patches, that Twirla may have an advantage in this regard.
We
have not performed a head-to-head comparison of Twirla to Evra/Xulane, however, a pharmacokinetic study that we conducted with Twirla was similar in design to the pharmacokinetic
study conducted with Evra that provided the information regarding the daily amount of EE delivered that is currently in the Evra/Xulane package insert. The figure below combines the results for
average EE concentrations from these two studies, and suggests a comparison of the observed blood concentration of EE for Twirla versus Evra versus observed and estimated data for the pill. The lower
amount of EE delivered from Twirla as compared to Evra can be observed. If Twirla is approved by the FDA, we will not be able to make direct comparative claims regarding the safety, efficacy or
pharmacokinetics of Twirla and Evra/Xulane, since none of our completed clinical trials studied Twirla in a head-to-head comparison with Evra/Xulane.
15
Table of Contents
EE Concentrations (pg/ml)
The
Evra curve presented in the graphic above was estimated based on the graph provided in the Evra label. In the legend to the figure above, "OC" refers to an oral contraceptive
containing 35 micrograms of EE. The OC data prior to Day 21 are estimated steady-state data based on Day 21 EE concentrations observed during our pharmacokinetic study.
Twirla
contains LNG, which is the progestin used as the reference standard when comparing risk of VTE between progestins. Evra/Xulane contains the progestin norelgestromin, which is a
prodrug of norgestimate, a second generation progestin that has not demonstrated an increased risk of VTE independent of EE. We do not expect any meaningful clinical differences between Twirla
and Evra/Xulane based on the progestin component, but our market research with ObGyns has demonstrated that they perceive LNG to be one of the safest progestins available.
Twirla Product Profile
Assuming approval of our marketing application by the FDA based on the results of the SECURE trial, we believe the clinical trial data from the
SECURE trial for Twirla will support our future marketing of Twirla as follows:
-
-
Twirla is a weekly contraceptive patch, designed to offer convenience and compliance.
-
-
Twirla is designed to meet the contraceptive needs and the busy lifestyle of today's women.
-
-
Twirla contains the active ingredients EE and LNG, both of which have been used in contraceptives for over 25 years.
-
-
Twirla delivers the low daily dose of EE of approximately 30 micrograms, comparable to low-dose oral contraceptives.
-
-
Twirla is designed to demonstrate efficacy comparable to other approved prescription contraceptives.
-
-
Twirla has a favorable safety and tolerability profile.
16
Table of Contents
-
-
Twirla was designed with Skinfusion technology, which has demonstrated adhesion over the seven-day wear period, even under conditions of heat,
humidity, showering, exposure to water and vigorous exercise.
-
-
Because Twirla contains the progestin LNG, we believe that the final approved label for Twirla will be consistent with the class labeling for
other contraceptives containing EE and LNG, including the class black box warning.
-
-
Based on the results of the SECURE clinical trial, we believe it is possible the final approved label for Twirla may contain language on the
use of Twirla in women based on weight.
Twirla Clinical Development Program
Clinical Trials Completed prior to SECURE
Our clinical program includes three Phase 1 studies, one Phase 2 study, and three Phase 3 studies, as well as other
supporting studies. In December 2016, we completed our third Phase 3 clinical trial, SECURE, in response to FDA comments and guidance. In Phase 1 and Phase 2 clinical trials, we
demonstrated that Twirla delivers levels of both EE and LNG to the blood stream that are consistent with currently marketed low-dose oral contraceptives. In our Phase 3 clinical trials
completed prior to SECURE, we demonstrated that Twirla was comparable to an approved low-dose oral contraceptive in two randomized studies, one that enrolled over 1,500 women over 12 months and
the other that enrolled over 400 women over six months. Across all completed clinical trials, Twirla was generally well-tolerated and had a favorable safety profile. Because we relied, in part, on the
FDA's findings of safety and efficacy from investigations for approved products containing EE and LNG and published scientific literature for which we have not obtained a right of reference, we were
not required to conduct preclinical studies. In the pharmacokinetic study comparing Twirla to an approved low-dose oral contraceptive, results demonstrated that Twirla delivers a daily dose of EE that
results in estrogen exposure similar to low-dose oral contraceptives containing approximately 30 micrograms.
Our
two Phase 3 trials completed prior to SECURE enrolled over 1,900 subjects to evaluate the safety and efficacy of Twirla. Each of these studies included an active comparator
arm with an approved low-dose oral contraceptive. The results of these studies demonstrated that Twirla was generally well-tolerated, with levels of adverse events generally comparable to those of
low-dose oral contraceptives. In these studies, subjects had a higher rate of self-reported compliance when using the patch as compared with the group using oral contraceptives. However, as discussed
further below, the FDA issued a CRL in response to our marketing application for Twirla and requested an additional Phase 3 study and additional chemistry manufacturing and control, or CMC,
information. The results of our prior clinical trials demonstrated that approximately only 3% of patches became completely detached from the skin of subjects during the seven-day period, and that the
patch generally remained adhered to the skin even when exposed to normal daily activities and conditions such as showering, swimming and other forms of exercise, heat and humidity.
More
specifically, our safety population included subjects who received at least one dose of Twirla or COC. In the combined safety population of our two Phase 3 trials completed
prior to SECURE, there
were a total of 22 serious adverse events, or SAEs, of which 16 were from the Twirla cohort, which had approximately 2.3 times as many subjects as the oral contraceptive comparator cohort. Three of
these SAEs (0.2% of the overall Twirla safety population) were considered to be possibly related to the study drug and included one drug overdose with Benadryl®, one case of uncontrollable
nausea and vomiting and one instance of upper extremity deep vein thrombosis. In addition to the SAEs described above, some subjects taking Twirla experienced non-serious adverse events, such as
nausea, headache, application site irritation and breast tenderness. Subjects receiving the oral contraceptive comparator also generally experienced similar non-serious adverse events such as nausea,
headache, and breast tenderness, though at different rates. We believe that Twirla will have a label consistent with all
17
Table of Contents
marketed
low-dose CHC products, which include class labeling that warns of risks of certain serious conditions, including venous and arterial blood clots, such as heart attacks, thromboembolism and
stroke, as well as liver tumors, gallbladder disease and hypertension, and a black box warning regarding risks of smoking and CHC use, particularly in women over 35 years old who smoke.
In
our Phase 3 trials, the primary measure of efficacy is the Pearl Index, or PI, which is calculated based on the number of observed on-treatment pregnancies and total number of
on-treatment cycles during the study. Specifically, the PI is expressed as the number of pregnancies per 100 WY of use. The pooled PI value in the previously completed Phase 3 trials for the
Twirla patch was 5.76 and for the combined oral contraceptive control arms was 6.72, which were higher than the range of 1.34 to 3.19 in pivotal studies conducted on products approved by the FDA in
the previous ten years. In addition, the upper bound of the associated confidence intervals were higher than those seen in clinical trials used for registration of other approved hormonal
contraceptives.
We
believe that the results for both the patch and oral contraceptive control arms in the two Phase 3 trials completed prior to SECURE were affected primarily by issues with study
conduct at several study sites, including rapid enrollment which led to inability to manage the study population, poor subject compliance, and high rates of loss to follow-up. In the larger of our
Phase 3 trials completed prior to SECURE, 96 sites enrolled subjects, 60 of which had no on-treatment pregnancies. Nineteen percent of the on-treatment pregnancies reported during this trial
came from one site. This site represented approximately 8% of the randomized subject population. Thirty six percent of on-treatment pregnancies were reported at four of the 96 sites. These four sites
represented approximately 15% of the randomized subject population.
Experts
agree that the characteristic most likely to impact contraceptive failure and pregnancy rates is the subject's likelihood of using a method inconsistently or incorrectly.
Consistent with expert opinions, our analyses have suggested that the results for both the patch and oral contraceptive control arms in the two Phase 3 trials completed prior to SECURE were
also affected in part by the study population, which comprised a disproportionately high number of new users and minority subjects, known to be at
higher risk of noncompliance and pregnancy, as compared to the majority of other recent CHC clinical trials which have gained approval in the United States.
Individuals
who immediately switch from one hormonal contraception method to another, referred to as current users, or who have recently used another method of hormonal contraception,
are less likely to experience contraceptive failure than a new user because they are less likely to have inconsistent or incorrect use. These experienced subjects are often selected for trial
participation because their inclusion will lower failure rates. Indeed, many contraceptive trials have enrolled a high proportion of these subjects. Direct comparisons across multiple trials are
limited by differences in study design and population, as well as differences in definitions of user status; however, as shown in the table below, some comparisons are possible. For example, when
compared against trials that captured current hormonal contraceptive use, in the larger of our two Phase 3 trials completed prior to SECURE, we had a lower proportion of subjects randomized to
receive Twirla that were current users, only 17.8%, reflecting a population with less experience using hormonal contraception, compared to two recently approved hormonal contraceptives. When compared
against trials that categorized subject experience more broadly by their use of hormonal contraception within the 6 months prior to enrollment, our trial also had a lower proportion of
experienced subjects, only 44%. In both the COC and Twirla groups, new users had approximately three times the rate of noncompliance compared to experienced users, as verified through blood tests
revealing non-detectable blood levels of EE and LNG. Similarly, the pooled PI values from our two Phase 3 trials completed prior to SECURE were more than twice as high among new users compared
to experienced users, and in the primary efficacy analysis population there were no pregnancies observed in current users of other hormonal contraception who immediately switched to the patch upon
entry into the trial.
18
Table of Contents
In addition, our two Phase 3 trials completed prior to SECURE also included a higher proportion of black and Hispanic subjects than most recent hormonal
contraceptive trials. Although the underlying reasons are not well-understood, several articles in medical journals, such as
Contraception
and the
American Journal of
Obstetrics & Gynecology
, and in at least one report by HHS, state that contraceptive failure rates are highest in black and
Hispanic subjects. In our two Phase 3 trials completed prior to SECURE, rates of laboratory-verified noncompliance were substantially higher in blacks and Hispanics compared to non-Hispanic
white subjects in the larger of our Phase 3 trials, and as shown in the table below, there were substantially higher PI values in the black and Hispanic subpopulations than in non-Hispanic
white subjects. Additionally, as shown in the table the observed PI values were more dramatically increased for new users who were also black or Hispanic.
Study Population Demographics in Selected Contraception Trials
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Contraceptive Product (Year of Approval) % of subjects in category*
|
|
Parameter
|
|
|
|
Twirla
|
|
Seasonique
(2006)
|
|
Yaz
(2006)
|
|
Lo-
Seasonique
(2008)
|
|
Natazia
(2010)
|
|
Quartette
(2013)
|
|
Hormonal contraception use
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Current Users
|
|
|
|
|
18
|
(a)
|
|
|
|
|
60
|
(b)
|
|
|
|
|
59
|
(c)
|
|
|
|
Within 6m of enrollment
|
|
Yes(d)
|
|
|
44
|
|
|
68
|
|
|
|
|
|
61
|
|
|
|
|
|
44
|
|
|
|
No(e)
|
|
|
56
|
|
|
32
|
|
|
|
|
|
39
|
|
|
|
|
|
56
|
|
Race/ethnicity
|
|
Hispanic
|
|
|
15
|
|
|
5
|
|
|
5
|
|
|
10
|
|
|
13
|
|
|
11
|
|
|
|
Black
|
|
|
22
|
|
|
11
|
|
|
4
|
|
|
12
|
|
|
7
|
|
|
18
|
|
-
*
-
Table
includes subjects randomized to Twirla in the larger of our Phase 3 trials completed prior to SECURE. The data pertaining to the approved drug products
were derived from multiple studies, with differing study designs, as reported in the FDA medical review documents for each product.
Current
user definitions (extrapolated for approved products):
-
(a)
-
Used
a hormonal contraceptive within 7 days of enrollment.
-
(b)
-
Using
an oral contraceptive at screening, just prior to study start.
-
(c)
-
Using
oral contraceptives prior to study start.
Use
within 6 months of enrollment definitions:
-
(d)
-
Twirla:
recent and current users; Quartette/Seasonique/Lo-Seasonique: continuous users.
-
(e)
-
Twirla:
new users; Seasonique/LoSeasonique: fresh start and prior users; Quartette: new start and prior user.
19
Table of Contents
Twirla Pearl Indices Stratified By New Users and Minority Subjects
|
|
|
|
|
|
|
Parameter
|
|
Demographic
|
|
Pearl Index*
|
|
Race/ethnicity
|
|
White (not Hispanic)
|
|
|
3.6
|
|
|
|
Hispanic
|
|
|
5.0
|
|
|
|
Black
|
|
|
15.1
|
|
Previous contraceptive use status
|
|
New users(a)
|
|
|
8.7
|
|
|
|
Experienced users(b)
|
|
|
3.0
|
|
|
|
Current users(c)
|
|
|
0.0
|
|
Race/ethnicity and Previous contraceptive use status
|
|
Hispanic subjects who were new users
|
|
|
7.5
|
|
|
|
Black subjects who were new users
|
|
|
16.0
|
|
-
*
-
Table
includes the pooled PI values for subjects in the primary efficacy analysis population randomized to Twirla.
-
(a)
-
New
users = never used hormonal contraception or had not used hormonal contraception in the 6 months prior to enrollment.
-
(b)
-
Experienced
users = recent (used a hormonal contraceptive within 6 months of enrollment) and current users.
-
(c)
-
Current
users = subjects who used a hormonal contraceptive within seven days of enrollment.
CRL and FDA Interactions
In February 2013, we received a CRL from the FDA indicating that the results from our two completed Phase 3 trials would not be
sufficient for approval, and the FDA proposed that we conduct an additional Phase 3 trial. Among the comments expressed in the letter were some regarding the PI values seen in the studies.
Specifically, the FDA indicated that the PI values and the upper bound of the associated confidence intervals in the studies, in both the subjects using the Twirla patch and the control arm using oral
contraceptives, were higher than seen in clinical trials used for registration of other approved hormonal contraceptives. The confidence interval is a range around a measurement that conveys how
precise a measurement is. The FDA recommended that we conduct an additional Phase 3 trial with a simplified clinical trial design and improved study conduct, including site monitoring and data
collection procedures. The FDA also requested that we study Twirla in a representative sample of U.S. women who are seeking hormonal contraception, without enrollment restrictions based on demographic
characteristics such as contraceptive user status, age, race, ethnicity, and body mass index, or BMI. The FDA also required additional information relating to the laser etching of label information on
each patch and required that the patch used in the new trial utilize the same etching as will be used for the commercial product, in order to demonstrate that it does not adversely affect the
performance of the patch. Furthermore, the FDA also requested in the CRL
additional information on controls and release specifications related to the patch, and manufacturing and control information related to the Drug Master File of one of the raw materials in Twirla.
In
October 2013, we met with the FDA and received further guidance on requirements for our planned Phase 3 trial. In addition, we had a follow-up written interaction with the FDA
in February 2014 and have received substantial written comments from the FDA in subsequent interactions. We enrolled the first subject in the SECURE clinical trial in the third quarter of 2014, and
completed the clinical trial in December 2016. The patches studied in the SECURE trial were laser etched using the same process as we anticipate for commercialization of Twirla, if approved. We have
continued to
20
Table of Contents
interact
with the FDA on its CMC questions and continued additional supportive testing in order to respond to the FDA's CMC questions.
The SECURE trial, our third Phase 3 Clinical Trial
SECURE, our third Phase 3 clinical trial, was a multicenter, single-arm, open-label, 13-cycle trial that evaluated the safety, efficacy
and tolerability of Twirla in 2032 healthy women, aged 18 and over, at 102 experienced investigative sites across the United States. The design and execution of SECURE was intended to address a number
of issues identified in the CRL, including but not limited to, improved clinical trial conduct and demonstration of efficacy as measured by an acceptable Pearl Index and related 95% confidence
interval in a representative sample of U.S. women who are seeking hormonal contraception, without enrollment restrictions based on demographic characteristics, such as contraceptive user status, age,
race, ethnicity, and BMI. The trial was designed in consultation with the FDA, and comprised a number of stringent trial design elements, including exclusion of treatment cycles not only for use of
back-up contraception but also for lack of sexual activity. SECURE had broad entry criteria, placed no limitations on BMI or other demographic factors during enrollment, and enrolled a large and
diverse population from the United States in order to allow for efficacy to be assessed across different groups, as requested by the FDA. These entry criteria resulted in the inclusion of a
substantial number of women with high BMI, who have frequently been under-represented in past contraceptive studies. The efficacy measure for SECURE was the Pearl Index in an intent-to-treat
population of subjects 35 years of age and under. The FDA also requested inclusion of pre-specified efficacy analyses related to BMI and body weight.
We
began enrollment for SECURE in the fourth quarter of 2014 and completed the clinical trial in December 2016. In January 2017, we announced the following highlights of the SECURE
clinical trial top-line results:
-
-
Consistent with its broad entry criteria, the SECURE clinical trial population was representative of the population of women in the United
States with respect to key demographic criteria, including:
-
-
Race (66.9% of subjects were white, 24.3% black and 8.8% other);
-
-
Ethnicity (19.7% were Hispanic, 80.3% non-Hispanic); and
-
-
BMI (39.4% of subjects had a normal baseline weight (BMI of under 25 kg/m
2
), 25.3% of subjects were overweight (BMI
of at least 25 kg/m
2
but less than 30 kg/m
2
), and 35.3% were obese (BMI 30 kg/m
2
or more). When classified as obese (BMI 30 kg/m
2
or more) or
non-obese (BMI less than 30 kg/m
2
), 35.3% of subjects were obese and 64.7% were non-obese).
-
-
Both new and experienced hormonal contraceptive users were enrolled (9.4% of subjects were new users).
-
-
51.4% of subjects discontinued prematurely from the study, which is a lower discontinuation rate than our previous Phase 3 clinical
trials and in line with other Phase 3 clinical trials for approved hormonal contraceptives. The main reasons for subject discontinuation from the trial were subject decision (15.3%), adverse
event (10.9%), and loss to follow-up. The most common (
³
1%) adverse reactions leading to discontinuation were bleeding irregularities (1.8%) and any
application site reaction (1.1%); all others were less than 1%. The loss to follow-up rate was 11.3%, which is in line with loss to follow-up rates observed in previous clinical trials of combined
hormonal products and substantially better than the 20% loss to follow-up rate observed in our previous Phase 3 trial.
21
Table of Contents
-
-
The Pearl Index for the overall intent to treat population of subjects 35 years of age and under was 4.80 with an upper-bound of the 95%
confidence interval of 6.06. As with all hormonal contraceptive trials, the number of pregnancies included in our calculation of the Pearl Index is subject to review by the FDA as part of its overall
review of the NDA for Twirla.
-
-
Consistent with other recent hormonal contraceptive clinical trials, including Ortho Evra® and Quartette®, and the 2015
meta-analysis conducted by FDA authors on the effect of obesity on the effectiveness of hormonal contraceptives, a relationship between obesity and efficacy was observed among subjects 35 years
of age and under:
|
|
|
|
|
|
|
|
|
|
|
|
|
BMI Category
|
|
BMI
(kg/m
2
)
|
|
% of Trial
Population
|
|
Pearl Index
|
|
Upper Bound
of 95% CI
|
|
Normal
|
|
< 25
|
|
|
39
|
%
|
|
3.03
|
|
|
4.62
|
|
Overweight
|
|
25 - < 30
|
|
|
25
|
%
|
|
5.36
|
|
|
7.98
|
|
Obese*
|
|
³
30
|
|
|
35
|
%
|
|
6.42
|
|
|
8.88
|
|
Non-Obese*
|
|
< 30
|
|
|
65
|
%
|
|
3.94
|
|
|
5.35
|
|
Obese*
|
|
³
30
|
|
|
35
|
%
|
|
6.42
|
|
|
8.88
|
|
-
*
-
In
its 2015 meta-analysis, the FDA examined the effect of obesity on two populations: non-obese (< 30 kg/m
2
) and obese
(
³
30 kg/m
2
). Non-obese includes subjects in the normal and overweight categories.
The
Pearl Index for subjects by minority and ethnicity status was as follows:
|
|
|
|
|
|
|
|
|
|
|
Race/Ethnicity
|
|
% of Trial
Population
|
|
Pearl Index
|
|
Upper Bound
of 95% CI
|
|
White (not Hispanic)
|
|
|
66.9
|
%
|
|
4.63
|
|
|
6.23
|
|
African-American
|
|
|
24.3
|
%
|
|
4.05
|
|
|
6.69
|
|
Hispanic
|
|
|
19.7
|
%
|
|
2.70
|
|
|
5.06
|
|
-
-
Twirla was generally well tolerated and had an overall favorable safety profile, consistent with publicly available information relating to
other low-dose combined hormonal products. The most frequent hormone-related adverse events, none of which were experienced by more than 5% of subjects, were generally in line with those events
observed in other low dose combined hormonal products and included:
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Adverse Event
|
|
SECURE
Trial
|
|
Prior Agile
Phase 3
Trial*
|
|
Ortho Evra
Trials**
|
|
Quartette
Trial**
|
|
Total in Safety Population
|
|
|
2032
|
|
|
1043
|
|
|
3322
|
|
|
3597
|
|
Headache
|
|
|
4.3
|
%
|
|
3.7
|
%
|
|
21.0
|
%
|
|
12.2
|
%
|
Nausea
|
|
|
4.1
|
%
|
|
4.3
|
%
|
|
16.6
|
%
|
|
6.7
|
%
|
Breast tenderness/pain/discomfort
|
|
|
2.0
|
%
|
|
1.8
|
%
|
|
22.4
|
%
|
|
2.2
|
%
|
Mood swings/changes/depression
|
|
|
2.7
|
%
|
|
2.8
|
%
|
|
6.3
|
%
|
|
2.9
|
%
|
Heavy/irregular vaginal bleeding***
|
|
|
1.8
|
%
|
|
2.1
|
%
|
|
6.4
|
%
|
|
9.7
|
%
|
-
*
-
AEs
from the larger of our Phase 3 clinical trials completed prior to SECURE; all potentially hormone-related adverse events included regardless of investigator
confirmation of AE relatedness to study drug.
-
**
-
Information
is based on currently marketed product labels and publicly available information. We have not performed a head-to-head comparison of Twirla to Ortho Evra
or Quartette.
-
***
-
1.4%
of subjects in the SECURE trial discontinued to a bleeding-related adverse event
22
Table of Contents
-
-
The percent of subjects reporting bleeding-related adverse events was low, 1.8%, and only 1.4% of women discontinued for bleeding issues.
-
-
Overall serious adverse events (SAEs) were observed in 2.0% of the SECURE trial study population, which is generally in line with those
observed in other low-dose combined hormonal products. For example, the rate in the Phase 3 clinical trial for Quartette was 1.6%. 0.6% of subjects in the SECURE trial had SAEs that were
considered potentially study drug related, including deep vein thrombosis or DVT, pulmonary embolism, or PE, gallbladder disease, ectopic pregnancy, and depression. In the combined safety database for
our three Agile Phase 3 trials (n >3,000), there were 5 subjects with potentially study drug related DVTs or PEs, 4 of whom were obese (BMI
³
30kg/m
2
).
-
-
Overall, patch-related irritation and itching rates were low. Of reported patches worn, 83% had no patch site irritation and 65% had no
itching. Generally, reported irritation and itching was mild. Severe itching or irritation were observed in 2.3% and 1.5% of patches worn, respectively.
-
-
The patch adhesion profile was favorable with a low rate of detachment. Of reported patches worn, the range of detachments was 10% in cycle 1
and reduced to 2% by cycle 13.
We
believe that the efficacy results observed in SECURE were a reflection of the study population and the clinical trial design. As recommended by the FDA, we had broad entry criteria
for the trial and placed no limitations on BMI or other demographic factors during our enrollment. These entry criteria resulted in the inclusion of a substantial number of women with overweight and
obese BMI, who have frequently been under-represented in past contraceptive studies. As noted above, we observed that BMI had an effect on the efficacy results for Twirla. We believe these
observations require further analysis of whether there are other important factors at work here, such as race/ethnicity, user profile and compliance rates, which we believe may have impacted the
results of our prior Phase 3 studies.
Several
scientists at the FDA published a paper in 2015,
"Effect of Obesity on the Effectiveness of Hormonal Contraceptives: an Individual Participant Data
Meta-Analysis,"
which focused on the issue of obesity and effectiveness of hormonal contraceptives (HC) by showing that obesity may increase the risk of unintended pregnancy in
women using HC. The FDA's Individual Participant Data meta-analysis of pivotal Phase 3 clinical trials of combination hormonal contraceptives suggested a 44% higher pregnancy rate during use of
combined oral contraceptives for obese women after adjusting for age and race. The authors of the paper highlighted the limitations of currently available prospective data due to historical exclusion
of obese women from contraceptive studies, calling for more data and additional analyses on obese women from Phase 3 clinical trials to allow further assessment of the effect of weight on the
probability of unintended pregnancy in women using HC. We believe our results from the SECURE clinical trial are consistent with the conclusions from the paper by the FDA scientists.
Additionally,
the observed PI values were not only impacted by the number of pregnancies that occurred in the study, but also by the number of cycles included in the analysis, which
affects the denominator of the PI calculation. Cycles in which a subject was not sexually active, or in which a subject used a back-up method of contraception were not counted toward the number of
cycles included in the calculation of the PI. Many contraceptive clinical trials have not historically included these stringent requirements, in particular the exclusion of cycles for lack of sexual
activity, in the clinical trial design. As a result, we believe that the SECURE results reflect evidence of efficacy in a real-world population.
The
highest PI for a hormonal contraceptive product approved by the FDA is 3.19 and the highest upper-bound of the 95% confidence interval of 5.03. As with all products, ultimate
approvability of a hormonal contraceptive is based on a risk/benefit assessment of the overall safety and efficacy profile of a product, not only a specific Pearl Index. For hormonal contraceptive
trials, the FDA generally evaluates safety and efficacy results of each individual study in the unique context of the study
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population
and trial design. PIs for approved hormonal contraceptives have steadily risen over time as study design and populations have changed. Numerous factors have likely contributed to these
increases, including more frequent pregnancy testing with more sensitive tests, and decreases in study-drug adherence among study populations. As experts have noted, with the growing enrollment of
more diverse, real-world populations that appear to be increasingly representative of the likely actual users once the product is marketed, contraceptive trials are yielding efficacy results that are
ever closer to actual use contraceptive failure rates for methods requiring adherence.
In
SECURE, we employed several measures to improve study conduct and, in particular, improve upon the loss to follow up rate. These measures included selecting a highly experienced
contract resource organization, or CRO, selecting experienced sites, increasing and improving monitoring and training, and the use of electronic diaries for subjects. We engaged Parexel International
Corporation, or Parexel, a CRO with substantial experience in contraception studies and excellent site monitoring capabilities, as the CRO for the SECURE trial. We actively participated in site
selection and in monitoring subject recruitment, and actively participated in site monitoring and oversight of Parexel's activities throughout the length of the trial.
Regarding
site selection, the SECURE trial was conducted at 102 experienced sites in the United States. Sites were evaluated extensively through a data-driven approach assessing
performance on previous clinical trials, staffing with experienced study coordinators, demographics of potential study subjects, and audit history. We also focused on ongoing training of study
coordinators at the investigator meeting and study initiation visits, at coordinator's meetings, and through ongoing communication. In addition, study sites that showed early trends toward higher
rates of loss to follow-up or overall poor study management were re-trained. We also focused closely on subject
recruitment in order to achieve our goal of a population intended to provide reliable and generalizable data in the SECURE trial. We trained our sites to provide individualized attention to
recruitment of subjects who were most likely to adhere to the study protocol with respect to compliance, including correct patch application, timing of patch removal and replacement, electronic diary,
or e-diary, completion and study visits. Subjects were also advised through the informed consent process that noncompliance with study procedures may lead to discontinuation from the trial. Enrollment
of the SECURE trial was completed in October 2015.
A
number of measures were also put in place in order to facilitate compliance with study procedures. To ensure subjects were adequately educated regarding their responsibilities during
the trial, a detailed subject teaching plan, along with materials, was developed and implemented, and subject education regarding the importance of compliance, including videos, brochures and
one-to-one education with study coordinators, was provided at repeated intervals throughout the study. A number of measures were put in place to support and monitor compliance through the study. One
key measure was the use of text message technology, which provided reminders to subjects for patch application, diary completion and study visits. Phone contact with subjects between visits was also
part of the study protocol, which increased the frequency of contact with subjects throughout the study. Subjects with consistent poor compliance despite re-education by site personnel were
discontinued from the trial.
An
independent Pregnancy Review Committee composed of experts in early ultrasound was selected to review all pregnancies and determine on or off-treatment status, which affects the
numerator of the PI calculation. Accurate and timely pregnancy adjudication is critically important in order to reduce the likelihood that pregnancies which occur off treatment will be included by the
FDA during the review process. In order to avoid pre- or post-treatment pregnancies being included, every pregnancy was assessed via ultrasound as soon as possible and full data was collected
regarding the relationship of the pregnancy to the subject's use of Twirla. We did not have an independent Pregnancy Review Committee for our previous clinical trials.
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We
plan to submit a complete response to our CRL that includes the additional clinical trial results and additional information relating to the manufacture of Twirla in a resubmission of
our NDA for Twirla to the FDA in the first half of 2017.
Twirla Line Extensions and Other Product Candidates
In addition to Twirla, our product pipeline consists of two classes of product candidates: Twirla line extensions and other transdermal
contraceptive product candidates. These product candidates are designed to address market needs and offer additional non-daily contraceptive options. Based on the results of our market research on
line extension regimen concepts conducted in December 2016, we believe that our line extension product candidates are commercially viable and could garner a share of the contraceptive market.
The
hormonal contraceptive market has a long history of manufacturers successfully using line extensions to extend the lifecycle of a brand, often by gaining additional exclusivity
periods for the product extension under the provisions of the Hatch-Waxman Act or with additional patents. Our lifecycle strategy with Twirla is to introduce line extensions that will have exclusivity
for some time period, either due to our intellectual property estate, or due to Hatch-Waxman exclusivity. The line extensions in our pipeline include using our Skinfusion technology to allow a 28-day
regimen where women will experience shorter, lighter withdrawal bleeding, as well as extending the cycle beyond the typical 28-day regimen to allow women to experience fewer withdrawal bleeds each
year. In addition, the line extension product candidates in our pipeline will utilize a unique aspect in the regimen, where a smaller patch, or SmP, that delivers a lower dose of both EE and LNG will
be worn during the final seven days of each cycle, rather than having a patch-free week, to allow for withdrawal bleed while minimizing hormonal fluctuations and potentially the side effects that
accompany changes in hormone levels. These regimens are protected by patents issued to us in 2015. A study to examine the pharmacokinetics and pharmacodynamics of the SmP will be required prior to
advancing the line extension product candidates through clinical development. In July 2016, we began preparations for an initial Phase 2 clinical trial examining the use of AG200-SP along with
a smaller lower-dose combination ethinyl estradiol/levonorgestrel patch (SmP) in the fourth week of the woman's cycle. We have decided to postpone the trial and will continue to evaluate the timing
for initiating dosing of subjects for this Phase 2 clinical trial, which is dependent on financial and other capital resources.
Our
Twirla line extensions include the following:
-
-
AG200-ER is an extended cycle regimen utilizing our current patch product designed to allow a woman to extend the time between her episodes of
withdrawal bleeding and thus have fewer periods per year. There are several currently approved oral contraceptives that provide an 84 or 91-day extended cycle regimen. However, there is no approved
contraceptive patch product offering an extended cycle regimen. AG200-ER is a contraceptive patch which is designed to address the limitations of the currently approved extended regimen oral
contraceptives by providing a more convenient, weekly dosing schedule. AG200-ER utilizes the same drug product as Twirla during the active phase of the cycle. We are currently evaluating the optimal
cycle length to advance into Phase 3 clinical development.
-
-
AG200-SP is a 28-day regimen designed to provide users with shorter, lighter withdrawal bleeds and potentially improve contraceptive efficacy.
AG200-SP may also provide benefit in patients with sensitivity to abrupt changes in hormone levels. Oral contraceptives that use a shortened hormone-free interval, or SHFI, by delivering hormones
beyond 21 days currently comprise 42% of U.S. branded TRx volume, demonstrating high acceptability among patients and providers. AG200-SP is designed to provide a simplified 28-day regimen
through use of the same drug product as Twirla for the first three weeks of the cycle, and a smaller lower-dose patch, or SmP, in the fourth week, which will allow patients to continuously apply
patches without interruption. AG200-SP requires additional patch development work on the SmP prior to potentially conducting a pharmacodynamics and pharmacokinetic study.
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-
-
AG200-ER (SmP) is an extended cycle regimen utilizing our current patch product and the SmP that is designed to allow a woman to extend the
time between her episodes of withdrawal bleeding and experience shorter, lighter periods. By adjusting the length of the contraceptive cycle, AG200-ER (SmP) is designed to potentially minimize
breakthrough bleeding and spotting, which is a commonly reported concern with patients using an extended regimen contraceptive product. AG200-ER (SmP) utilizes the same drug product as Twirla during
the active phase of the cycle and will utilize the SmP during the final week of the cycle. AG200-ER (SmP) requires additional patch development work on the SmP prior to potentially conducting a
pharmacodynamics and pharmacokinetic study.
Our
other product candidate is a P-only contraceptive patch described below:
-
-
AG890 is an LNG-only contraceptive patch, intended for use by women who are unable or unwilling to take estrogen, including those who are
breastfeeding or who are at greater risk of VTE, such as women who smoke, are over 35 years of age, or who are obese. Currently, the P-only market consists of pills and several non-oral
options, including IUDs, implants and injections. AG890 is intended to fulfill an unmet medical need for a non-daily, easily reversible form of contraception in the P-only market. We have conducted a
Phase 1 clinical trial with AG890. In addition, the National Institutes of Health, through a clinical trial agreement with us, conducted a Phase 1/2 trial with AG890. The
Phase 1/2 study was a multicenter study to evaluate the pharmacokinetics, safety and mechanisms of potential contraceptive efficacy of AG890. The trial is complete and continue to evaluate the
findings. Once we have completed our analysis of the data, it is possible that additional patch development work for dose selection may be required, including additional Phase 1 and
Phase 2 studies to determine the optimal formulation and dose to advance to Phase 3.
We
do not expect to be required to conduct preclinical studies for any of these product candidates. Based upon a number of factors, including, but not limited to, our available capital resources and
feedback from the FDA, we continue to review the clinical path and the budgetary requirements for each of these three product candidates. Substantially all of our resources are currently dedicated to
developing and seeking regulatory approval for Twirla. We will require additional capital to advance the development of our other product candidates.
Sales and Marketing
Twirla Commercialization Strategy
We expect to build a sales and marketing infrastructure in the United States to support the launch of Twirla for contraception, if approved. We
anticipate that a targeted sales force focused initially on ObGyns, NPs, PAs and primary care providers who comprise the top prescribers of contraceptives will be highly effective. Outside the United
States, in the future we may decide to commercialize Twirla, if approved, by entering into third-party collaboration agreements with pharmaceutical partners. We will require additional capital for the
commercial launch of Twirla.
Twirla Promotion Strategy
We have employed several key strategies during the development of Twirla to prepare us for the launch of Twirla. These
include:
-
-
Seeking advice and input from key opinion leaders, or KOLs, in women's health and contraception;
-
-
Sponsoring continuing medical education, or CME, programs at key congresses and symposia around the country;
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-
-
Establishing relationships with women's health advocacy groups;
-
-
Conducting extensive market research to better understand the market dynamics and identify product positioning and messages for Twirla with
prescribers and consumers;
-
-
Assuring that data from our clinical trials are presented in a timely manner at clinical congresses and published in appropriate peer-reviewed
medical journals; and
-
-
Developing and registering the trademark Twirla and developing key branding elements, including packaging design for submission with the NDA.
Prescribing
in the CHC category is primarily driven by ObGyns, who write 43% of the total prescriptions. In addition, NPs and PAs, who are often affiliated with an ObGyn practice but can
also be in a primary care setting, write 29% of all CHC prescriptions. The ObGyns, NPs and PAs combine to write nearly 72% of total CHC prescriptions. In addition, 34% of all prescriptions written by
ObGyns are for contraceptives. We plan to focus the promotion of Twirla on these key prescribers and other key customer groups, including consumers and commercial managed care plans. We believe that
we can deploy a focused sales force effort targeting the approximately 22,000 prescribers responsible for 80% of branded CHC prescriptions. We believe that this universe of branded prescribers can be
covered adequately by a specialty sales force of between 70 and 100 total representatives. In areas of the country where it is not efficient to deploy a sales representative, remote promotion can be
used to reach these prescribers.
We
plan to deploy patient promotion at the launch of Twirla, both in the physician's office, and through targeted media campaigns. We plan to use both branded and unbranded campaigns to
create awareness of Twirla among consumers. We believe there are cost-effective means to reach our target demographic of females aged 18 to 34 years, the so-called Millennials, who are more
likely to seek health information online and through social networks. Traditional mass-market direct-to-consumer advertising on television may not be required to reach these consumers. Marketing
tactics aimed at today's female consumer need to be optimized for mobile technology, because smartphones and text messaging are the preferred means of communication. Millennials also engage in online
activities to a high degree. For example, approximately 80% use a social network and approximately 40% read blogs. We believe that a focused consumer promotion plan that uses digital media and other
mass-market advertising vehicles will generate consumer awareness and demand for Twirla if approved.
Managed
care plans have traditionally used differential co-pays to attempt to drive patients to use either generic products or products for which they have a contract with the
manufacturer. Many plans encourage patients to obtain their branded contraceptives through mail-order, incentivizing them with a 90-day co-pay that is often less on a per-month basis than that for a
30-day supply. Most manufacturers of contraceptive brands offer a coupon to patients covered by non-governmental payors to offset the difference in co-pay between a generic and Tier 2 or
Tier 3 for their promoted brands. These co-pay coupons are a useful tactic to overcome barriers to initiating therapy in such patients. When used in conjunction with product samples given out
by the physician, a co-pay coupon often allows the patient to then fill their first prescription for free or at a steep discount, and limits the out of pocket expenditure for the patient for several
months. This co-pay assistance creates brand loyalty, particularly for a brand where there is no generic alternative. We believe that we will be able to use free product samples and co-pay coupons or
vouchers at the time of Twirla's launch to gain use of the product by patients covered by non-governmental payors while we are negotiating contracts with select commercial health plans and awaiting
formulary review. In addition, we believe the enactment of the ACA, and specifically the requirements for contraceptive coverage required by the ACA, provides a favorable managed care environment for
Twirla. The ACA requires all insurers to provide at least one product in
each of the 18 methods referenced in the FDA Birth Control Guide with no cost-sharing to the patient, including no co-pays, coinsurance, or deductibles. The FDA Birth Control Guide lists "Patch" as a
unique method, therefore insurers must provide access to at least one contraceptive patch product with
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no
cost-sharing to the patient. Currently, there is only one other patch product available on the market, Xulane (the generic version of Ortho Evra), and we believe the safety and tolerability profile
of Twirla, if approved, will be superior to that of Xulane. Therefore, we believe Twirla will be well-positioned to be the no-cost patch option on formulary, either based on its clinical profile, or
based upon negotiated rebates and discounts. In addition, we expect to be able to provide co-pay assistance in the form of a coupon for patients on plans where Twirla requires a co-pay.
In
March 2017, the U.S. Congress proposed legislation, which, if signed into law by the new administration, would repeal certain aspects of the ACA. Further, on January 20, 2017,
the new administration signed an Executive Order directing federal agencies with authorities and responsibilities under the ACA to waive, defer, grant exemptions from, or delay the implementation of
any provision of the ACA that would impose a fiscal or regulatory burden on states, individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices among
others. Congress also could consider subsequent legislation to repeal and replace elements of the ACA that are repealed. We will continue to monitor the healthcare reform efforts. While there is
uncertainty about the specific effects of healthcare reform, we expect to be able to compete in either a managed care environment that maintains elements of the ACA that require contraceptive coverage
or an environment that requires negotiated rebates and discounts.
Market Research
We have conducted market research with healthcare professionals (HCPs), consumers and managed care decision-makers to determine market drivers,
unmet needs and the reaction to the Twirla product profile. A total of over 800 healthcare professionals and over 3,300 consumers have participated in our market research on Twirla and the
contraceptive market. The main findings of the market research conducted in December 2016 are discussed below.
Topline Summary of Our ObGyn/NP Market Research:
-
-
HCPs are extremely influential in driving women's choice of hormonal contraceptive
-
-
HCPs admit to presenting oral contraceptives first, ostensibly because of their long history of safety and the HCPs own comfort
with the pill
-
-
Patient ability to comply drives hormonal contraceptive choice
-
-
HCPs believe patient engagement in the choice increases personal investment in her birth control and enhances adherence
-
-
Determinants of choice are willingness/ability to be responsible to take/apply birth control, desire to control menses, and
tolerance for insertion or injection
-
-
The Pearl Index (PI) is not cited as an important factor driving contraceptive choice and it is not a well understood measure. Efficacy is a
given and all hormonal contraceptives are expected to be efficacious
-
-
HCPs consider body mass index (BMI) in their prescribing, however one third of HCPs consider efficacy in women with high BMI a least important
attribute
-
-
Young women with busy lives, susceptible to "forgetting" daily contraceptives, are a strong target audience for the Agile patch portfolio
Two
of our more recent market research studies have included an allocation exercise to estimate the potential uptake of Twirla and peak market share. In both of these studies, ObGyns and
NPs indicated their allocation of contraceptive prescriptions before and after reviewing a product profile like Twirla. In the 2010 study, which was conducted prior to the implementation of the ACA,
ObGyns
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estimated
use of a product like Twirla in 17% of their CHC patients. A proprietary calibration model developed by the research firm was applied to the peak share estimate, to adjust for physician
overstatement, resulting in an estimated peak market share of 9% of the CHC market. In the most recent study completed in December 2016, ObGyns and NP/PAs estimated use of Twirla in 22% of their CHC
patients, which was also calibrated to adjust for overstatement, resulting in an estimated peak market share of 14% of the CHC market.
Even
with the evolving healthcare landscape, we continue to believe a peak CHC market share of 9% can be achieved with Twirla within seven years of launch, allowing us time to establish
a presence in the CHC market and to overcome any perceptions or barriers among prescribers due to the past history of Evra and to account for potential changes in the ACA and overall healthcare
landscape.
Topline Summary of Our Consumer Market Research:
-
-
Familiarity and availability sway hormonal contraceptive selection initially toward the pill. Few explore choices extensively through dialogue
with HCP, and/or research of their own. Thus, HCP recommendation can be very influential. However, with time and experience, many become disenchanted with the pill because it ties them to a daily
schedule.
-
-
Among those who least prefer the contraceptive patch option, their strong impressions were based on issues such as skin irritation from
adhesive, blood clots, and weight gain, despite extremely limited exposure to the contraceptive patch.
-
-
Several mention a desire to have a hormonal contraceptive, or HC, method that fits in with their busy lifestyle while still offering control
over the HC-taking experience (i.e., unlike implant/IUD which is inserted and forgotten).
-
-
Twirla offers a convenient, less-frequent form of HC that women are interested in trialing for themselves
-
-
Potential downsides are patch cleanliness/appearance and adhesion (particularly while showering or exercising), but women admit
they couldn't gauge this without trying the patch first.
-
-
Based solely on the Twirla product profile, approximately 15% of women surveyed in the 2016 Adelphi study indicated they would be "extremely
likely" to ask their doctor for a prescription for Twirla.
Topline Summary of Our Managed Care Market Research:
The managed care research summarized below was conducted with medical and pharmacy directors in September 2016. In regard to forward-looking
questions, subjects were asked to assume that the ACA and Contraceptive Mandate would still be in effect.
-
-
Payers are not highly focused on the prescription contraceptive market, and knowledge of individual prescription products was low.
-
-
The category is mainly managed by tier and, to a smaller degree, by closed formularies.
-
-
20% of plans abandoned all management efforts in the category and allowed coverage of all generics and all unique brands at a $0 cost share.
-
-
All respondents indicated they would consider working with a manufacturer to make one product preferred in a contraceptive category. However,
preferred status could be in "name only", as many of the preferred products had the same $0 co-pay as non-preferred products.
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-
-
Net cost is the most important pricing baseline, but rebates for many plans are still considered a profit center. Most plans would entertain
preferred or co-preferred status in return for a modest contract.
-
-
7 of the 10 respondents reacted to the Twirla product profile positively, while 3 responses were neutral. Most indicated the comparator was
Xulane, and that a comparable price with an improved safety profile would result in equivalent coverage.
Competition
The industry for contraceptive products is characterized by intense competition and strong promotion of proprietary products. While we believe
that our Skinfusion technology provides us with a competitive advantage, we face potential competition from many different sources, including large pharmaceutical companies, specialty pharmaceutical
and generic drug companies, and medical device companies. Any product candidates that we successfully develop and commercialize will compete with existing products and new products that may become
available in the future.
We
face competition from a variety of non-permanent birth control products. There are non-hormonal barrier methods, such as the contraceptive sponge, diaphragm, cervical cap or shield
and condoms. Then, there are hormonal methods, which is the category for our product candidates, such as oral contraceptives, injections, implants, IUDs and vaginal ring and transdermal contraceptive
products.
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The
following table is the 2016 FDA Birth Control Chart, which outlines the 18 unique forms of birth control and compares the effectiveness of each method.
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Although
there are over 200 CHC products, including brands and generics, available on the market today, 50.5% of the total market sales, or $1.97 billion in 2016, consisted of
sales of just seven branded products. Our potential competitors include large, well-established pharmaceutical companies, and specialty pharmaceutical sales and marketing companies. The product with
the highest dollar sales in the CHC market for the 12 months ending December 2016 was Nuvaring®, marketed by Merck, the only contraceptive vaginal ring available on the market, with
over $786 million in sales for 2016. The Loestrin® franchise, marketed by Allergan (formerly known as Actavis), consisting of two oral contraceptives, Minastrin® 24 and
LoLoestrin®, totaled approximately $898 million in sales in 2016. Other competing products include: Gianvi® and Quartette®, marketed by Teva,
Beyaz® and Yaz®, which totaled over $178 million in sales in 2016, marketed by Bayer. Although not a branded product, Xulane, the generic to Ortho Evra and the only
patch currently available on the market, generated $211 million in sales in 2016 for Mylan. Additionally, several generics manufacturers currently market and continue to introduce new generic
contraceptives, including Sandoz, Glenmark, Lupin, Amneal and Mylan. Based on the market experience of other non-oral CHC dosage forms, including Evra and Nuvaring, we believe there is a continuing
demand for an innovative transdermal contraceptive patch that can provide convenience in a low-dose transdermal format.
There
are other contraceptive products, recently approved or in development that may compete with Twirla and our other product candidates. Kyleena® a Bayer product, approved
in September 2016, is a hormonal IUD that releases a small amount of hormone to prevent pregnancy for up to 5 years. Also recently approved was Taytulla® from Allegran, which is the
only oral contraceptive in a capsule. Companies that have new contraceptive products in various stages of development include Bayer, with a contraceptive patch, an oral contraceptive and a P-only
vaginal ring, each in Phase 3 development. Allergan has a vaginal ring in development, which is a generic equivalent to Nuvaring, a P-only ring for which they received a CRL from the FDA, and
an additional vaginal ring. This ring is in Phase 3 development which is a 12-month vaginal ring that was developed by the Population Council for use in the developing world. In the past few
years, some of the large pharmaceutical companies such as Johnson & Johnson and Pfizer have dissolved their women's health specialty marketing and sales teams, and Bayer has shifted their focus
away from their CHC products to their IUD franchise.
We
are aware of only one other CHC transdermal patch in development. This patch is being developed by Bayer, and contains the active ingredients EE and gestodene, a third generation
progestin. Bayer has stated that their gestodene patch is small, round, and transparent, and delivers a daily EE dose comparable to a 20 microgram EE oral contraceptive. Phase 3 studies of the
Bayer gestodene patch began in 2004, and they completed a Phase 3 efficacy trial in the United States in December 2010. Bayer also completed Phase 3 efficacy trials in the European
Union, or E.U., and Latin America in September 2011, submitted a marketing application to the E.U. in September 2012, and received approval to market the gestodene patch in the E.U. in February 2014.
At the time of the E.U. submission, Bayer reported that they were in talks with the FDA regarding a U.S. submission, but there
has been no further public information regarding a U.S. submission or approval, and the most recent Bayer pipeline information does not list the gestodene patch.
To
date, there are no contraceptives containing gestodene available in the United States. We are aware that Wyeth was developing oral contraceptives containing gestodene in the late
1980s, with an NDA filed for an oral contraceptive containing gestodene and EE in 1988, and Wyeth planned filing an NDA for a second oral contraceptive containing gestodene in 1991. These products
were never approved, and in a Wyeth pipeline report from 1996, there was no mention of any gestodene-containing product candidates among its contraceptives in development. Although not available in
the United States, gestodene has been widely used outside the United States for a number of years. As with other third generation progestins, epidemiologic studies have reported a two-fold increase in
risk of VTE with contraceptives containing gestodene compared to those containing LNG. We believe that if Bayer were to obtain FDA approval for the gestodene patch, the approved labeling may contain
the same language that products containing third generation progestins have, which states that these contraceptives have a two-fold increase in risk of VTE as compared with contraceptives containing
second generation progestins.
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Manufacturing
We do not own any manufacturing facilities. We currently rely, and expect to continue to rely, on a third party for the manufacture of our
product candidates for clinical trials, as well as for commercial manufacture if any of our product candidates receive marketing approval. In 2006, we entered into an exclusive agreement with Corium
International, Inc., or Corium, to develop Twirla using our Skinfusion technology, and also for AG890, which is a P-only contraceptive patch in Phase 1/2 of clinical development. Our
Corium agreement is an exclusive arrangement until Corium has commercially produced a significant, agreed-upon quantity of patches, currently projected to occur no earlier than five years following
commercial launch of Twirla. Pursuant to the terms of our agreement, Corium is required to use commercially reasonable efforts to maintain sufficient manufacturing capabilities to supply the
quantities of Twirla required for its initial commercial launch and commercial sales thereafter. Corium needs to conduct the equipment and facility validation and expansion of its manufacturing
capabilities in order to be capable of supplying projected commercial quantities of Twirla, if approved. Based on our interactions with the FDA on the CMC issues raised in the CRL and our plan with
Corium to validate the commercial scale equipment to manufacture Twirla, we expect to be able to address these issues in the resubmission of our NDA. We expect the validation and
expansion to be completed in coordination with our planned commercialization activities. Corium is responsible for all aspects of Twirla manufacturing.
Strategic Agreements
Agreement with Corium
Pursuant to our manufacturing agreement, Corium's exclusive right to manufacture Twirla and AG890 extends until Corium has commercially produced
a significant, agreed-upon quantity of patches, currently projected to occur no earlier than five years following commercial launch of Twirla, at which point the agreement will expire. Under the terms
of our agreement, we will pay Corium a defined price per finished patch, whether used for samples or commercial sale. We will owe no royalties to Corium in connection with the production of finished
patches. The contract may be terminated by either party for the other party's uncured material breach. Following the end of the exclusivity period, if we were to seek a second source of supply, we
would be required to obtain FDA approval through an NDA supplement for an additional manufacturing sites. The process of acquiring a second source of supply and obtaining FDA approval generally takes
two years or more, and would require us to make substantial investments in new facilities and equipment.
Under
our agreement, Corium has performed process development and manufacturing of Twirla for each of our clinical trials. For the development work performed, we paid Corium for time and
materials related to the achievement of certain development goals. To date, we have made approximately $1.7 million of milestone payments to Corium, all of which were paid between the years
2006 and 2009. Corium is not eligible for any milestone payments in the future. During 2012, we paid Corium an aggregate of $3.5 million towards leasehold improvements incurred by Corium to its
facilities to provide for adequate manufacturing space for our product candidates.
In
order to accommodate our anticipated commercial launch of Twirla, if approved, Corium has completed a substantial build-out of its facilities in Grand Rapids, Michigan, and it has
installed over $10.0 million of equipment we purchased. This additional equipment and these facilities may require FDA pre-notification, pre-approval or inspection; however, we believe we can
accomplish this expansion through an Annual Report filing to the Twirla NDA.
Reimbursement
Managed care plans have traditionally used differential co-pays to attempt to drive patients to use either generic products or products for
which they have a contract with the manufacturer. Typically, a
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managed
care plan's formulary is organized into between three and six tiers. Each tier is then associated with a set range of co-pay amounts, with products in the lower tiers having a lower co-pay.
Many plans encourage patients to obtain their branded contraceptives through mail-order, incentivizing them with a 90-day co-pay that may be less on a per-month basis than that for a 30-day supply.
Contraceptive brands are generally placed on Tier 2 only if there is a contract with the plan, although there are a few plans that place several branded products on Tier 2.
Prior
to May 2015, managed care plans have individually interpreted the requirement for coverage of contraceptives under the ACA. Some plans have designated that all contraceptives
containing the same progestin are equivalent, and therefore only cover a select few products containing each progestin, usually the least expensive generics, with no co-pay. Other plans have defined
contraceptive methods into categories such as "hormonal", "emergency contraception", and "barrier methods", and they cover just one product for each method with no co-pay. In May 2015, a clarification
in the form of an FAQ was issued by the applicable government agencies (HHS, DOL, and Treasury) which clarified the requirements for coverage of contraceptives under the ACA. The FAQ states that plans
and issuers must cover without cost-sharing at least one form of contraception in each of the 18 methods the FDA has identified for women in its current Birth Control Guide. The patch is identified as
a specific method in the FDA Birth Control Guide, and therefore insurers must cover at least one patch product with no cost-sharing to the patient. Because this clarifying guidance is applied for plan
years (or in the individual market, policy years) beginning on or after 60 days from the date of publication of the FAQs, patients did not have had the benefit of this clarification until their
new plan year, which generally started in January 2016.
In
March 2017, the U.S. Congress proposed legislation, which, if signed into law by the new administration, would repeal certain aspects of the ACA. Further, on January 20, 2017,
the new administration signed an Executive Order directing federal agencies with authorities and responsibilities under the ACA to waive, defer, grant exemptions from, or delay the implementation of
any provision of the ACA that would impose a fiscal or regulatory burden on states, individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices among
others. Congress also could consider subsequent legislation to repeal and replace elements of the ACA that are repealed. Therefore, it is difficult to determine the full effect of the ACA or any other
healthcare reform efforts on our business. We will continue to monitor the healthcare reform efforts.
Government Regulation
Government authorities in the United States, at the federal, state and local level, and in other countries extensively regulate, among other
things, the research, development, testing, manufacture, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, import and export of pharmaceutical products such
as those we are developing. The processes for obtaining regulatory approvals in the United States and in foreign countries, along with subsequent compliance with applicable statutes and regulations,
require the expenditure of substantial time and financial resources.
FDA Regulation
In the United States, the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act, or FDCA, and its implementing regulations. The
process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and
financial resources. Failure to comply with the applicable U.S. requirements at any time during the product development process, approval process or after approval, may subject an applicant to a
variety of administrative or judicial sanctions, such as the FDA's refusal to approve pending NDAs, withdrawal of an approval, imposition of a clinical hold or termination, issuance of Warning,
Untitled, or Cyber Letters, requests for product recalls, product
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seizures
or detention, total or partial suspension or restriction of production, marketing or distribution, injunctions, fines, debarment, refusal to allow the import or export of product, adverse
publicity, modification of promotional materials or labeling, refusals of government contracts, exclusion from participation in federal and state healthcare programs, restitution, disgorgement,
imprisonment, consent decrees and corporate integrity agreements, or civil or criminal penalties.
The
process required by the FDA before a drug may be marketed in the United States generally involves the following:
-
-
Completion of preclinical laboratory tests, animal studies and formulation studies in compliance with the FDA's Good Laboratory Practice, or
GLP, regulations;
-
-
Submission to the FDA of an Investigational New Drug Application, or IND, which must become effective before human clinical trials may begin;
-
-
Approval by an independent Institutional Review Board, or IRB, for each clinical site before each trial may be initiated;
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Performance of human clinical trials, including adequate and well- controlled clinical trials, in accordance with cGCPs to establish the safety
and efficacy of the proposed drug product for each indication;
-
-
Submission to the FDA of an NDA;
-
-
Satisfactory completion of an FDA advisory committee review, if applicable;
-
-
Satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the product is produced to assess compliance
with cGMP and to assure that the facilities, methods and controls are adequate to preserve the drug's identity, strength, quality and purity, as well as the potential for completion of an FDA
inspection of selected clinical sites to determine cGCP compliance; and
-
-
FDA review and approval of the NDA.
Preclinical Studies and IND Submission
Preclinical studies include laboratory evaluation of drug substance chemistry, pharmacology, toxicity and drug product formulation, as well as
animal studies to assess potential safety and efficacy. An IND sponsor must submit the results of the preclinical tests and preclinical literature, together with manufacturing information, analytical
data and any available clinical data or literature, among other things, to the FDA as part of an IND, unless the sponsor is relying on prior FDA findings of safety or efficacy of the drug product, in
which case, some of the above information may be omitted. Some preclinical testing may continue even after the IND is submitted. An IND automatically becomes effective 30 days after receipt by
the FDA, unless before that time the FDA raises concerns or questions related to one or more proposed clinical trials and places the trial on a clinical hold. In such a case, the IND sponsor and the
FDA must resolve any outstanding concerns before the clinical trial can begin. As a result, submission of an IND may not result in the FDA allowing clinical trials to commence.
Clinical Trials
Clinical trials involve the administration of an investigational new drug to human subjects under the supervision of qualified investigators in
accordance with cGCP requirements, which includes the requirements that all research subjects provide their informed consent in writing for their participation in any clinical trial, and the review
and approval of the study by an IRB. Clinical trials are conducted under protocols detailing, among other things, the objectives of the trial, the trial procedures, the
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parameters
to be used in monitoring safety and the efficacy criteria to be evaluated and a statistical analysis plan. A protocol for each clinical trial and any subsequent protocol amendments must be
submitted to the FDA as part of the IND. In addition, an IRB for each clinical trial site participating in the clinical trial must review and approve the plan for any clinical trial before it
commences, and the IRB must continue to oversee the clinical trial while it is being conducted, including any changes. Information about certain clinical trials, including a description of the study
and study results, must be submitted within specific timeframes to the National Institutes of Health, or NIH, for public dissemination on their ClinicalTrials.gov website.
Human
clinical trials are typically conducted in three sequential phases, which may overlap or be combined. In Phase 1, the drug is initially introduced into healthy human
subjects or subjects with the target disease or condition and tested for safety, dosage tolerance, absorption, metabolism, distribution, excretion and, if possible, to gain an initial indication of
its effectiveness. In Phase 2, the drug typically is administered through controlled studies to a limited subject population with the target disease or condition to identify possible adverse
effects and safety risks, to preliminarily evaluate the efficacy of the drug for specific targeted diseases and to determine dosage tolerance and optimal dosage. In Phase 3, the drug is
administered to an expanded subject population, generally at geographically dispersed clinical trial sites, in two adequate and well-controlled clinical trials to generate enough data to statistically
evaluate the efficacy and safety of the product candidate for approval, to establish the overall risk-benefit profile of the product candidate and to provide adequate information for the labeling of
the product candidate. In the case of a 505(b)(2) NDA, which is a marketing application in which sponsors may rely on investigations that were not conducted by or for the applicant and for which the
applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted, some of the above-described studies and preclinical studies may not be required
or may be abbreviated. Bridging studies may be needed, however, to demonstrate the applicability of the studies that were previously conducted by other sponsors to the drug that is the subject of the
marketing application. In addition to the above traditional kinds of data required for the approval of an NDA, the recently passed 21st Century Cures Act, provides for FDA acceptance of new
kinds of data such as such as patient experience data, real world evidence, and, for appropriate indications sought through supplemental marketing applications, data summaries.
The
manufacture of investigational drugs for the conduct of human clinical trials is subject to cGMP requirements. Investigational drugs and active pharmaceutical ingredients imported
into the United States are also subject to regulation by the FDA relating to their labeling and distribution. Further, the export of investigational drug products outside of the United States is
subject to regulatory requirements of the receiving country as well as U.S. export requirements under the FDCA.
Progress
reports detailing the results of the clinical trials must be submitted at least annually to the FDA and the IRB and more frequently if serious adverse events occur. Information
about certain clinical trials, including a description of the study and study results, must be submitted within specific timeframes to the National Institutes of Health, or NIH, for public
dissemination on their ClinicalTrials.gov website. Marketing application applicants must also report certain investigator financial interests to FDA.
Phase 1,
Phase 2 and Phase 3 clinical trials may not be completed successfully within any specified period, or at all. Furthermore, the FDA or the sponsor may
suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects are being exposed to an unacceptable health risk. Similarly, an IRB can suspend or
terminate approval of a clinical trial at its institution if
the clinical trial is not being conducted in accordance with the IRB's requirements or if the drug has been associated with unexpected serious harm to subjects. Additionally, some clinical trials are
overseen by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board or committee. This group regularly reviews accumulated data and
advises the study sponsor regarding the continuing safety of trial subjects, potential trial subjects,
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and
the continuing validity and scientific merit of the clinical trial. We may also suspend or terminate a clinical trial based on evolving business objectives or competitive climate.
U.S. Marketing Approval
Assuming successful completion of the required clinical testing, the results of the preclinical and clinical studies, including negative or
ambiguous results as well as positive findings, together with detailed information relating to the product's chemistry, manufacture, controls and proposed labeling, among other things, are submitted
to the FDA as part of an NDA requesting approval to market the product for one or more indications. In most cases, the submission of an NDA is subject to a substantial application user fee. These user
fees must be filed at the time of the first submission of the application, even if the application is being submitted on a rolling basis. A user fee for the Twirla contraceptive patch was submitted
with the original NDA. Under the Prescription Drug User Fee Act, or PDUFA, guidelines that are currently in effect, the FDA has agreed to certain performance goals regarding the timing of its review
of an application. The FDA's standard review goal is to act on 90% of all Non-New Molecular Entity applications within ten months of FDA receipt of the application. The FDA's review goal for an
NDA resubmission, such as Twirla, is to act on 90% of such applications within six months of FDA receipt. This time period may be extended by FDA should an applicant submit new information to the
agency during the course of FDA's review of the marketing application. The time period is also only a goal and may not be met by FDA. We expect that our products, if and when approved, will be subject
to a standard review goal.
In
addition, under the Pediatric Research Equity Act, or PREA, an NDA or supplement to an NDA for a new active ingredient, indication, dosage form, dosage regimen or route of
administration must contain data that are adequate to assess the safety and efficacy of the drug for the claimed indications in all relevant pediatric subpopulations, and to support dosing and
administration for each pediatric subpopulation for which the product is safe and effective. The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of
some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements. We believe that we may be able to obtain a waiver
from the conduct of a PREA study as, historically, waivers have been granted for other contraceptive applicants.
The
FDA conducts a preliminary review of all NDAs within the first 60 days after submission, before accepting them for filing, to determine whether they are sufficiently complete
to permit substantive review. The FDA may request additional information rather than accept an NDA for filing. In this event, the application must be resubmitted with the additional information. The
resubmitted application is also subject to review before the FDA accepts it for filing. Once the submission is accepted for filing, the FDA begins an in-depth substantive review. The FDA reviews an
NDA to determine, among other things, whether the drug is safe and effective and whether the facility in which it is manufactured, processed, packaged or held, as well as the manufacturing processes
and controls, meet standards designed to ensure the product's continued safety, quality and purity.
The
FDA may refer a marketing application to an external advisory committee for questions pertaining to issues such as clinical trial design, safety and efficacy, and public health
questions. An advisory committee is a panel of independent experts, including clinicians and other scientific experts, that reviews, evaluates and provides a recommendation as to whether the
application should be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it typically follows such recommendations and considers such
recommendations carefully when making decisions.
Before
approving an NDA, the FDA will inspect the facility or facilities where the product is manufactured, referred to as a Pre-Approval Inspection. The FDA will not approve an
application unless it determines that the manufacturing processes and facilities are in compliance with cGMP
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requirements
and adequate to assure consistent production of the product within required specifications by the manufacturer and all of its subcontractors and contract manufacturers. Additionally,
before approving an NDA, the FDA will typically inspect one or more clinical trial sites to assure compliance with cGCP. Also, as part of its regulatory review, the FDA verifies the data contained in
the NDA.
The
testing and approval process for an NDA requires substantial time, effort and financial resources, and may take several years to complete. Data obtained from preclinical and clinical
testing are not always conclusive and may be susceptible to varying interpretations, which could delay, limit or prevent regulatory approval. The FDA may not grant approval of an NDA on a timely
basis, or at all.
After
evaluating the NDA and all related information, including the advisory committee recommendation, if any, and inspection reports regarding the manufacturing facilities and clinical
trial sites, the FDA may issue an approval letter, or, in some cases, a CRL. A CRL indicates that the review cycle of the application is complete and the application is not ready for approval. A CRL
generally
contains a statement of specific conditions that must be met in order to secure final approval of the NDA and may require additional clinical or preclinical testing, or other information in order for
the FDA to reconsider the application. We received a CRL for Twirla, have conducted the additional required clinical trial and other analyses, and intend to resubmit the NDA for Twirla to the FDA with
this updated information. We expect the FDA's review timeline for our Twirla resubmission to be approximately six months after submission. Even with submission of this additional information, the FDA
ultimately may decide that the application does not satisfy the regulatory criteria for approval. If and when those conditions have been met to the FDA's satisfaction, the FDA may issue an approval
letter. An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications.
Even
if the FDA approves a product candidate, it may limit the approved indications for use of the product candidate and require that contraindications, warnings or precautions be
included in the product labeling, including a black box warning. The FDA also may not approve the inclusion of labeling claims necessary for successful marketing. Moreover, the FDA may require that
post-approval studies, including Phase 4 clinical trials, be conducted to further assess certain aspects of a drug's safety and efficacy after approval, require testing and surveillance
programs to monitor the product after commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms. For example, the FDA may require a risk
evaluation and mitigation strategy, or REMS, as a condition of approval or following approval to mitigate any identified or suspected serious risks and ensure safe use of the drug. The REMS plan could
include medication guides, physician communication plans, assessment plans, and elements to assure safe use, such as restricted distribution methods, patient registries or other risk minimization
tools. A REMS could materially affect the potential market and profitability of the product. The FDA may prevent or limit further marketing of a product based on the results of post-marketing studies
or surveillance programs. After approval, some types of changes to the approved product, such as adding new indications, manufacturing changes, and additional labeling claims, are subject to further
testing requirements, submission of a supplemental application, and FDA review and approval. Further, should new safety information arise, additional testing, product labeling or FDA notification may
be required.
Hatch-Waxman Act
Section 505 of the FDCA describes three types of marketing applications that may be submitted to the FDA to request marketing
authorization for a new drug. A Section 505(b)(1) NDA is an application that contains full reports of investigations of safety and efficacy. A 505(b)(2) NDA is an application that contains full
reports of investigations of safety and efficacy but where at least some of the information required for approval comes from investigations that were not conducted by or for the applicant and for
which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted. This regulatory pathway enables the applicant to rely,
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in
part, on the FDA's prior findings of safety and efficacy for an existing product, or published literature, in support of its application. Section 505(j) establishes an abbreviated approval
process for a generic version of approved drug products through the submission of an Abbreviated New Drug Application, or ANDA. An ANDA provides for marketing of a generic drug product that has the
same active ingredients, dosage form, strength, route of administration, labeling, performance characteristics and intended use, among other things, to a previously approved product. ANDAs are termed
"abbreviated" because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and efficacy. Instead, generic applicants must scientifically
demonstrate that their product is bioequivalent to, or performs in the same manner as, the innovator drug through
in vitro
,
in
vivo
, or other testing. The generic version must deliver the same amount of active ingredients into a subject's bloodstream in the same amount of time as the innovator drug and
can often be substituted by pharmacists under prescriptions written for the reference listed drug. In seeking approval for a drug through an NDA, applicants are required to list with the FDA each
patent with claims that cover the applicant's drug or a method of using the drug. Upon approval of a drug, each of the patents listed in the application for the drug is then published in the FDA's
Approved Drug Products with Therapeutic Equivalence Evaluations, commonly known as the Orange Book. Drugs listed in the Orange Book can, in turn, be cited by potential competitors in support of
approval of an ANDA or 505(b)(2) NDA.
Upon
submission of an ANDA or a 505(b)(2) NDA, an applicant must certify to the FDA that (1) no patent information on the drug product that is the subject of the application has
been submitted to the FDA; (2) such patent has expired; (3) the date on which such patent expires; or (4) such patent is invalid or will not be infringed upon by the manufacture,
use or sale of the drug product for which the application is submitted. Generally, the ANDA or 505(b)(2) NDA cannot be approved until all listed patents have expired, except where the ANDA or
505(b)(2) NDA applicant challenges a listed patent through the last type of certification, also known as a paragraph IV certification. If the applicant does not challenge the listed patents or
indicates that it is not seeking approval of a patented method of use, the ANDA or 505(b)(2) NDA application will not be approved until all of the listed patents claiming the referenced product have
expired.
If
the ANDA or 505(b)(2) NDA applicant has provided a Paragraph IV certification to the FDA, the applicant must send notice of the Paragraph IV certification to the NDA and
patent holders once the application has been accepted for filing by the FDA. The NDA and patent holders may then initiate a patent infringement lawsuit in response to the notice of the
paragraph IV certification. If the paragraph IV certification is challenged by an NDA holder or the patent owner(s) asserts a patent challenge to the paragraph IV certification,
the FDA may not make an approval effective until the earlier of 30 months from the receipt of the notice of the paragraph IV certification, the expiration of the patent, when the
infringement case concerning each such patent was favorably decided in the applicant's favor or settled, or such shorter or longer period as may be ordered by a court. This prohibition is generally
referred to as the 30-month stay. In instances where an ANDA or 505(b)(2) NDA applicant files a paragraph IV certification, the NDA holder or patent owner(s) regularly take action
to trigger the 30-month stay, recognizing that the related patent litigation may take many months or years to resolve. Thus, approval of an ANDA or 505(b)(2) NDA could be delayed for a
significant period of time depending on the patent certification the applicant makes and the reference drug sponsor's decision to initiate patent litigation.
The
Hatch-Waxman Act establishes periods of regulatory exclusivity for certain approved drug products, during which the FDA cannot approve (or in some cases accept) an ANDA
or 505(b)(2) application that relies on the branded reference drug. For example, the holder of an NDA, including a 505(b)(2) NDA, may obtain five years of exclusivity upon approval of a new
drug containing new chemical entities, or NCEs, that have not been previously approved by the FDA. A drug is a new chemical entity if the FDA has not previously approved any other new drug containing
the same active
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moiety,
which is the molecule or ion responsible for the therapeutic activity of the drug substance. During the exclusivity period, the FDA may not accept for review an ANDA or a 505(b)(2) NDA
submitted by another company that contains the previously approved active moiety. However, an ANDA or 505(b)(2) NDA may be submitted after four years if it contains a certification of patent
invalidity or non-infringement.
The
Hatch-Waxman Act also provides three years of marketing exclusivity to the holder of an NDA (including a 505(b)(2) NDA) for a particular condition of approval, or change to a
marketed product, such as a new formulation for a previously approved product, if one or more new clinical studies (other than bioavailability or bioequivalence studies) was essential to the approval
of the application and was conducted/sponsored by the applicant. This three-year exclusivity period protects against FDA approval of ANDAs and 505(b)(2) NDAs for the condition of the new drug's
approval. As a general matter, the three year exclusivity does not prohibit the FDA from approving ANDAs or 505(b)(2) NDAs for generic versions of the original, unmodified drug product. Five-year and
three-year exclusivity will not delay the submission or approval of a full NDA; however, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to all of the
preclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and efficacy.
Our
NDA for Twirla was submitted under Section 505(b)(2), and we expect that some of our other drug candidates will utilize the Section 505(b)(2) regulatory pathway. Even
though several of our drug products utilize active drug ingredients that are commercially marketed in the United States in other dosage forms, we need to establish safety and efficacy of those active
ingredients in the formulation and dosage forms that we are developing. All approved products, both innovator and generic, are listed in the FDA's Orange Book.
U.S. Post-Approval Requirements
Drugs manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among
other things, requirements relating to manufacturing recordkeeping, periodic reporting, product sampling and distribution, advertising and promotion, reporting of adverse experiences with the product
and drug shortages, and compliance with any post-approval requirements imposed as a condition of approval, such as Phase 4 clinical trials, REMS and surveillance to assess safety and efficacy
after commercialization. After approval, most changes to the approved product, such as adding new indications or other labeling claims are subject to prior FDA review and approval. There also are
continuing, annual user fee requirements for any approved products and the establishments at which such products are manufactured, as well as new application fees for supplemental applications with
clinical data other than bioavailability or bioequivalence studies. In addition, drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to
register their establishments with the FDA and state agencies, list drugs manufactured at their facilities with the FDA, and are subject to periodic announced and unannounced inspections by the FDA
and these state agencies for compliance with cGMP and other requirements. Changes to the manufacturing process are strictly regulated and often require prior FDA approval before being implemented, or
FDA notification. FDA regulations also require investigation and correction of any deviations from cGMP and impose reporting and documentation requirements upon the sponsor and any third-party
manufacturers that the sponsor may decide to use. Accordingly, manufacturers must continue to expend time, money and effort in the area of production and quality control to maintain cGMP compliance.
Once
an approval is granted, the FDA may withdraw the approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches
the market.
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Later
discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with
regulatory requirements, may result in mandatory revisions to the approved labeling to add new safety information; imposition of post-market studies or clinical trials to assess new safety risks; or
imposition of distribution or other restrictions under a REMS program. Other potential consequences include, among other things:
-
-
Restrictions on the marketing, distribution or manufacturing of the product, complete withdrawal of the product from the market or requests for
product recalls;
-
-
Fines, or Untitled, Cyber or Warning Letters or holds on or termination of post-approval clinical trials;
-
-
Refusal of the FDA to approve pending NDAs or supplements to approved NDAs, or suspension or revocation of product license approvals;
-
-
Product seizure or detention, or refusal to permit the import or export of products;
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Injunctions or the imposition of civil or criminal penalties including disgorgement, restitution, fines and imprisonment;
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Consent decrees, corporate integrity agreements or exclusion from federal healthcare programs;
-
-
Debarment;
-
-
Mandated modification of promotional materials and labeling and the issuance of corrective information; or
-
-
The FDA or other regulatory authorities may issue safety alerts, Dear Healthcare Provider letters, press releases or other communications
containing warnings or other safety information about the product.
The
FDA strictly regulates marketing, labeling, advertising and promotion of products that are placed on the market. Although physicians, in the practice of medicine, may prescribe
approved drugs for unapproved indications, pharmaceutical companies are prohibited from marketing or promoting their drug products for uses outside the approved label, a practice known as off-label
promotion. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may
be subject to significant liability, including criminal and civil penalties under the FDCA and False Claims Act, exclusion from participation in federal healthcare programs, mandatory compliance
programs under corporate integrity agreements, debarment and refusal of government contracts.
In
addition, the distribution of prescription pharmaceutical products, including samples, is subject to the Prescription Drug Marketing Act, or PDMA, which regulates the distribution of
drugs and drug samples at the federal level. Both the PDMA and state laws limit the distribution of prescription pharmaceutical product samples and impose requirements to ensure accountability in
distribution.
Moreover,
the Drug Quality and Security Act imposes obligations on manufacturers of pharmaceutical products related to product tracking and tracing. Among the requirements of this
legislation, manufacturers are required to provide certain information regarding the drug product to individuals and entities to which product ownership is transferred, will be required to label drug
product with a product identifier toward the end of 2017 and are required to keep certain records regarding the drug product. The transfer of information to subsequent product owners by manufacturers
will be required to be done electronically toward the end of 2017. Manufacturers must also verify that purchasers of the manufacturers' products are appropriately licensed. Further, under this
legislation, manufactures have drug product investigation, quarantine, disposition, and FDA and trading partner notification responsibilities related to counterfeit, diverted, stolen and intentionally
adulterated products, as well as products that are the subject of fraudulent transactions or which are otherwise unfit for distribution such that they would be reasonably likely to result in serious
health consequences or death.
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U.S. Fraud and Abuse, Data Privacy and Security and Transparency Laws and Regulations
In addition to FDA restrictions on marketing of pharmaceutical products, federal and state fraud and abuse laws restrict business practices in
the biopharmaceutical industry. These laws include, among other things, anti-kickback, physician payment transparency and false claims laws and regulations as well as data privacy and security laws
and regulations.
The
federal Anti-Kickback Statute prohibits, among other things, any person or entity, from knowingly and willfully offering, paying, soliciting or receiving any remuneration, directly
or indirectly, overtly or covertly, in cash or in kind, to induce or in return for purchasing, leasing, ordering, or arranging for or recommending the purchase, lease, or order of any item or service
reimbursable under Medicare, Medicaid or other federal healthcare programs. The term "remuneration" has been interpreted broadly to include anything of value. Additionally, the intent standard under
the Anti-Kickback Statute and criminal healthcare fraud statutes was also amended by the ACA to a stricter standard such that a person or entity no longer needs to have actual knowledge of the statute
or specific intent to violate it in order to have committed a violation. In addition, the ACA provided that the government may assert that a claim including items or services resulting from a
violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal civil False Claims Act. The Anti-Kickback Statute has been interpreted to apply to
arrangements between pharmaceutical manufacturers on one hand and prescribers, purchasers, and formulary managers on the other. There are a number of statutory exceptions and regulatory safe harbors
protecting some common activities from prosecution. Practices that involve remuneration that may be alleged to be intended to induce prescribing, purchases, or recommendations may be subject to
scrutiny if they do not qualify for an exception or safe harbor. Failure to meet all of the requirements of a statutory exception or regulatory safe harbor does not make the conduct per se illegal
under the Anti-Kickback Statute. Instead, the legality of the arrangement will be evaluated on a case-by-case basis based on a cumulative review of all of its facts and circumstances.
The
federal civil False Claims Act prohibits, among other things, any person or entity from knowingly presenting, or causing to be presented, a false or fraudulent claim for payment to,
or approval by, the federal government or knowingly making, using, or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government. A claim
includes "any request or demand" for money or property presented to the U.S. government. The civil False Claims Act has been used to assert liability on the basis of kickbacks and other improper
referrals, improperly reported government pricing metrics such as Best Price or Average Manufacturer Price, improper promotion of off-label uses not expressly approved by the FDA in a drug's label,
and allegations as to misrepresentations with respect to the services rendered. Additionally, the civil monetary penalties statute, which, among other things, imposes fines against any person who is
determined to have presented, or caused to be presented, claims to a federal healthcare program that the person knows, or should know, is for an item or service that was not provided as claimed or is
false or fraudulent. The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, also created federal criminal statutes that prohibit knowingly and willfully executing, or
attempting to execute, a scheme to defraud or to obtain, by means of false or fraudulent pretenses, representations, or promises, any of the money or property owned by, or under the custody or control
of, any healthcare benefit program, including private third party payors and knowingly and willfully falsifying, concealing or covering up by
trick, scheme or device a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services
relating to healthcare matters. Also, many states have similar fraud and abuse statutes or regulations that apply to items and services reimbursed under Medicaid and other state programs, or, in
several states, that apply regardless of the payor.
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In addition, we may be subject to data privacy and security regulation by both the federal government and the states in which we conduct our business. HIPAA, as
amended by the Health Information Technology for Economic and Clinical Health Act, or HITECH, and their respective implementing regulations, including the final omnibus rule published on
January 25, 2013, imposes specified requirements relating to the privacy, security and transmission of individually identifiable health information. Among other things, HITECH makes security
standards and certain privacy standards directly applicable to business associates. HITECH also created four new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties
directly applicable to business associates, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek
attorneys' fees and costs associated with pursuing federal civil actions. In addition, state laws may govern the privacy and security of health information in certain circumstances, many of which
differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.
Additionally,
federal physician payment transparency laws, including the federal Physician Payment Sunshine Act created under Section 6002 of the ACA and its implementing
regulations, require that manufacturers of drugs for which payment is available under Medicare, Medicaid or the Children's Health Insurance Program, with certain exceptions, report annually to the
government information related to payments or other "transfers of value" made or distributed to physicians, which is defined to
include doctors of medicine, dentists, optometrists, podiatrists and chiropractors, generally, with some exceptions, and teaching hospitals, or to entities or individuals at the request of, or
designated on behalf of, physicians and teaching hospitals. Additionally, applicable manufacturers and group purchasing organizations are required to report annually to the government certain
ownership and investment interests held by physicians and their immediate family members. , Manufacturers must submit reports by the 90th day of each calendar year. Disclosure of such
information is made on a publicly available website.
There
are also an increasing number of analogous state laws that require manufacturers to file reports with states on pricing and marketing information, and to track and report gifts,
compensation, other remuneration and items of value provided to healthcare professionals and healthcare entities. Many of these laws contain ambiguities as to what is required in order to comply with
such laws. For example, several states have enacted legislation requiring pharmaceutical companies to, among other things, establish and implement commercial compliance programs, file periodic reports
with the state, make periodic public disclosures on sales, marketing, pricing, clinical trials and other activities, or register their sales representatives. Certain state laws also regulate
manufacturers' use of prescriber-identifiable data. These laws may affect our future sales, marketing and other promotional activities by imposing administrative and compliance burdens. In addition,
given the lack of clarity with respect to these laws and their implementation, our reporting actions once we commercialize could be subject to the penalty provisions of the pertinent state and federal
authorities.
If
our operations are found to be in violation of any of the laws or regulations described above or any other laws that apply to us, we may be subject to a variety of penalties,
depending upon the law found to have been violated, potentially including criminal and significant civil monetary penalties, damages, fines, imprisonment, exclusion from participation in government
healthcare programs, corporate integrity agreements, refusal of government contracts, contract debarment and the curtailment or restructuring of our operations, any of which could adversely affect our
ability to operate our business and our results of operations. To the extent that any of our products are sold in a foreign country, we may be subject to similar foreign laws and regulations, which
may include, for instance, applicable post-marketing requirements, including safety surveillance, anti-fraud and abuse laws, and implementation of corporate compliance programs and reporting of
payments or transfers of value to healthcare professionals.
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Coverage and Reimbursement Generally
The commercial success of our product candidates and our ability to commercialize any approved product candidates successfully will depend in
part on the extent to which governmental payor programs at the federal and state levels, including Medicare and Medicaid, private health insurers and other third-party payors provide coverage for and
establish adequate coverage of and reimbursement levels for our product candidates. Government authorities, private health insurers and other organizations generally decide which drugs they will pay
for and establish reimbursement levels for healthcare. In particular, in the United States, private health insurers and other third-party payors often provide reimbursement for products and services
based on the level at which the government provides reimbursement through the Medicare or Medicaid programs for such products and services. In the United States, the European Union and other
potentially significant markets for our product candidates, government authorities and third-party payors are increasingly attempting to limit or regulate the price of medical products and services,
particularly for new and innovative products and therapies, which often has resulted in average selling prices lower than they would otherwise be. Further, the increased emphasis on managed healthcare
in the United States and on country and regional pricing and reimbursement controls in the European Union will put additional pressure on product pricing, reimbursement and utilization, which may
adversely affect our future product sales and results of operations. These pressures can arise from rules and practices of managed care groups, judicial decisions and governmental laws and regulations
related to Medicare, Medicaid and healthcare reform, pharmaceutical coverage and reimbursement policies and pricing in general. Patients who are prescribed treatments for their conditions and
providers performing the prescribed services generally rely on third-party payors to reimburse all or part of the associated healthcare costs. Sales of our product candidates will therefore depend
substantially, both domestically and abroad, on the extent to which the costs of our products will be paid by health maintenance organizations, managed care, pharmacy benefit and similar healthcare
management organizations, or reimbursed by government health administration authorities, such as Medicare and Medicaid, private health insurers and other third-party payors.
Third-party
payors are increasingly imposing additional requirements and restrictions on coverage and limiting reimbursement levels for medical products, including pharmaceuticals. For
example, federal and state governments reimburse covered prescription drugs at varying rates generally below average wholesale price. These restrictions and limitations influence the purchase of
healthcare services and products. Third-party payors are developing increasingly sophisticated methods of controlling healthcare costs. Third-party payors may limit coverage to specific drug products
on an approved list, or formulary, which might not include all of the FDA-approved drug products for a particular indication. Third-party payors are increasingly challenging the price and examining
the medical necessity and cost-effectiveness of medical products and services, in addition to their safety and efficacy. We may need to conduct expensive pharmacoeconomic studies in order to
demonstrate the medical necessity and cost-effectiveness of our products, in addition to the costs required to obtain FDA approvals. Our product candidates may not be considered medically necessary or
cost-effective. Moreover, a payor's decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved. Adequate third-party reimbursement may not be
available to enable us to maintain price levels sufficient to realize an appropriate return on our investment in drug development for a product candidate. Legislative proposals to reform healthcare or
reduce costs under government insurance programs may result in lower reimbursement for our product candidates or exclusion of our product candidates from coverage. The cost containment measures that
healthcare payors and providers
are instituting and any healthcare reform could significantly reduce our revenues from the sale of any approved product candidates. We cannot provide any assurances that we will be able to obtain and
maintain third-party coverage or adequate reimbursement for our product candidates in whole or in part.
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Healthcare Reform
Legislative proposals to reform healthcare or reduce costs under government healthcare programs may result in lower reimbursement for our
product candidates or exclusion of our product candidates from coverage. There have been a number of legislative and regulatory changes to the healthcare system that could affect our ability to
profitably sell our product candidates, if approved. Among policy makers and payors in the United States and elsewhere, there is significant interest in promoting changes in healthcare systems with
the stated goals of containing healthcare costs, improving quality and expanding access. In the United States, the pharmaceutical industry has been a particular focus of these efforts and has been
significantly affected by major legislative initiatives.
In
March 2010, the ACA was enacted, which included provisions on comparative clinical effectiveness research extended the initiatives of the American Recovery and Reinvestment Act of
2009, also known as the stimulus package, which provided $1.1 billion in funding to study the comparative effectiveness of healthcare treatments. This funding was designated for, among other
things, conducting, supporting or synthesizing research that compares and evaluates the risks and benefits, clinical outcomes, effectiveness and appropriateness of products. The ACA also appropriated
additional funding to comparative clinical effectiveness research. Although Congress has indicated that this funding is intended to improve the quality of healthcare, it remains unclear how the
research will impact current Medicare coverage and reimbursement or how new information will influence other third-party payor policies.
It
is possible that comparative effectiveness research demonstrating benefits in a competitor's product could adversely affect the sales of our product candidates. If third-party payors
do not consider our product candidates to be cost-effective compared to other available therapies, they may not cover our product candidates, once approved, as a benefit under their plans or, if they
do, the level of payment may not be sufficient to allow us to sell our product candidates on a profitable basis.
In
addition, in August 2011, President Obama signed into law the Budget Control Act of 2011, as amended, which, among other things, created the Joint Select Committee on Deficit
Reduction to recommend proposals in spending reductions to Congress. The Joint Select Committee on Deficit Reduction did not achieve its targeted deficit reduction of at least $1.2 trillion for the
years 2013 through 2021, triggering the legislation's automatic reductions to several government programs. These reductions include aggregate reductions to Medicare payments to providers of 2% per
fiscal year, which went into effect on April 1, 2013 and will stay in effect through 2024 unless additional Congressional action is taken. In November 2015, the Bipartisan Budget Act was
enacted into law, which, among other things, extended sequestration through 2025. These and other healthcare reform initiatives may result in additional reductions in Medicare and other healthcare
funding, which could have a material adverse effect on our financial operations. We expect that additional state and federal healthcare reform measures will be adopted in the future, any of which
could limit the amounts that federal and state governments will pay for healthcare products and services, which could further limit the prices we are able to charge, or the amounts of reimbursement
available, for our product candidates if they are approved.
In
March 2017, the U.S. Congress proposed legislation, which, if signed into law by the new administration, would repeal certain aspects of the ACA. Further, on January 20, 2017,
the new administration signed an Executive Order directing federal agencies with authorities and responsibilities under the ACA to waive, defer, grant exemptions from, or delay the implementation of
any provision of the ACA that would impose a fiscal or regulatory burden on states, individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices among
others. Congress also could consider subsequent legislation to repeal and replace elements of the ACA that are repealed.
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The Foreign Corrupt Practices Act
The Foreign Corrupt Practices Act, or FCPA, prohibits any U.S. individual or business from paying, offering, or authorizing payment or offering
of anything of value, directly or indirectly, to any foreign official, political party or candidate for the purpose of influencing any act or decision of the foreign entity in order to assist the
individual or business in obtaining or retaining business. The FCPA also obligates companies whose securities are listed in the United States to comply with accounting provisions requiring the company
to maintain books and records that accurately and fairly reflect all transactions of the corporation, including international subsidiaries, and to devise and maintain an adequate system of internal
accounting controls for international operations. Activities that violate the FCPA, even if they occur wholly outside the United States, can result in criminal and civil fines, imprisonment,
disgorgement, oversight and debarment from government contracts.
Foreign Regulation
In order to market any product outside of the United States, we would need to comply with numerous and varying regulatory requirements of other
countries regarding safety and efficacy and governing, among other things, clinical trials, marketing authorization, commercial sales and distribution of our products. For example, in the European
Union, we must obtain authorization of a clinical trial application, or CTA, in each member state in which we intend to conduct a clinical trial. Whether or not we obtain FDA approval for a product,
we would need to obtain the necessary approvals by the comparable regulatory authorities of foreign countries before we can commence clinical trials or marketing of the product in those countries. The
approval process varies from country to country and can involve additional product testing and additional administrative review periods. The time required to obtain approval in other countries might
differ from and be longer than that required to obtain FDA approval. Regulatory approval in one country does not ensure regulatory approval in another, but a failure or delay in obtaining regulatory
approval in one country may negatively impact the regulatory process in others.
Research and Development
Conducting research and development is central to our business model. We have invested and expect to continue to invest significant time and
capital in our research and development operations. Our research and development expenses were $20.9 million, $25.6 million, and $13.4 million for the years ended
December 31, 2016, 2015, and 2014, respectively. In 2017, we expect the expenses associated with the SECURE clinical trial to decrease as we complete the close-out activities associated with
the trial, and no additional clinical trials are planned at this time. During 2017, we expect to increase activities related to equipment qualification and validation of our commercial manufacturing
process as we continue to prepare for the commercialization of Twirla.
Intellectual Property
We strive to protect the proprietary technologies that we believe are important to our business, including seeking and maintaining patent
protection intended to cover our Skinfusion technology, its methods of use, related technologies and other inventions that are important to our business. As more fully described below, our patents and
patent applications are directed to our Skinfusion technology or aspects thereof including certain transdermal delivery systems having an active
adhesive matrix and methods of using such transdermal delivery systems for controlling fertility. We also rely on manufacturing trade secrets and careful monitoring of our proprietary information to
protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection.
Our
success will depend significantly on our ability to obtain new patents and maintain existing patents and other proprietary protection for commercially important technology,
inventions and
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know-how
related to our business, defend and enforce our patents, preserve the confidentiality of our trade secrets and operate without infringing valid and enforceable patents and other proprietary
rights of third parties.
A
third party may hold intellectual property, including patent rights, which are important or necessary to the development of our product candidates. It may be necessary for us to use
the patented or proprietary technology of third parties to commercialize our product candidates, in which case we would be required to obtain a license from these third parties on commercially
reasonable terms. If we were not able to obtain a license on commercially reasonable terms, our business could be harmed, possibly materially.
We
plan to continue to expand our intellectual property estate by filing patent applications directed to novel and nonobvious transdermal contraceptive products. The active
pharmaceutical ingredients, or API, in our product candidates are generic and therefore our patents do not include claims directed solely to the API. We anticipate seeking additional patent protection
in the United States and internationally for additional transdermal delivery systems and their methods of use.
The
patent positions of pharmaceutical companies like us are generally uncertain and involve complex legal, scientific and factual questions. In addition, the coverage claimed in a
patent application can be significantly reduced before the patent is issued, and the patent's scope can be modified after issuance. Consequently, we do not know whether any of our product candidates
will remain protected by enforceable and valid patents. We cannot predict whether the patent applications we are currently pursuing will issue as patents in any particular jurisdiction or whether the
claims of any issued patents will provide sufficient proprietary protection from competitors. Any patents that we hold may be challenged, circumvented or invalidated by third parties.
Because
patent applications in the United States and certain other jurisdictions generally are maintained in secrecy for 18 months, and since publication of discoveries in the
scientific or patent
literature often lags behind actual discoveries, we cannot be certain of our entitlement to patent rights in the inventions covered in our issued patents and pending patent applications. Moreover, we
may have to participate in interference proceedings declared by the U.S. Patent and Trademark Office, USPTO, to determine priority of invention, or in post-grant challenge proceedings in the USPTO or
foreign patent offices such as oppositions, reexamination, inter-partes review, post grant review, or a derivation proceeding, that challenge our entitlement to an invention or the patentability of
one or more claims in our patent applications or issued patents. Such proceedings could result in substantial cost, even if the eventual outcome is favorable to us.
More
specifically, Twirla is a transdermal contraceptive hormone delivery system. The system is a patch for application to the skin and contains two API, the hormones levonorgestrel, or
LNG, which is a synthetic progestin, and ethinyl estradiol, a synthetic estrogen. The API are formulated with a combination of skin penetration enhancers, which promote penetration through the dermis
and into the bloodstream, such that effective blood levels of the active agents are achieved to suppress ovulation and thereby prevent pregnancy. One of our other product candidates, AG890, is similar
to Twirla, except that it contains only a single API, LNG.
In
both our Twirla product candidate line and in AG890, the active adhesive system consists of the active ingredients in a polyacrylate adhesive polymer matrix comprising the permeation
enhancers dimethylsulfoxide, ethyl lactate, capric acid and lauryl lactate. The active blend is coated onto a release liner, and a backing layer is added on top of the active blend. The peripheral
adhesive system, also called the overlay, comprising three layers is added onto the backing layer. The overlay comprises a polyisobutylene adhesive layer, an acrylic adhesive layer, and an overlay
covering. The overlay covering is a commercially available silk-like polyester fabric. The adhesive components of the overlay, in addition to their adhesive function, create an
in situ seal
with the
disposable release liner, trapping evaporable solvents in the active blend, thereby extending the usable shelf life of the product
candidate
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and
contributing to the comfort and effectiveness of the transdermal system during use. Prior to use of any of our product candidates, the release liner is removed by the user and discarded. The patch
is then applied to the skin.
Eight
U.S. patents, issuing from three patent families, have been or are being submitted to the FDA for listing in the Orange Book upon approval of Twirla. These patents include claims
directed to transdermal delivery systems having an active adhesive matrix and claims directed to methods of controlling fertility by applying such transdermal delivery systems, and in all cases
including a skin permeation enhancer. One of our eight issued U.S. patents will expire November 22, 2020. Four will expire March 14, 2021. Two will expire July 10, 2028. The
eighth will expire August 26, 2028.
U.S.
Patent No. 7,045,145 is directed to the adhesive matrix of the transdermal delivery system used in Twirla and expires in March 2021; product-by-process claims cover patches
manufactured by drying wet formulations of the active adhesive matrix. U.S. Patent No. 7,384,650, U.S. Patent No. 8,221,784, and U.S. Patent No. 8,221,785 are all directed to the
dry final product formulation of the transdermal delivery system used in Twirla, and expire in March 2021. U.S. Patent No. 8,221,784 covers both Twirla and AG890. Foreign counterparts to these
patents have been granted in Australia, Brazil, Canada, China, Europe, France, Germany, Great Britain, Ireland, Italy, India, Israel, Japan, Korea, Mexico, Netherlands, New Zealand, Norway, Spain,
Switzerland, and South Africa. U.S. Patent No. 8,883,196 is directed to a method of controlling fertility by applying Twirla or AG890 once each week for three weeks followed by a one week rest
interval, or in an extended regimen without a rest interval for a selected number of weeks, and expires November 22, 2020.
U.S.
Patent Nos. 8,246,978, 8,747,888, and 9,050,348 are directed to structural features of the transdermal delivery system used in Twirla and AG890 patch design for transdermal
delivery of hormones or of other drugs. As such, these patents protect a platform technology for delivery of LNG, EE, other hormones, and other drugs. These patents expire in July and August 2028.
Foreign counterparts are granted in Australia, Canada, China, Spain, France, Netherlands, Italy, UK, Ireland, Germany, Switzerland, Japan, Russia and New Zealand and are pending elsewhere.
U.S.
Patent Nos. 9,198,876, 9,192,614, 9,198,919 and 9,198,920 are directed to various novel dosing regimens, each of which employs transdermal delivery of contraceptive doses of
ethinyl estradiol and levonorgestrel during a "treatment interval" and transdermal delivery of low dose ethinyl estradiol and low dose levonorgestrel during a "withdrawal interval". We expect these
patents will be relevant to two of the products in our pipeline, AG200-SP and AG200-ER, as well as other new potential regimens.
U.S.
Patent No. 9,364,487 is directed to a composition and device for transdermal delivery of levonorgestrel for P-only therapy. The composition contains an anti-oxidant to
protect the progestin against oxidative degradation caused by other components of the composition. We expect this patent to be relevant to at least one product in our pipeline, AG890.
We
own a total of about 45 granted patents in jurisdictions other than the United States, including patents in New Zealand, Australia, Canada, Austria, Germany, Ireland, Italy, The
Netherlands, Spain, Switzerland, Israel, India, Japan, South Korea, Mexico, Norway, the Philippines, Taiwan and South Africa. These issued foreign patents include claims directed to transdermal
delivery systems having an active adhesive matrix and claims directed to methods of controlling fertility by applying such transdermal delivery systems, and in all cases including a skin permeation
enhancer. In addition, we have about 37 pending patent applications in the United States and certain foreign jurisdictions for Twirla and AG890, and for unique patch dosage regimens intended to align
with future label expansions and line extensions, such as AG200ER and AG200SP, including an antioxidant formulation and a desogestrel patch.
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Regulatory Exclusivity
Our NDA for Twirla was submitted under Section 505(b)(2) of the Food, Drug, and Cosmetic Act, or FDCA. Even though Twirla utilizes API
that were previously approved in the United States, Twirla utilizes LNG in a new dosage form, specifically a transdermal patch, and we provided new clinical data essential to approval in our NDA to
establish the safety and efficacy of Twirla. Therefore, if approved by the FDA, we expect to receive three years of U.S. marketing exclusivity for Twirla. The exclusivity will prohibit the FDA from
approving ANDAs and 505(b)(2) NDAs for the conditions of the Twirla approval. We will consider whether we are going to pursue patent term restoration, however, we do not expect to receive patent term
restoration because, as explained above, Twirla will not be the first approval of the API.
Employees
As of December 31, 2016, we had 19 full time employees, including eleven in research and development and eight in general and
administrative roles. None of our employees are represented by a labor union or subject to a collective bargaining agreement. We have not experienced a work stoppage and consider our relations with
our employees to be good.
Corporate Information
We were incorporated in Delaware in December 1997. Our offices are located at 101 Poor Farm Road, Princeton, New Jersey 08540, and our telephone
number is (609) 683-1880.
Available Information
Our corporate website address is www.agiletherapeutics.com. Information contained on or accessible through our website are not a part of this
annual report on Form 10-K, and the inclusion of our website address in this annual report is an inactive textual reference only. We make our annual report on Form 10-K, quarterly
reports on Form 10-Q, current reports on Form 8-K and all amendments to those reports available free of charge on our website as soon as reasonably practicable after we file such reports
with, or furnish such reports to, the Securities and Exchange Commission, or SEC.
We
are an "emerging growth company," as defined in the Jumpstart Our Business Startups Act of 2012. We will remain an emerging growth company until the earlier of (1) the last day
of the fiscal year (a) following the fifth anniversary of the completion of our initial public offering, (b) in which we have total annual gross revenue of at least $1.0 billion,
or (c) in which we are deemed to be a large accelerated filer, which means the market value of our common stock that is held by non-affiliates exceeded $700 million as of the prior
March 31
st
, and (2) the date on which we have issued more than $1.0 billion in non-convertible debt during the prior three-year period.
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Item 1A. Risk Factors.
Investing in our common stock involves a high degree of risk. You should carefully consider the risk factors set forth
below as well as the other information contained in this Annual Report on Form 10-K and in our other public filings in evaluating our business. Any of the following risks could materially and
adversely affect our business, financial condition or results of operations. The risks described below are not the only risks facing us. Additional risks and uncertainties not currently known to us or
that we currently view to be immaterial may also materially adversely affect our business, financial condition or results of operations. In these circumstances, the market price of our common stock
would likely decline.
Risks Related to the Clinical Trial Process and Regulatory Approval for Our Product Candidates
We have not obtained regulatory approval for any of our product candidates in the United States or any other
country.
We currently do not have any product candidates that have gained regulatory approval for sale in the United States or any other country, and we
cannot guarantee that we will ever have marketable products. Our business is substantially dependent on our ability to complete the development of, obtain regulatory approval for and successfully
commercialize product candidates in a timely manner. We cannot commercialize product candidates in the United States without first obtaining regulatory approval to market each product candidate from
the U.S. Food and Drug Administration, or FDA; similarly, we cannot commercialize product candidates outside of the United States without obtaining regulatory approval from comparable foreign
regulatory authorities. We are not currently pursuing any regulatory approvals for Twirla or any other product candidate outside the United States.
We
have previously conducted two Phase 3 clinical trials for Twirla, and we filed a new drug application, or NDA, with the FDA for Twirla in April 2012. The FDA issued a Complete
Response Letter, or CRL, in February 2013, identifying certain issues, including a request for additional clinical data, quality information and chemistry, manufacturing and controls information,
which must be addressed before approval can be granted. We have continued to interact with the FDA on its CMC and other questions and continued additional supportive testing in order to respond to the
FDA's CMC questions. In addition, we are gathering the requested information and conducted an additional Phase 3 clinical trial for Twirla®, which we refer to as the SECURE clinical
trial. The SECURE clinical trial commenced enrollment during the third quarter of 2014 and completed in December 2016. In January 2017, we announced top-line results. Based on the results of the
SECURE clinical trial and additional information relating to the manufacture of Twirla, we plan to resubmit our NDA in the first half of 2017. Although we met with the FDA in October 2013 to discuss
our new Phase 3 clinical trial and have received substantial written comments from the FDA in subsequent interactions, we have not sought and have not obtained agreement with the FDA on a
special protocol assessment regarding the new Phase 3 trial. We cannot predict whether regulators will agree with our conclusions regarding the results of the SECURE clinical trial or any
clinical trials we have conducted to date, including whether our data are reliable and generalizable. For example, based on the SECURE top-line data, the Pearl Index for the overall intent to treat
population of subjects 35 years of age and under was 4.80 with an upper-bound of the 95% confidence interval of 6.06, but in the obese subpopulation of subjects 35 years of age
and under, the Pearl Index was 6.42 with an upper-bound of the 95% confidence interval of 8.88. If we were to exclude the top-line data on the obese subpopulation, our Pearl Index for non-obese
patients was 3.94 with an upper-bound of the 95% confidence interval of 5.35. The highest Pearl Index for a hormonal contraceptive product approved by the FDA to date was 3.19 and the highest
upper-bound of the 95% confidence interval was 5.03. In the combined safety database for our three
Agile Phase 3 trials (n>3,000), there were 5 subjects with potentially study drug related DVTs or PEs, 4 of whom were obese
(BMI
³
30kg/m
2
). Although ultimate approvability of a hormonal contraceptive is based on a
risk/benefit assessment of the overall safety and efficacy profile of a product, not only a specific Pearl Index, the FDA could conclude that the Pearl Index is too high to
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demonstrate
efficacy and an adequate risk/benefit profile for either the overall study population or a subgroup of the study population. Accordingly, FDA may not approve our Twirla NDA. Alternatively,
FDA may determine that for a specific subgroup of patients, Twirla has lower efficacy and presents a higher risk, necessitating labeling restrictions. For instance, FDA may require labeling
restrictions on the use of Twirla for patients in certain BMI categories. As such, we may not obtain approval of Twirla based on these data or any other basis, or if approved, may only receive
approval with significant labeling restrictions. In addition, the FDA may re-inspect our manufacturing partner's facilities as well as SECURE clinical trial sites during its review of our resubmission
before approval can be granted.
Before
obtaining regulatory approvals for the commercial sale of any product candidate for a target indication, we must demonstrate in preclinical studies and well-controlled clinical
trials and, with respect to approval in the United States, to the satisfaction of the FDA, that the product candidate is safe and effective for use for that target indication and that the
manufacturing facilities, processes and controls are adequate. In the United States, it is necessary to submit an NDA to obtain FDA approval. An NDA must include extensive preclinical and clinical
data and supporting information to establish the product candidate's safety and efficacy for each desired indication, although we may partially rely on published scientific literature or the FDA's
prior approval of similar products. The NDA must also include significant information regarding the chemistry, manufacturing and controls for the product. The FDA may further inspect our manufacturing
facilities to ensure that the facilities can manufacture our product candidates and our products, if and when approved, in compliance with the applicable regulatory requirements, as well as inspect
our clinical trial sites to ensure that our studies are properly conducted. Obtaining approval of an NDA is a lengthy, expensive and uncertain process, and approval may not be obtained. Upon
submission, or resubmission, of an NDA, the FDA must make an initial determination that the application is sufficiently complete to accept the submission for filing. We cannot be certain that any
submissions will be accepted for filing and review by the FDA, or ultimately be approved. If the application is not accepted for review or approved, the FDA may require that we conduct additional
clinical or preclinical trials, or take other actions before it will reconsider our application. If the FDA requires additional studies or data, we would incur increased costs and delays in the
marketing approval process, which may require us to expend more resources than we have available. In addition, the FDA may not consider any additional information to be complete or sufficient to
support approval.
Regulatory
authorities outside of the United States, such as in Europe and Japan and in emerging markets, also have requirements for approval of drugs for commercial sale with which we
must comply prior to marketing in those areas. Regulatory requirements can vary widely from country to country and could delay or prevent the introduction of our product candidates. Clinical trials
conducted in one
country may not be accepted by regulatory authorities in other countries, and obtaining regulatory approval in one country does not mean that regulatory approval will be obtained in any other country.
However, the failure to obtain regulatory approval in one jurisdiction could have a negative impact on our ability to obtain approval in a different jurisdiction. Approval processes vary among
countries and can involve additional product candidate testing and validation and additional administrative review periods. Seeking foreign regulatory approval could require additional non-clinical
studies or clinical trials, which could be costly and time consuming. Foreign regulatory approval may include all of the risks associated with obtaining FDA approval. For all of these reasons, if we
seek foreign regulatory approval for Twirla or any of our other product candidates, we may not obtain such approvals on a timely basis, if at all.
The
process to develop, obtain regulatory approval for and commercialize product candidates is long, complex and costly both inside and outside of the United States, and approval is
never guaranteed. Even if our product candidates were to successfully obtain approval from regulatory authorities, any such approval might significantly limit the approved indications for use,
including more limited patient populations, require that precautions, contraindications or warnings be included on the
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product
labeling, including black box warnings, require expensive and time-consuming post-approval clinical studies, risk evaluation and mitigation strategies, or REMS, or surveillance as conditions
of approval, or, through the product label, the approval may limit the claims that we may make, which may impede the successful commercialization of our product candidates. For example, we believe
that Twirla, if approved, will have labeling consistent with all other marketed hormonal contraceptive products, which include class labeling that warns of risks of certain serious conditions,
including venous and arterial blood clots, such as heart attacks, thromboembolism and stroke, as well as liver tumors, gallbladder disease, and hypertension, and a boxed warning regarding risks of
smoking and CHC use, particularly in women over 35 years old who smoke. However, regulatory authorities may require the inclusion of additional statements about adverse events in the labeling,
including additional black box warnings or contraindications. Following any approval for commercial sale of our product candidates, certain changes to the product, such as changes in manufacturing
processes and additional labeling claims, as well as new safety information, will be subject to additional FDA notification, or review and approval. Also, regulatory approval for any of our product
candidates may be withdrawn. If we are unable to obtain regulatory approval for our product candidates in one or more jurisdictions, or any approval contains significant limitations, our ability to
market to our full target market will be reduced and our ability to realize the full market potential of our product candidates will be harmed. Furthermore, we may not be able to obtain sufficient
funding or generate sufficient revenue and cash flows to continue or complete the development of any of our current or future product candidates.
The reported results of the SECURE clinical trial are based on top-line data and may ultimately differ from
actual results once additional data are received and fully evaluated.
The reported results of the SECURE clinical trial that we have publicly disclosed, and that are discussed herein, consist of top-line data.
Top-line data are based on a preliminary analysis of currently available efficacy and safety data, and therefore the reported results, findings and conclusions related to the SECURE clinical trial are
subject to change following a comprehensive review of the more extensive data that we expect to receive related to the SECURE clinical trial. Top-line data are based on important assumptions,
estimations, calculations and information currently available to us, and we have not received or had an opportunity to fully and carefully evaluate all of the data related to the SECURE clinical
trial. As a result, the top-line results of the SECURE clinical trial that we have reported may differ from future results, or different conclusions or considerations may qualify such results, once
additional data have been received and fully evaluated. In addition, third parties, including regulatory agencies, may not accept or agree with our assumptions, estimations, calculations or analyses
or may interpret or weigh the importance of data differently, which could impact the potential for approval of Twirla, or if approved, the labeling and commercial value of Twirla and our business in
general. If the top-line data that we have reported related to the SECURE clinical trial differ from actual results, our ability to obtain approval for, and commercialize, our products may be harmed,
which could harm our business, financial condition, operating results or prospects.
The FDA may disagree with our interpretation of clinical results obtained from the SECURE clinical trial, our
results do not guarantee support for a resubmission of our NDA or for regulatory approval, and, even if the SECURE clinical trial data are deemed to be positive by the FDA, the FDA may disagree with
other aspects of the SECURE clinical trial and decline to approve Twirla for the proposed indication.
We have reported positive top-line data from the SECURE clinical trial. However, even if we believe that the data from the SECURE clinical trial
are positive, the FDA could determine that the data from the SECURE clinical trial were negative or inconclusive or could reach a different conclusion than we did on that same data. Negative or
inconclusive results of a clinical trial or difference of opinion could cause the FDA to decline to approve our application or require us to repeat the trial or conduct additional clinical trials
prior to obtaining approval for commercialization, and there is no guarantee that additional trials would achieve positive results to the satisfaction of the
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FDA
or that the FDA will agree with our interpretation of the results. Any such determination by the FDA would delay the timing of our commercialization plan for Twirla or prevent its further
development, or the further development of our other product candidates, and adversely affect our
business operations. Additionally, the FDA may provide review commentary at any time during the resubmission and review process which could delay the review timeline, adversely affect the review
process, or even prevent the approval of Twirla, any of which would adversely affect our business. We may not be able to appropriately remedy issues that the FDA may raise in its review of our
NDA resubmission, and we may not have sufficient time or financial resources to conduct future activities to remediate issues raised by the FDA.
There
is no guarantee that the data obtained from the SECURE clinical trial will be supportive of, or guarantee, an NDA resubmission, or result in our successfully obtaining FDA approval
of Twirla in a timely fashion and for a commercially viable indication, if at all. For example, the FDA could determine that the trial did not meet its objectives or the FDA could still have concerns
regarding the conduct of the SECURE clinical trial, including regarding discontinuance of subjects from the trial. At any future point in time, the FDA could require us to complete further clinical or
preclinical trials, or take other actions which could delay or preclude any NDA resubmission or approval of the NDA and would require us to obtain significant additional funding. There is no guarantee
such funding would be available to us on favorable terms, if at all, nor is there any guarantee that FDA would consider any additional information complete or sufficient to support approval. If the
Twirla NDA is resubmitted, the FDA may hold an advisory committee meeting to obtain committee input on the safety and efficacy of Twirla. Typically, advisory committees will provide responses to
specific questions asked by the FDA, including the committee's view on the approvability of the product candidate under review. Advisory committee decisions are not binding but an adverse decision at
the advisory committee may have a negative impact on the regulatory review of Twirla. Additionally, we may choose to engage in the dispute resolution process with the FDA if we do not receive
approval, which could extend the timeline for any potential approval.
Further,
if we are able to resubmit an NDA for Twirla with the clinical data from the SECURE clinical trial, there is no guarantee that such data will be deemed sufficient by the FDA.
While we designed the protocols for the SECURE clinical trial to address the issues raised in the CRL, there is no guarantee that the FDA will deem such protocols or results from the study sufficient
to address those issues when they are formally reviewed as a part of an NDA resubmission or to demonstrate safety and efficacy to the satisfaction of the FDA. The FDA has significant discretion in the
review process, and we cannot predict whether the FDA will agree with our conclusions regarding the results of the SECURE clinical trial, including whether our data are reliable and generalizable. For
example, the FDA may disagree with our calculations relating to the number of pregnancies occurring on study, or may view the SECURE data as insufficient to demonstrate a favorable benefit/risk
profile for approval for the proposed indication. In addition, based on top-line data, the Pearl Index for the overall intent to treat population of subjects 35 years of age and under was 4.80
with an upper-bound of the 95% confidence interval of 6.06, but in the obese subpopulation of subjects 35 years of age and under, the Pearl Index was 6.42 with an upper-bound of the 95%
confidence interval of 8.88. If we were to exclude the top-line data on the obese subpopulation, our Pearl Index for non-obese patients was 3.94 with an upper-bound of the 95% confidence interval of
5.35. The highest Pearl Index for a hormonal contraceptive product approved by the FDA to date was 3.19 and the highest upper-bound of the 95% confidence interval was 5.03. In the combined safety
database for our three Agile Phase 3 trials (n>3,000), there were 5 subjects with potentially study drug related DVTs or PEs, 4 of whom were obese
(BMI
³
30kg/m
2
). Although ultimate approvability of a hormonal contraceptive is based on a
risk/benefit assessment of the overall safety and efficacy profile of a product, not only a specific Pearl Index, the FDA could conclude that our Pearl Index for either the overall study population or
a subgroup of the study population or only the non-obese study population is too high to demonstrate efficacy and an adequate risk/benefit profile, and as such, the FDA could decline to approve Twirla
on
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this
or any other basis. Further, the FDA may not agree with our analysis of the relationship between BMI and efficacy for Twirla and the FDA may interpret our overall data differently than we do and
may decline to approve Twirla on this or any other basis.
Moreover,
even if we obtain approval of Twirla, any such approval might significantly limit the approved indications for use, including by limiting the approved label for use by more
limited patient populations than we propose, require that precautions, contraindications or warnings be included on the product labeling, including black box warnings, require expensive and
time-consuming post-approval clinical studies, risk evaluation and mitigation strategies, or REMS, or surveillance as conditions of approval, or, through the product label, the approval may limit the
claims that we may make, which may impede the successful commercialization of Twirla. For example, the FDA may deem the higher Pearl Index in the obese subpopulation when combined with safety findings
for this subpopulation to warrant a labeling limitation or warning for such subpopulation, which could limit the commercial potential of the product, if approved. Moreover, because we did not conduct
any head-to-head studies of Twirla against Ortho Evra, we will not be able to make direct comparative claims regarding the safety, efficacy or pharmacokinetics of Twirla and Ortho Evra or its generic
version, Xulane®.
Failure can occur at any stage of clinical development. If the clinical trials for Twirla or any of our
current or future product candidates are unsuccessful, we could be required to abandon development.
Clinical testing is expensive and can take many years to complete, and its outcome is inherently uncertain. A failure of one or more clinical
trials can occur at any stage of testing for a variety of reasons. The outcome of preclinical testing and early clinical trials may not be predictive of the outcome of later clinical trials, and
interim results of a clinical trial do not necessarily predict final results. In some instances, there can be significant variability in safety or efficacy results between different trials of the same
product candidate due to numerous factors, including changes in or adherence to trial protocols, differences in size and type of the subject populations and the rates of dropout among clinical trial
subjects. Our future clinical trial results therefore may not demonstrate safety and efficacy sufficient to obtain regulatory approval for our product candidates. For example, we received a CRL from
the FDA with respect to an NDA previously filed for Twirla, in which the FDA requested, among other items, additional Phase 3 clinical data to support the application. The SECURE
Phase 3 clinical trial was designed in consultation with the FDA and is different than the design of our previous clinical trials of Twirla and it is possible that there could be significant
variability in the safety and efficacy results of these trials. Additionally, while our SECURE Phase 3 clinical trial was designed and implemented in a manner to address the FDA's comments and
guidance, it is possible that the trial may not be successful or the FDA could conclude the data are not reliable or generalizable. A number of companies in the biopharmaceutical industry have
suffered significant
setbacks in advanced clinical trials due to lack of efficacy or adverse safety profiles, notwithstanding promising results in earlier trials. Our future clinical trials may not be successful.
Flaws
in the design of a clinical trial may not become apparent until the clinical trial is well-advanced. We have limited experience in designing contraceptive clinical trials and may
be unable to design and execute clinical trials to support regulatory approval of our product candidates. In addition, clinical trials often reveal that it is not practical or feasible to continue
development efforts for a product candidate.
We
may voluntarily suspend or terminate our clinical trials if at any time we believe that they present an unacceptable risk to subjects. Furthermore, regulatory agencies, Institutional
Review Boards, or IRBs, or data safety monitoring boards, if utilized in our clinical trials, may at any time order the temporary or permanent discontinuation of our clinical trials or request that we
cease using certain investigators in the clinical trials if such regulatory agencies or boards believe that the clinical trials are not being conducted in accordance with applicable regulatory
requirements or that they present an
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unacceptable
safety risk to subjects. Since our inception, we have not voluntarily or involuntarily suspended or terminated a clinical trial due to unacceptable safety risks to subjects.
If
the results of the clinical trials for our current product candidates or clinical trials for any future product candidates do not achieve the primary efficacy endpoints or demonstrate
unexpected safety issues, the prospects for approval of our product candidates will be materially adversely affected. For example, in the CRL that we received from the FDA in connection with the NDA
previously filed for Twirla, one of the FDA's comments was that acceptable evidence of efficacy was not demonstrated, as measured by Pearl Index, or PI. Specifically, in our completed Phase 3
trials, the PI was higher than that seen in registration trials for previously approved hormonal contraceptives. Experts seem to agree that inconsistent or incorrect use is a major contributor to the
increased PI seen in more recent contraceptive trials. The PI values from clinical trials are also affected by additional factors, including differences in study design, increased sensitivity of early
pregnancy tests, weight and body mass index, or BMI, of the study population and user experience. For example, consistent with other recent hormonal contraceptive clinical trials, including Ortho
Evra® and Quartette®, and the 2015 meta-analysis conducted by FDA authors on the effect of obesity on the effectiveness of hormonal contraceptives, a relationship between
obesity and efficacy was observed among subjects 35 years of age and under in our SECURE clinical trial. Moreover, preclinical and clinical data are often susceptible to varying
interpretations and analyses, and many companies that believed their product candidates performed satisfactorily in preclinical studies and clinical trials have failed to achieve similar results in
later clinical trials, including longer-term trials, or have failed to obtain regulatory approval of their product candidates. Many compounds that initially showed promise in clinical trials or
earlier preclinical studies have later been found to cause undesirable or unexpected adverse effects that have prevented further development of the compound. Our SECURE Phase 3
clinical trial for our primary product candidate, Twirla, may not produce successful results and the FDA may interpret the data from the SECURE trial differently than we do and may decline to approve
Twirla on this or any other basis.
In
addition to the circumstances noted above, we may experience numerous unforeseen events that could cause our clinical trials to be delayed, suspended or terminated, or which could
delay or prevent our ability to receive regulatory approval for or commercialize our product candidates, including:
-
-
Clinical trials of our product candidates may produce negative or inconclusive results, and we may decide, or regulators may require us, to
conduct additional clinical trials or implement a clinical hold;
-
-
The number of subjects required for clinical trials of our product candidates may be larger than we anticipate, enrollment in these clinical
trials may be slower than we anticipate or participants may drop out of these clinical trials at a higher rate than we anticipate. For instance, we experienced a high withdrawal rate in our
Phase 3 clinical trials for Twirla and we experienced slower than anticipated enrollment in our SECURE clinical trial;
-
-
Our third party contract research organization, or CRO, or study sites may fail to comply with regulatory requirements or the clinical trial
protocol, or meet their contractual obligations to us in a timely manner, or at all. For instance, investigator compliance with study procedures was an issue that we encountered in our two
Phase 3 clinical trials for Twirla completed prior to SECURE;
-
-
Regulators or IRBs may not authorize us or our investigators to commence a clinical trial or conduct a clinical trial at a prospective trial
site or amend a trial protocol;
-
-
We may have delays in reaching or fail to reach agreement on acceptable clinical trial contracts or clinical trial protocols with prospective
trial sites and our CRO;
-
-
We may have delays in adding new investigators or clinical trial sites, or we may experience a withdrawal of clinical trial sites;
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-
-
We may elect or be required to suspend or terminate clinical trials of our product candidates based on a finding that the subjects are being
exposed to health risks, or due to other reasons;
-
-
The cost of clinical trials for our product candidates may be greater than we anticipate;
-
-
The supply or quality of our product candidates or other materials necessary to conduct clinical trials of our product candidates may be
insufficient or inadequate;
-
-
There may be changes in government regulations or administrative actions;
-
-
Our product candidates may have undesirable adverse effects or other unexpected characteristics;
-
-
We may not be able to demonstrate that a product candidate's clinical and other benefits outweigh its safety risks;
-
-
We may not be able to demonstrate that a product candidate provides an advantage over current standards of care or future competitive therapies
in development; and
-
-
There may be changes in the approval policies or regulations that render our data insufficient for approval.
If
we elect or are required to suspend or terminate a clinical trial for any of our product candidates, or our product candidate development is otherwise delayed, our development costs
may increase, our commercial prospects will be adversely impacted, any periods during which we may have the exclusive right to commercialize our product candidates may be shortened and our ability to
generate product revenues may be delayed or eliminated.
In
December 2016, we completed our SECURE Phase 3 clinical trial for Twirla and, as we have previously announced, we expect to conduct additional clinical trials in the future for
our other product candidates subject to available funding. Subject enrollment for our future clinical trials, which is a significant factor in the timing of clinical trials, is affected by a variety
of factors, including the following:
-
-
Size and nature of the subject population;
-
-
Proximity of subjects to clinical sites and the number of sites;
-
-
Effectiveness of publicity created by clinical trial sites regarding the trial;
-
-
Eligibility and exclusion criteria for the trial;
-
-
Design of the clinical trial, including factors such as frequency of required assessments, length of the study and ongoing monitoring
requirements;
-
-
Competing clinical trials;
-
-
Clinician and subject perceptions as to the potential advantages or disadvantages of the product candidate being studied in relation to other
available therapies, including any products that may be approved for the indications we are investigating;
-
-
Subjects' ability to comply with the specific instructions related to the trial protocol, proper documentation and use of the drug product. For
instance, in our two Phase 3 clinical trials for Twirla completed prior to SECURE, there was a high rate of subject noncompliance;
-
-
Inability to obtain or maintain subject informed consents;
-
-
Risk that enrolled subjects will drop out before completion;
-
-
Subject's relationship with her partner; and
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-
-
Other events that may occur and are beyond our control.
Furthermore,
we plan to rely on a CRO and clinical trial sites to ensure the proper and timely conduct of our clinical trials, and while we may have agreements governing their committed
activities, we have limited influence over their actual performance. Additionally, the CRO and clinical trial sites may have business, regulatory, personnel or other issues that keep us from
satisfactorily completing our clinical trials. Any delays or unanticipated problems during clinical trials, such as additional monitoring of clinical trial sites, slower than anticipated enrollment in
our clinical trials or subjects dropping out of or being excluded from participation in our clinical trials at a higher rate than we anticipate, could increase our costs, slow down our product
development and approval process and harm our business. For example, we experienced a slower than expected rate of enrollment for our SECURE Phase 3 clinical trial of Twirla, which we
began enrolling in the fourth quarter of 2014, and, as a result, we completed the clinical trial in December 2016.
Regulatory approval may be substantially delayed or may not be obtained for one or all of our product
candidates if regulatory authorities require additional time or studies to assess the safety and efficacy of our product candidates.
We may be unable to initiate or complete development of our product candidates on schedule, if at all. The timing for the completion of the
studies for our product candidates other than Twirla will require funding beyond our existing cash and cash equivalents. In addition, if regulatory authorities require additional time or studies to
assess the safety or efficacy of Twirla, we may not have or be able to obtain adequate funding to complete the necessary steps for approval for any or all of our product candidates. Additional delays
may result if the FDA, an FDA Advisory Committee or other regulatory authority recommends non-approval or restrictions on approval. Studies required to demonstrate the safety and efficacy of our
product candidates are time consuming, expensive and together take several years or more to complete. In addition, approval policies,
regulations or the type and amount of clinical data necessary to gain approval may change during the course of a product candidate's clinical development and may vary among jurisdictions. We have not
obtained regulatory approval for any product candidate and it is possible that none of our existing product candidates or any product candidates we may seek to develop in the future will ever obtain
regulatory approval. Delays in regulatory approvals or rejections of applications for regulatory approval in the United States, Europe, Japan or other markets may result from many factors,
including:
-
-
Our inability to obtain sufficient funds required for a clinical trial;
-
-
Regulatory requests for additional analyses, reports, data, non-clinical and preclinical studies and clinical trials;
-
-
Regulatory questions regarding interpretations of data and results and the emergence of new information regarding our product candidates or
other products;
-
-
Clinical holds, other regulatory objections to commencing or continuing a clinical trial or the inability to obtain regulatory approval to
commence a clinical trial in countries that require such approvals;
-
-
Failure to reach agreement with the FDA or non-U.S. regulators regarding the scope or design of our clinical trials;
-
-
Our inability to enroll or retain a sufficient number of subjects who meet the inclusion and exclusion criteria in our clinical trials;
-
-
Our inability to conduct our clinical trials in accordance with regulatory requirements or our clinical trial protocols;
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-
-
Unfavorable or inconclusive results of clinical trials and supportive non-clinical studies, including unfavorable results regarding safety or
efficacy of our product candidates during clinical trials;
-
-
Failure to meet the level of statistical significance required for approval;
-
-
Any determination that a clinical trial presents unacceptable health risks to subjects;
-
-
Lack of adequate funding to commence or continue our clinical trials due to unforeseen costs or other business decisions;
-
-
Our inability to reach agreements on acceptable terms with prospective CROs and trial sites, the terms of which can be subject to extensive
negotiation and may vary significantly among different CROs and trial sites;
-
-
Our inability to identify and maintain a sufficient number of sites, many of which may already be engaged in other clinical trial programs,
including other clinical trials for the same indications targeted by our product candidates;
-
-
Our inability to obtain approval from IRBs to conduct clinical trials at their respective sites;
-
-
Our inability to timely obtain from our third party manufacturer sufficient quantities or quality of the product candidate or other materials
required for a clinical trial;
-
-
Our inability to adequately address the FDA's request in the CRL for additional information on controls and release specifications related to
Twirla, and manufacturing and control information related to the Drug Master File of one of the raw materials in Twirla, and validate our commercial manufacturing process;
-
-
We may be unable to obtain approval for the manufacturing processes or facilities of the third party manufacturer with whom we contract for
clinical and commercial supplies;
-
-
We may be unable to obtain agreement from the FDA on product labeling;
-
-
We may have insufficient funds to pay the significant user fees required by the FDA upon the filing of any future NDAs; and
-
-
We may have difficulty in maintaining contact with subjects, resulting in incomplete data.
In
December 2016, we completed our Phase 3 SECURE clinical trial and announced top line data in early January 2017. We plan to resubmit our NDA for Twirla in the first half of
2017. The FDA's review of our NDA is subject to all the risks described above in addition to, among other things, the FDA's assessment of our specific response to the 2013 CRL and the efficacy and
safety of Twirla as demonstrated in the final SECURE clinical trial results. The lengthy and unpredictable approval process, as well as the unpredictability of future clinical trial results, may
result in our failure to obtain regulatory approval to market Twirla or any of our other product candidates, which would significantly harm our business, results of operations and prospects.
Changes in regulatory requirements and guidance may also occur and we may need to amend clinical trial
protocols submitted to applicable regulatory authorities or conduct additional studies to reflect these changes. Amendments and additional studies may require us to resubmit clinical trial protocols
to Institutional Review Boards and regulatory authorities for re-examination, which may impact the costs, timing or successful completion of a clinical trial.
If we are required to conduct additional clinical trials or other studies with respect to any of our product candidates beyond those that we
contemplated, if we are unable to successfully complete our clinical trials or other studies or if the results of these studies are not positive or are only modestly positive, we may be delayed in
obtaining regulatory approval for our product candidates, we may not be able to obtain regulatory approval at all or we may obtain approval for indications that are not as
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broad
as intended. For example, the FDA issued a CRL in response to our NDA for Twirla requesting, among other items, an additional Phase 3 clinical study, which has delayed our ability to
obtain regulatory approval for that product candidate. We may also experience delays due to changes in regulatory requirements and guidance, which may require protocol amendments or the conduct of
additional studies. These amendments and additional studies may require regulatory or IRB approval. The approval and conduct of these studies may delay, limit or preclude regulatory approval for our
product candidates. Our product development costs will also increase if we experience delays in testing or approvals and we may not have sufficient funding to complete the testing and approval process
for any of our product candidates. Significant clinical trial delays could allow our competitors to bring products to market before we do and impair our ability to commercialize our products if and
when approved. If any of this occurs, our business will be materially harmed.
Our product candidates may have undesirable adverse effects, which may delay or prevent regulatory approval
or, if approval is received, require our products to be taken off the market, require them to include safety warnings or otherwise limit their sales.
Unforeseen adverse effects from any of our product candidates could arise either during clinical development or, if approved, after the approved
product has been marketed. In the combined safety population of our previously completed Phase 3 trials, there were a total of 22 serious adverse events, or SAEs, of which 16 occurred in the
Twirla cohort, which had approximately 2.3 times as many subjects as the oral contraceptive comparator cohort. Three of the 16 SAEs in the Twirla cohort (0.2% of the overall Twirla safety population)
were considered to be possibly related to Twirla, and included one drug overdose with Benadryl, one case of uncontrollable nausea and vomiting and one instance of deep vein thrombosis, or DVT. In
addition to the SAEs described above, some subjects taking Twirla experienced non-serious adverse events, such as nausea, headache, application site irritation and breast tenderness. Subjects
receiving the oral contraceptive comparator also experienced non-serious adverse events such as nausea, headache and breast tenderness, though at different rates. In the SECURE clinical trial, SAEs
were observed in 2.0% of the SECURE trial population, and 0.6% of subjects had SAEs that were considered potentially study drug related, including DVT, pulmonary embolism, or PE, gallbladder disease,
ectopic pregnancy, and depression. In the combined safety database for the three Agile Phase 3 trials (n >3,000), there were 5 subjects with potentially study drug related DVTs or PEs, 4 of
whom were obese (BMI >30kg/m
2
).
Any
undesirable adverse effects that may be caused by our product candidates could interrupt, delay or halt clinical trials and could result in more restrictive labeling or the denial of
regulatory approval by the FDA or other regulatory authorities for any or all targeted indications, and in turn prevent us from commercializing our product candidates and generating revenues from
their sale. For instance, FDA may determine that for specific subgroups of patients. Twirla has lower efficacy and presents a higher risk. Accordingly, FDA may not approve our Twirla NDA or may
require labeling restrictions. By example, FDA may require labeling restrictions on the use of Twirla for patients in certain BMI categories. Adverse effects could also impact subject recruitment or
the ability or willingness of
enrolled subjects to complete the trial, or result in product liability claims. Any of these occurrences may harm our business, financial condition and prospects significantly.
In
addition, if any of our product candidates receive regulatory approval and we or others later identify undesirable adverse effects caused by the product, we could face one or more of
the following consequences:
-
-
We may suspend marketing of, withdraw or recall the product;
-
-
Regulatory authorities may require the addition of labeling statements, such as a black box warning or a contraindication, or other labeling
changes;
-
-
Regulatory authorities may withdraw their approval of the product;
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-
-
Regulatory authorities may seize or detain the product or seek an injunction against its manufacture or distribution;
-
-
The FDA or other regulatory authorities may issue safety alerts, Dear Healthcare Provider letters, press releases or other communications
containing warnings or other safety information about the product;
-
-
The FDA may require the establishment or modification of a REMS or a comparable foreign authority may require the establishment or modification
of a similar strategy that may, for instance, require us to issue a medication guide outlining the risks of such adverse effects for distribution to patients, or restrict distribution of the product,
if and when approved, and impose burdensome implementation requirements on us;
-
-
We may be required to conduct additional trials;
-
-
We may be required to change the way that the product is administered;
-
-
We may be subject to litigation or product liability claims, fines, injunctions or criminal penalties;
-
-
Regulatory authorities may impose additional restrictions on marketing and distribution of the product; and
-
-
Our reputation may suffer.
Any
of these events could prevent us from achieving or maintaining market acceptance of the affected product or could substantially increase the costs and expenses of commercializing
such product, which in turn could delay or prevent us from generating significant revenues from its sale.
Our development and commercialization strategy for Twirla depends, in part, on published scientific
literature and the FDA's prior findings regarding the safety and efficacy of approved products containing Ethinyl Estradiol and Levonorgestrel based on data not developed by us, but upon which the FDA
may rely in reviewing our NDA.
The Hatch-Waxman Act added Section 505(b)(2) to the Federal Food, Drug and Cosmetic Act, or FDCA, Section 505(b)(2) permits the
filing of an NDA where at least some of the information required for approval comes from investigations that were not conducted by or for the applicant and for which the applicant has not obtained a
right of reference or use from the person by or for whom the investigations were conducted. The FDA interprets Section 505(b)(2) of the FDCA, for purposes of approving an NDA, to permit the
applicant to rely, in part, upon published literature or the FDA's previous findings of safety and efficacy for an approved product. The FDA may also require companies to perform additional clinical
trials or measurements to support any deviation from the previously approved product. The FDA may then approve the new product candidate for all or some of the label indications for which the
referenced product has been approved, as well as for any new indication sought by the Section 505(b)(2) applicant. The label, however, may require all or some of the limitations,
contraindications, warnings or precautions included in the reference product's label, including a black box warning, or may require additional limitations, contraindications, warnings or precautions.
We have submitted an NDA for Twirla under Section 505(b)(2) and as such the NDA relied, in part, on the FDA's previous findings of safety and efficacy from investigations for approved products
containing ethinyl estradiol, or EE, and levonorgestrel, or LNG and published scientific literature for which we have not received a right of reference. We received a CRL in response to our
Section 505(b)(2) NDA for Twirla, in which the FDA requested, among other things, that we conduct an additional Phase 3 clinical trial. Even though we may be able to take advantage of
Section 505(b)(2) to support potential U.S. approval for Twirla, the FDA may require us to perform additional clinical trials or measurements to support approval over and above the clinical
trials that we have already
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completed.
In addition, notwithstanding the approval of many products by the FDA pursuant to Section 505(b)(2), over the last few years some pharmaceutical companies and others have objected to
the FDA's interpretation of Section 505(b)(2). If the FDA changes its interpretation of Section 505(b)(2), or if the FDA's interpretation is successfully challenged in court, this could
delay or even prevent the FDA from approving any Section 505(b)(2) NDAs that we submit. Such a result could require us to conduct additional testing and costly clinical trials, which could
substantially delay or prevent the approval and launch of our product candidates, including Twirla.
Risks Related to Our Financial Position and Need for Capital
We have never been profitable. Currently, we have no products approved for commercial sale, no source of
revenue and we may never become profitable.
We have never been profitable and do not expect to be profitable in the foreseeable future. We have no products approved for commercial sale and
to date have not generated any revenue from product sales. Our ability to generate revenue and become profitable depends upon our ability to successfully complete the development of and obtain the
necessary regulatory approvals for our product candidates. We have been engaged in developing Twirla and our Skinfusion® technology since our inception. To date, we have not generated any
revenue from Twirla, and we may never be able to obtain regulatory approval for the marketing of Twirla. Further, even if we are able to gain approval for and commercialize Twirla or any other product
candidate, there can be no assurance that we will generate significant revenues or ever achieve profitability. Our ability to generate product revenue depends on a number of factors, including our
ability to:
-
-
Successfully complete clinical development of, and receive regulatory approval for, our product candidates;
-
-
Obtain additional capital for the commercial launch of Twirla, if approved, as well as advancing the development or our other product
candidates;
-
-
Set an acceptable price for our products, if approved, and obtain adequate coverage and reimbursement from third party payors;
-
-
Obtain commercial quantities of our products, if approved, at acceptable cost levels; and
-
-
Successfully market and sell our products, if approved, in the United States and abroad.
In
addition, because of the numerous risks and uncertainties associated with product candidate development, we are unable to predict the timing or amount of increased expenses, or when,
or if, we will be able to achieve or maintain profitability. In addition, our expenses could increase beyond our current expectations if we are required by the FDA or other regulatory authorities to
perform studies in addition to those that we currently anticipate. Even if our product candidates are approved for commercial sale, we anticipate incurring significant costs associated with the
commercial launch of these products.
Our
ability to become and remain profitable depends on our ability to generate revenue. Even if we are able to generate revenues from the sale of our products, if approved, we may not
become profitable and may need to obtain additional funding to continue operations. If we fail to become profitable or obtain additional funding, or are unable to sustain profitability on a continuing
basis, then we may be unable to continue our operations at planned levels and be forced to reduce our operations. Even if we do achieve profitability, we may not be able to sustain or increase
profitability on a quarterly or annual basis. Our failure to become and remain profitable would decrease the value of our company and could impair our ability to raise capital, expand our business or
continue our operations. A decline in the value of our company could also cause you to lose all or part of your investment.
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We have incurred operating losses in each year since our inception and expect to continue to incur
substantial losses for the foreseeable future.
We have incurred losses in each year since our inception in December 1997. Our net loss was $ 28.7 million, $30.3 million
and $16.1 million for the years ended December 31, 2016, 2015 and 2014, respectively. As of December 31, 2016, we had an accumulated deficit of $193.5 million.
Specialty
pharmaceutical product development is a speculative undertaking, involves a substantial degree of risk and is a capital-intensive business. We expect to incur expenses without
corresponding revenues until we are able to obtain regulatory approval and subsequently sell Twirla in significant quantities, which may not happen. We have devoted most of our financial resources to
research and development, including our non-clinical development activities and clinical trials. We expect to incur increased expenses as we complete the development of Twirla, respond to the CRL and
supplement our NDA with the results of the SECURE trial, complete the qualification and validation of our commercial manufacturing process, initiate pre-launch commercial activities, commercially
launch Twirla, advance our other product candidates and expand our research and development programs. Substantially all of our resources are currently dedicated to developing and seeking regulatory
approval for Twirla. We will require additional capital for the commercial launch of Twirla, if approved, as well as advancing the development of our other product candidates. To date, we have
financed our operations primarily through sales of common stock, convertible preferred stock and convertible promissory notes and to a lesser extent, through term loans and government grants. Our
product candidates will require the completion of regulatory review, significant marketing efforts and substantial investment before they can provide us with any revenue.
Assuming
we obtain FDA approval, we expect that our expenses will increase as we prepare for the commercial launch of Twirla. As a result, we expect to continue to incur substantial
losses for the foreseeable future, and these losses may increase. We are uncertain when or if we will be able to achieve or sustain profitability. If we achieve profitability in the future, we may not
be able to sustain profitability in subsequent periods. Failure to become and remain profitable would impair our ability to sustain operations and adversely affect the price of our common stock and
our ability to raise capital.
If we fail to obtain the capital necessary to fund our operations, we may be unable to obtain regulatory
approval of or commercialize Twirla in the United States and we could be forced to share our rights to commercialize Twirla with third parties on terms that may not be favorable to us.
We need large amounts of capital to support our development and commercialization efforts for Twirla. If we are unable to secure sufficient
capital to fund our operations, we will not be able to continue these efforts and we might have to enter into strategic collaborations that could require us to share commercial rights to Twirla with
third parties in ways that we currently do not intend or on terms that may not be favorable to us. Our cash and cash equivalents were $48.8 million as of December 31, 2016. Based on our
current business plan, we believe that our cash and cash equivalents as of December 31, 2016 will be sufficient to meet our operating requirements into the second quarter of 2018. Our current
business plan assumes resubmission of the NDA for Twirla in the first half of 2017, a six month FDA review of our resubmission, initiation of pre-commercial activities and initiation of validation of
our commercial manufacturing process in coordination with the commercialization of Twirla. In the event of unforeseen changes to our planned timelines, we have the ability to postpone certain
commercial and validation spending in order to continue the funding of our operations into the second quarter of 2018. We anticipate requiring additional capital to fund operating needs thereafter,
including among other items, the commercial launch for Twirla and advancing the development of our other product candidates. We may also need to raise additional funds sooner if we choose to expand
more rapidly than we presently anticipate or we encounter any unforeseen events that affect our current business plan. Adequate additional funding
may not be available to us on acceptable terms, or at all. If we are unable to raise capital when needed or on attractive terms and not enter into strategic
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collaborations,
we would be forced to delay, reduce or eliminate our research and development programs or future commercialization efforts.
Our operating activities may be restricted as a result of covenants related to the outstanding indebtedness
under our loan agreement and we may be required to repay the outstanding indebtedness in an event of default, which could have a materially adverse effect on our business.
In February 2015, we entered into a loan and security agreement, referred to herein as the Hercules Loan Agreement, with Hercules
Capital, Inc., or Hercules, for a term loan of up to $25.0 million. The Hercules Loan Agreement was amended effective August 25, 2016. A first tranche of $16.5 million was
funded upon execution of the Hercules Loan Agreement, approximately $15.5 million of which was used to repay our term loan with Oxford. Under terms of the Hercules Loan Agreement, we may, but
are not obligated to, draw an additional tranche of up to $8.5 million through March 31, 2017, subject to the achievement of certain clinical milestones. We are currently in discussions
with Hercules to extend the period during which the additional tranche of $8.5 million may be drawn. We can make no assurances that our discussions will ultimately be successful and, if such
discussions result in an extension of the period in which we may draw the additional tranche of $8.5 million, we could incur additional fees payable to Hercules.
The
Hercules Loan Agreement subjects us to various customary covenants, including requirements as to financial reporting and insurance, and restrictions on our ability to dispose of our
business or property, change our line of business, liquidate or dissolve, enter into any change in control transaction, merge or consolidate with any other entity or acquire all or substantially all
the capital stock or property of another entity, incur additional indebtedness, incur certain types of liens on our property, including our intellectual property, pay any dividends or other
distributions on our capital stock other than dividends payable solely in capital stock or redeem our capital stock. Our business may be adversely affected by these restrictions on our ability to
operate our business.
The
Hercules Loan Agreement is secured by substantially all of our property other than our intellectual property. As a result of the amendment to the Hercules Loan Agreement, we are
currently required to make interest-only payments through January 2017. On February 1, 2017, we began making principal payments with respect to the Hercules Loan. The Hercules Loan Agreement
currently bears interest at rate of 9.0% per annum and matures on December 1, 2018.
Additionally,
we may be required to repay the outstanding indebtedness under the term loan if an event of default occurs under the Hercules Loan Agreement. Under the Hercules Loan
Agreement, an event of default will occur if, among other things, we fail to make payments under the Hercules Loan Agreement we breach any of our covenants under the Hercules Loan Agreement, subject
to specified cure periods with respect to certain breaches; Hercules determines in good faith that we are unable to satisfy our obligations under the Hercules Loan Agreement as they become due and
that our principal investors do not intend to fund amounts necessary to satisfy such obligations; we or our assets become subject to certain legal proceedings, such as bankruptcy proceedings; we are
unable to pay our debts as they become due; or we default on contracts with third parties which would permit Hercules to accelerate the maturity of such indebtedness or that could have a material
adverse effect on us. We may not have enough available cash or be able to raise additional funds through equity or debt financings to repay such indebtedness at the time any such event of default
occurs. In that case, we may be required to delay, limit, reduce or terminate our product candidate development or commercialization efforts or grant to others rights to develop and market product
candidates that we would otherwise prefer to develop and market ourselves. Hercules could also exercise its rights as collateral agent to take possession and dispose of the collateral securing the
loan for its benefit, which collateral includes all of our property other than our intellectual property. Our business, financial condition and results of operations could be materially adversely
affected as a result of any of these events.
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We will need to obtain additional financing to fund our operations and, if we are unable to obtain such
financing, we may be unable to complete the development and commercialization of our product candidates.
Our operations have consumed substantial amounts of cash since inception. From our inception to December 31, 2016, we have cumulative net
cash flows used by operating activities of $170.1 million. We will need to obtain additional financing to fund our future operations, including completing the development and commercialization
of our product candidates. We will need to obtain additional financing to conduct additional trials for the approval of our product candidates if requested by regulatory authorities, and to complete
the development of any additional product candidates we might acquire. Moreover, our fixed expenses such as rent, interest expense and other contractual commitments are substantial and are expected to
increase in the future.
Our
future funding requirements will depend on many factors, including, but not limited to:
-
-
Time and cost necessary to obtain regulatory approvals that may be required by regulatory authorities;
-
-
Our ability to successfully commercialize our product candidates, if approved;
-
-
Our ability to have commercial product successfully manufactured consistent with FDA regulations;
-
-
Amount of sales and other revenues from product candidates that we may commercialize, if any, including the selling prices for such potential
products and the availability of adequate third-party coverage and reimbursement;
-
-
Sales and marketing costs associated with commercializing our products, if approved, including the cost and timing of expanding our marketing
and sales capabilities;
-
-
Progress, timing, scope and costs of our clinical trials, including the ability to timely enroll subjects in our ongoing, planned and potential
future clinical trials;
-
-
Terms and timing of any potential future collaborations, licensing or other arrangements that we may establish;
-
-
Cash requirements of any future acquisitions or the development of other product candidates;
-
-
Costs of operating as a public company;
-
-
Time and cost necessary to respond to technological and market developments;
-
-
Costs of filing, prosecuting, defending and enforcing any patent claims and other intellectual property rights; and
-
-
Costs associated with any potential business or product acquisitions, strategic collaborations, licensing agreements or other arrangements that
we may establish.
Until
we can generate a sufficient amount of revenue, we may finance future cash needs through public or private equity offerings, license agreements, debt financings, collaborations,
strategic alliances and marketing or distribution arrangements. Additional funds may not be available when we need them on terms that are acceptable to us, or at all. If adequate funds are not
available, we may be required to delay or reduce the scope of or eliminate one or more of our research or development programs or our commercialization efforts. We may seek to access the public or
private capital markets whenever conditions are favorable, even if we do not have an immediate need for additional capital at that time. In addition, if we raise additional funds through
collaborations, strategic alliances or marketing, distribution or licensing arrangements with third parties, we may have to relinquish valuable rights to our technologies, future revenue streams or
product candidates or to grant licenses on terms that may not be favorable to us.
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Based
on our current business plan, we believe that our cash and cash equivalents as of December 31, 2016 will be sufficient to meet our operating requirements into the second
quarter of 2018. Our current business plan assumes resubmission of the NDA for Twirla in the first half of 2017, a six month FDA review of our resubmission and successful completion of validation of
its commercial manufacturing process in coordination with the commercialization of Twirla. We expect that these funds will not be sufficient to enable us to complete all necessary development of our
product candidates other than Twirla, or commercially launch Twirla or our other current product candidates. Accordingly, we will be required to obtain further funding through other public or private
offerings, debt financing, collaboration or licensing arrangements or other sources. Adequate additional funding may not be available to us on acceptable terms, or at all. If we are unable to raise
capital when needed or on attractive terms, we would be forced to delay, reduce or eliminate our research and development programs or future commercialization efforts. Our forecast of the period of
time through which our financial resources will be adequate to support our operating requirements is a forward- looking statement and involves risks and uncertainties, and actual results could vary as
a result of a number of factors, including the factors discussed elsewhere in this "Risk Factors" section. We have based this estimate on a number of assumptions that may prove to be wrong, and
changing circumstances beyond our control may cause us to consume capital more rapidly than we currently anticipate. Our inability to obtain additional funding when we need it could seriously harm our
business.
Raising additional capital may cause dilution to our existing stockholders or restrict our operations.
We may seek additional capital through a combination of private and public equity offerings, debt financings and strategic collaborations. The
sale of additional equity or convertible debt securities could result in the issuance of additional shares of our capital stock and could result in dilution to our stockholders. The incurrence of
indebtedness would result in increased fixed payment obligations and could also result in certain restrictive covenants, such as limitations on our ability to incur additional debt, limitations on our
ability to acquire or license intellectual property rights and other operating restrictions that could adversely impact our ability to conduct our business. We cannot guarantee that future financing
will be available in sufficient amounts or on terms acceptable to us, if at all. If we are unable to raise additional capital in sufficient amounts or on terms acceptable to us, we will be prevented
from pursuing research and development efforts. This could harm our business, operating results and financial condition and cause the price of our common stock to fall.
We are a development stage company which may make it difficult for you to evaluate the success of our
business to date and to assess our future viability.
We are a development stage company. We were incorporated and commenced active operations in 1997. Our operations to date have been limited to
organizing and staffing our company, business planning, raising capital and developing our product candidates. We have not yet demonstrated our ability to successfully complete a Phase 3
registration trial for, obtain regulatory approval of, or manufacture on a commercial scale any of our product candidates, or arrange for a
third party to do so on our behalf, or conduct sales and marketing activities necessary for successful product commercialization. Consequently, any predictions about our future success or viability
may not be as accurate as they could be if we had a longer operating history.
In
addition, as a development stage company, we may encounter unforeseen expenses, difficulties, complications, delays and other known and unknown factors. We will need to transition
from a company with a focus on product candidate development to a company capable of supporting commercial activities. We may not be successful in such a transition.
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Risks Relating to the Commercialization of Our Product Candidates
We are substantially dependent on the commercial success of Twirla.
Assuming FDA approval, Twirla will be the first product that we commercialize. The rest of our pipeline of products are in earlier stages of
clinical development and will require additional clinical and product development and funding in order to advance towards commercialization, which could take considerable time. If Twirla is not
approved, our ability to advance our pipeline would be significantly adversely affected. In addition, we will require additional capital for the commercial launch of Twirla. Our ability to generate
revenues and become profitable will depend in large part on the commercial success of Twirla. Potential prescribers of Twirla include physicians, nurse practitioners (NPs), physician's assistants
(PAs) and pharmacists. Registered Pharmacists (RPh) are authorized to prescribe contraceptives in some states currently, and others have pending legislation that would allow pharmacists to prescribe
contraceptives. If Twirla or any other product that we commercialize in the future does not gain an adequate level of acceptance among prescribers, patients and third parties, we may not generate
significant product revenues or become profitable. Market acceptance of Twirla, and any other product that we commercialize, by prescribers, patients and third party payors will depend on a number of
factors, some of which are beyond our control, including:
-
-
Efficacy, safety and other potential advantages of our product candidates in relation to alternative treatments;
-
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Relative convenience and ease of administration of our product candidates;
-
-
Availability of adequate coverage or reimbursement of our product candidates by third parties, such as insurance companies and other payors,
and by government healthcare programs, including Medicare, Medicaid and state health insurance exchanges;
-
-
Prevalence and severity of adverse events associated with our product candidates;
-
-
Cost of our product candidates in relation to alternative treatments, including generic products;
-
-
Extent and strength of our third-party manufacturer and supplier support;
-
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Extent and strength of our marketing and distribution support;
-
-
Limitations or warnings contained in our product's FDA approved labeling; and
-
-
Distribution and use restrictions imposed by the FDA or to which we agree as part of a mandatory REMS or voluntary risk management plan.
For
example, if Twirla is approved by the FDA, prescribers and patients may not be immediately receptive to a transdermal contraceptive system, as opposed to a pill or any other method,
and may be slow to adopt it as an accepted treatment for the prevention of pregnancy. In addition, even though we believe Twirla has significant advantages over other treatment options, because no
head-to-head trials comparing Twirla to the competing approved patch product have been conducted, the prescribing information approved by the FDA may not contain claims that Twirla is safer or more
effective than the currently approved patch product, or other claims that may be necessary for successful marketing of Twirla. Accordingly, we will not be permitted to promote Twirla, if approved, for
any comparative advantages to the currently marketed contraceptive patch. The availability of numerous inexpensive generic forms of contraceptive products may also limit acceptance of Twirla among
prescribers, patients and third party payors. If Twirla does not achieve an adequate level of acceptance among prescribers, patients and third party payors, we may not generate significant product
revenues or become profitable.
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It will be difficult for us to profitably sell Twirla, if approved, or any other product that we obtain
marketing approval for in the future if coverage and reimbursement for such product is limited.
Market acceptance and sales of Twirla, if approved, or any other product that we obtain marketing approval for in the future, will depend on
coverage and reimbursement policies and may be affected by future healthcare reform measures. Government authorities and third party payors, such as private health insurers and health maintenance
organizations, decide which medications they will pay for and establish reimbursement levels for approved medications. A primary trend in the U.S. healthcare industry is cost containment. Government
authorities and these third party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular medications. We cannot be sure that coverage or
reimbursement will be available for Twirla, if approved, or any other product that we obtain marketing approval for in the future and, if coverage is available, we cannot be sure of the level of
reimbursement. Reimbursement may impact the demand for, or the price of, Twirla, if approved, and any other products that we obtain marketing approval for and commercialize. Numerous generic products
may be available at lower prices than branded therapy
products, such as Twirla, which may also reduce the likelihood and level of reimbursement for Twirla or other products. If coverage and reimbursement are not available or are available only at limited
levels, we may not be able to successfully commercialize Twirla, if approved, or any other product for which we obtain marketing approval.
If we are unable to establish effective marketing and sales capabilities for Twirla, if approved, or enter
into agreements with third parties to market and sell Twirla, we may be unable to generate product revenues.
We are seeking approval for Twirla from the FDA for a contraception indication. Following our original submission of the NDA, we received a CRL
from the FDA requesting, among other things, additional Phase 3 data. Our ability to commercialize Twirla, and the timing of Twirla commercialization, is dependent on FDA's review of our data
from the SECURE trial and our NDA for Twirla, and other items such as timely and successful completion of validation of equipment for commercial manufacturing, ultimate FDA approval, and additional
capital. In our current business plan, we have assumed resubmission of our NDA for Twirla to the FDA in the first half of 2017, a six-month FDA review of our resubmission and completion of validation
of our commercial manufacturing process in coordination with our commercialization of Twirla. We cannot assure you that the FDA will approve Twirla or that the FDA's timeline for review will be within
six months.
At
present, we have no sales personnel and a limited number of marketing personnel. Depending on our available capital resources, we do not intend to begin to hire additional marketing
personnel until shortly prior to the final submission to our NDA or establish our own sales force or engage a contract sales organization in the United States until shortly prior to FDA approval of
Twirla. At the time of our anticipated commercial launch of Twirla, assuming regulatory approval by the FDA, our sales and marketing team will have worked together for only a limited period of time.
If our regulatory review period by the FDA is extended beyond six months, we may need to postpone initiating certain commercial activities in order to preserve cash, in which case our ability to
launch Twirla would be compromised. We cannot guarantee that we will be successful in marketing Twirla in the United States.
We
may not be able to establish our own sales force or a contract sales force in a cost-effective manner or realize a positive return on this investment. In addition, we will have to
compete with other pharmaceutical and biotechnology companies to recruit, hire, train and retain sales and marketing personnel. Factors that may inhibit our efforts to commercialize Twirla, if
approved, in the United States without strategic partners or licensees include:
-
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Our ability to obtain additional capital;
-
-
Our inability to timely recruit and retain adequate numbers of effective sales and marketing personnel;
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-
-
The inability of sales personnel to obtain access to or persuade adequate numbers of prescribers to prescribe Twirla;
-
-
The lack of complementary products to be offered by sales personnel, which may put us at a competitive disadvantage relative to companies with
more extensive product lines;
-
-
The costs associated with training sales and marketing personnel on legal and regulatory compliance matters and monitoring their actions;
-
-
Liability for sales or marketing personnel who fail to comply with the applicable legal and regulatory requirements; and
-
-
Unforeseen costs and expenses associated with creating an independent sales and marketing organization or engaging a contract sales
organization.
If
we are not successful in recruiting sales and marketing personnel or in building a sales and marketing infrastructure, or if we do not successfully enter into appropriate
collaboration arrangements, we will have difficulty commercializing Twirla, which would adversely affect our business, operating results and financial condition.
If
we intend to commercialize Twirla outside the United States, we will likely enter into collaboration agreements with pharmaceutical partners, and we may have limited or no control
over the sales, marketing and distribution activities of these third parties. Our future revenues may depend on the success of the efforts of these third parties.
To
the extent that we rely on, or partner with, third parties to commercialize Twirla, if approved, or any other product candidate for which we obtain marketing approval in the future,
we may receive less revenue than if we commercialized these products ourselves. In addition, we would have less control over the sales efforts of any other third parties involved in our
commercialization efforts. We, however, will remain responsible for the conduct of any contract sales force, which could expose us to legal and regulatory enforcement actions and liability. In the
event that we are unable to partner with a third party marketing and sales organization, our ability to generate product revenues may be limited in the United States, internationally or both.
A variety of risks associated with potential international business relationships could materially adversely
affect our business.
We may enter into agreements with third parties for the development and commercialization of Twirla and possibly other product candidates in
international markets. If we do so, we would be subject to additional risks related to entering into international business relationships, including:
-
-
Differing regulatory requirements in foreign countries including, among others, requirements relating to drug approvals, reimbursement and
sales and marketing practices;
-
-
Potentially reduced protection for intellectual property rights;
-
-
The potential for so-called parallel importing, which is when a local seller, faced with higher local prices, opts to import goods from a
foreign market with lower prices, rather than buying them locally;
-
-
Unexpected changes in tariffs, trade barriers and regulatory requirements;
-
-
Economic weakness, including inflation, or political instability in foreign economies and markets;
-
-
Compliance with tax, employment, immigration and labor laws for employees traveling and working abroad;
-
-
Foreign taxes;
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-
-
Foreign currency fluctuations, which could result in increased operating expenses and reduced revenues, and other risks incident to doing
business in another country;
-
-
Workforce uncertainty in countries where labor unrest is more common than in the United States;
-
-
Production shortages resulting from any events affecting raw material supply or manufacturing capabilities abroad; and
-
-
Business interruptions resulting from geo-political actions, including war and terrorism, or natural disasters, including earthquakes,
volcanoes, typhoons, floods, tsunamis, hurricanes and fires.
These
and other risks may materially adversely affect our ability to develop and commercialize products in international markets and may harm our business.
Even if we receive regulatory approval for Twirla, we still may not be able to successfully commercialize it
and the revenue that we generate from its sales, if any, may be limited.
The commercial success of Twirla in any indication for which we obtain marketing approval from the FDA or other regulatory authorities will
depend upon the contraceptive market landscape as well as acceptance and uptake of Twirla by prescribers, patients and third-party payors.
Risks
related to the contraceptive market landscape include:
-
-
The prescription contraceptive market could experience a decrease in growth or negative growth if fewer women choose to use hormonal
contraception;
-
-
The perceived safety of hormonal contraceptives could be negatively affected by media reports of adverse effects and advertisements for class
action lawsuits due to adverse effects;
-
-
Price pressures from third party payors, including managed care organizations and government-sponsored health systems, could limit our revenue;
-
-
The proportion of the contraceptive market comprised of generic products continues to increase, making introduction of a branded contraceptive
difficult and expensive;
-
-
Competition in the contraceptive market could increase, with the introduction of new contraceptives, including the potential of a new generic
or branded competitive contraceptive patch;
-
-
Competition from generic contraceptive products could increase as additional generic contraceptives receive FDA approval;
-
-
Healthcare reform activities, including, without limitation, the repeal, reform or replacement of the Patient Protection and Affordable Care
Act, as amended by the Healthcare and Education Reconciliation Act of 2010 or, collectively, the Affordable Care Act, or ACA, and its effect on pharmaceutical coverage, reimbursement and pricing could
limit our revenue; and
-
-
Access to the prescriber universe, particularly obstetrics and gynecology physicians, could be limited, decreasing our ability to promote
Twirla efficiently.
-
-
Our ability to access pharmacists in states where they are authorized by law to prescribe contraceptives could be limited, decreasing our
ability to promote Twirla
The
degree of acceptance and uptake of Twirla, if approved, by prescribers, patients and third-party payors will depend upon a number of factors,
including:
-
-
The level of contraceptive effectiveness of Twirla demonstrated in our clinical trials;
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-
-
The incidence and severity of adverse effects associated with Twirla;
-
-
Limitations on use or warnings contained in FDA-approved labeling, which could include, for example, limitations on the use of Twirla for women
based on BMI or weight;
-
-
Acceptability to patients of the appearance and feel of Twirla;
-
-
Willingness of patients to try a new contraceptive and to use a transdermal patch as their form of contraception;
-
-
Willingness of prescribers to prescribe a contraceptive patch in light of safety issues and restrictive labeling of the currently marketed
contraceptive patch;
-
-
The cost of Twirla to the patient, as compared to other contraceptive products and methods;
-
-
Our ability to obtain and maintain sufficient third party coverage or reimbursement for Twirla from private health insurers, government
healthcare programs (including Medicare, Medicaid and 340B Clinics) and other third party payors; and
-
-
The effectiveness of our or any future collaborators' sales and marketing strategies.
In
addition, even if we obtain regulatory approval, the timing of an approval may reduce our ability to commercialize Twirla successfully. For example, if the approval process takes too
long, we may miss market opportunities, give other companies the ability to develop competing products, and require us to raise additional capital, which could delay our commercial launch. Any
regulatory approval we ultimately obtain may be limited or subject to restrictions or post-approval commitments that render Twirla not commercially viable. For example, regulatory authorities may
grant approval contingent on the performance of costly post- marketing clinical trials or other post-marketing commitments, including REMS, or may approve Twirla with a label that contains fewer, or
more limited, indications than requested, warnings, precautions or contraindications, including black box warnings, and the label may not include the claims necessary or desirable for the successful
commercialization of Twirla. Any of the foregoing scenarios could materially harm the commercial prospects for Twirla.
Moreover,
we may face additional generic or other drug product competition sooner than we anticipate for Twirla or our other product candidates, which would potentially limit their
commercial success. We believe that we may be eligible for three years of FDA marketing exclusivity for Twirla and our other product candidates. The FDCA provides a period of three years of marketing
exclusivity for an NDA, Section 505(b)(2) NDA or supplement to an existing NDA for a drug product that contains a previously approved active moiety, if new clinical investigations, other than
bioavailability or bioequivalence studies, were conducted or sponsored by the applicant and are determined by the FDA to be essential to the approval of the application. This three year marketing
exclusivity, however, does not protect drug products from all competition. For instance, it does not protect against the approval of a full NDA. It also would only protect against the approval of a
product that contains the same conditions of approval as our product candidates. We may not receive the three year exclusivity for any of our product
candidates, and, even if we do, it may not adequately protect us from competition. Competition that our product candidates may face from generic or similar versions of our product candidates could
materially and adversely impact our future revenue, profitability and cash flows and substantially limit our ability to obtain a return on the investments we have made in those product candidates.
If
Twirla is approved, but does not achieve an adequate level of acceptance by prescribers, third-party payors and patients, we may not generate sufficient revenue and we may not be able
to achieve or sustain profitability. Our efforts to educate prescribers, patients and third party payors on the benefits of Twirla may require significant resources and may never be successful. Even
if we are able to demonstrate and maintain a competitive advantage over our competitors and become profitable, if the
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market
for hormonal contraceptives fails to achieve expected future growth or decreases, we may not generate sufficient revenue or sustain profitability.
The proportion of the contraceptive market that is made up of generic products continues to increase, making
introduction of a branded contraceptive difficult and expensive.
The proportion of the U.S. market that is made up of generic products has been increasing over time. In 2005, generic contraceptive products
held 47% of prescription volume and 34% of sales and, by 2011, those values had risen to 68% and 44%, respectively. For the year ended December 31, 2016, approximately 83% of the prescription
volume and approximately 43% of sales of combined hormonal contraceptives, or CHCs, in the U.S. were generated by generic products. If this trend continues, it may be more difficult to introduce
Twirla, if approved, as a branded contraceptive, at a price that will maximize our revenue and profits. Also, there may be additional marketing costs to introduce Twirla in order to overcome the trend
towards generics and to gain access to reimbursement by payors. If we are unable to introduce Twirla at a price that is commensurate with that of current branded contraceptive products, or we are
unable to gain reimbursement from payors for Twirla, or if patients are unwilling to pay any price differential between Twirla and a generic contraceptive, our revenues will be limited. For example,
in light of the introduction of the generic version of the Ortho Evra product by Mylan Inc. in April 2014, and the subsequent discontinuation of distribution of Ortho Evra in October 2014 by
Janssen in order to be competitive and gain market share, we may increase the rebates available to commercial payors or we may provide incentives to consumers covered by non-governmental payors, such
as coupons or rebates, in order to make up for the difference in the co-payment for Twirla and the generic patch product.
Prescribers, patients and payors may not adopt a new contraceptive patch due to concerns based upon the prior
experience with or perception of the currently marketed contraceptive patch.
The Ortho Evra® contraceptive patch, or Evra, was introduced in early 2002 and was the first FDA-approved contraceptive patch. The
following is a brief history of the Evra market experience:
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Evra had rapid uptake in the contraceptive market, achieving a 10% share of the CHC market by September 2003. The initial approved labeling for
Evra indicated that it delivered a daily EE dose of 20 micrograms.
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Following the approval of Evra, users of Evra began to report thrombotic and thromboembolic events to the FDA.
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A pharmacokinetic study was conducted in 2005 and later published in the Journal of Clinical Pharmacology comparing Evra to an oral
contraceptive, which demonstrated that Evra was delivering higher serum concentrations of EE compared to an oral contraceptive with an EE dose of 35 micrograms. A pharmacokinetic study evaluates how
the body handles a given drug over time; these studies are conducted by measuring the amount of time it takes for the drug to be absorbed, distributed and eliminated throughout the body.
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Johnson & Johnson, the manufacturer of Evra, revised the Evra labeling in November 2005 to include information that EE exposure with
Evra is 60% higher than that of an oral contraceptive containing EE of 35 micrograms, based on area under the curve, a commonly-used metric for measuring EE exposure in contraceptives. This
information was ultimately included in a unique black box warning and bolded warning in the Evra labeling.
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The FDA held a Joint Meeting of the Advisory Committees for Reproductive Health Drugs and Drug Safety and Risk Management on December 9,
2011. The Committees concluded that users of Evra have an increased risk of venous thromboembolism, or VTE compared to users of second generation contraceptives, such as those containing LNG. The
Committees, through a
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We
have conducted pharmacokinetic studies of Twirla to demonstrate that it delivers a daily EE dose of approximately 30 micrograms, comparable to a low-dose oral contraceptive. However,
because none of our completed or planned clinical trials studied or expect to study Twirla in a head-to-head comparison with Evra, if Twirla is approved by the FDA, we will not be able to make direct
comparative claims regarding the safety and efficacy of Twirla as compared to Evra. While we expect Twirla, if approved, to have the same black box warning currently required for all CHCs, we cannot
predict whether the FDA will require that we include information in the Twirla labeling or black box warning regarding the additional risks associated with the Evra patch. Assuming approval, if we are
not able to convince prescribers, patients and payors that Twirla delivers a low daily dose of EE, this may limit uptake and usage of Twirla and our revenue will be limited.
We face competition from other biotechnology and pharmaceutical companies and our operating results will
suffer if we fail to compete effectively.
The biotechnology and pharmaceutical industries are intensely competitive. We would have significant competition with contraceptive products
already in the marketplace, many of which have substantially greater name recognition, commercial infrastructures and financial, technical and personnel resources than we have. Any new product that
competes with a previously approved product may need to demonstrate compelling advantages in efficacy, convenience, tolerability or safety to be commercially successful. In addition, new products
developed by others could emerge as competitors to Twirla, if approved. If we are not able to compete effectively against our current and future competitors, our business will not grow and our
financial condition and operations will suffer.
Our
potential competitors include large, well-established pharmaceutical companies, and specialty pharmaceutical sales and marketing companies. These companies include
Merck & Co., Inc., or Merck, which markets Nuvaring®, Allergan, Inc., or Allergan, which markets several branded and generic contraceptives including
Loestrin® 24, Minastrin® 24 and LoLoestrin®, Teva Pharmaceutical Industries Ltd., or Teva, which markets several branded and generic contraceptives including
Gianvi® and Quartette®, Bayer AG, or Bayer, which markets Beyaz® and Mirena®, Johnson & Johnson, which markets Ortho-Tri-Cyclen® Lo,
Pfizer Inc., which markets Alesse® and Mylan Inc. which markets Xulane, a generic version of Ortho Evra. Additionally, several generic manufacturers currently
market and continue to introduce new generic contraceptives, including Sandoz International GmbH, Glenmark Pharmaceuticals Ltd., Lupin Pharmaceuticals, Inc., and Amneal
Pharmaceuticals LLC.
There
are other contraceptive product candidates in development that, if approved, would potentially compete with Twirla. Specifically, Bayer has a contraceptive patch approved in the
European Union, or E.U. Bayer entered into a license and distribution agreement for the sale of this contraceptive patch in Europe with Gedeon Richter Ltd. Other companies that have new
contraceptive product candidates in various stages of development include Teva (oral contraceptive in Phase 3), Merck (vaginal ring and oral contraceptive in Phase 3), Allergan (vaginal
ring in Phase 3) and Antares Pharma, Inc. (transdermal gel contraceptive in Phase 2).
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Sales of our products, if approved, may be adversely affected by the consolidation among wholesale drug
distributors and the growth of large retail drug store chains.
The network through which we will sell our products, if and when approved, has undergone significant consolidation marked by mergers and
acquisitions among wholesale distributors and the growth of large retail drugstore chains. As a result, a small number of large distributors control a significant share of the market. In 2012, three
companies generated about 85% of all revenues from drug distribution in the United States, and in 2010, four chain pharmacy companies owned about 30% of all retail pharmacy outlets. Consolidation of
drug wholesalers and retailers, as well as any increased pricing pressure that those entities face from their customers, including the U.S. government, may increase pricing pressure and place other
competitive pressures on drug manufacturers, including us.
Recently enacted and future legislation may increase the difficulty and cost for us to obtain marketing
approval of and to commercialize Twirla and our other product candidates and may affect the prices we may obtain.
In the United States and some foreign jurisdictions, there have been a number of legislative and regulatory changes and proposed changes
regarding the healthcare system that could prevent or delay marketing approval for Twirla, restrict or regulate post-approval activities and affect our ability to profitably sell Twirla.
Legislative
and regulatory proposals have been made to expand post-approval requirements and restrict sales and promotional activities for pharmaceutical products. We do not know whether
additional legislative changes will be enacted, or whether the FDA's regulations, guidance or interpretations will change, or what the impact of such changes on the potential marketing approval of
Twirla, if any, may be. In addition, increased scrutiny by the U.S. Congress of the FDA's approval process may significantly delay or prevent marketing approval, as well as subject us to more
stringent product labeling and post-marketing testing and other requirements.
In
March 2010, President Obama signed into law the ACA, a sweeping law intended to broaden access to health insurance, reduce or constrain the growth of healthcare spending, enhance
remedies against fraud and abuse, add new transparency requirements for healthcare and health insurance industries, impose new taxes and fees on the healthcare industry and impose additional
healthcare policy reforms. The ACA, among other things, increased the Medicaid rebates owed by manufacturers under the Medicaid Drug Rebate Program for both branded and generic drugs, extended the
rebate program to certain individuals enrolled in Medicaid managed care organizations, addressed new methodologies by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are
calculated for drugs that are line extension products and expanded the 340B drug discount program (excluding orphan drugs) to other entities. Further, the ACA imposed a significant annual tax on
companies that manufacture or import branded prescription drug products. Substantial new provisions affecting compliance have also been enacted, which may require us to modify our business practices
with regard to healthcare practitioners.
Of
particular relevance to our business is the ACA requirement that all health plans, with limited exceptions, cover certain preventive services for women with no cost-sharing, which
means no deductible, no co-insurance and no co-payments by the patient. Contraceptive methods and counseling, including all FDA-approved contraceptive methods as prescribed, are included in the ACA
mandate, and this has come to be known as the "contraceptive mandate." Under the ACA, payors are only required to cover one favored product within each contraceptive "method" without imposing any
cost-sharing obligations on the patient. For example, the introduction of a generic contraceptive patch product with a price that will likely be lower than the price of Twirla makes it less clear that
Twirla would have a preferred position, such as coverage without a co-insurance payment, under the ACA contraceptive mandate. Other products within the same method may also be covered, but payors are
allowed to use reasonable medical management techniques, such as the application of cost-sharing
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obligations.
An amendment was issued that provided an exemption to the contraceptive mandate for group health plans established or maintained by religious employers. However, the contraceptive mandate
has remained controversial, with several legal challenges filed around the country. In June 2014, the U.S. Supreme Court ruled that owners of certain private companies can object to the contraceptive
mandate on religious grounds and in November 2015, the Court agreed to hear arguments from non-profit organizations requesting similar treatment. Although it is too early to determine the full effect
of the contraceptive mandate and other provisions of the ACA on our business, the law appears likely to continue the pressure on pharmaceutical pricing, especially under the Medicare program, and may
also increase our regulatory burdens and operating costs. In March 2017, the U.S. Congress proposed legislation, which, if signed into law by the new administration, would repeal certain aspects of
the ACA. Further, on January 20, 2017, the new administration signed an Executive Order directing federal agencies with authorities and responsibilities under the ACA to waive, defer, grant
exemptions from, or delay the implementation of any provision of the ACA that would impose a fiscal or regulatory burden on states, individuals, healthcare providers, health insurers, or manufacturers
of pharmaceuticals or medical devices among others. Congress also could consider subsequent legislation to repeal and replace elements of the ACA that are repealed. There are several proposals to
reform the federal healthcare laws being advocated and it is still unclear whether such reform efforts will succeed and if so, which proposals will ultimately be successful. Therefore, it is difficult
to determine the full effect of the ACA or any other healthcare reform efforts on our business.
In
addition, other legislative changes have been proposed and adopted in the United States since the ACA was enacted. On August 2, 2011, the Budget Control Act of 2011, among
other things, created measures for spending reductions by Congress. A Joint Select Committee on Deficit Reduction, tasked with recommending a targeted deficit reduction of at least $1.2 trillion for
the years 2013 through 2021, was unable to reach required goals, thereby triggering the legislation's automatic reduction to several government programs. This includes aggregate reductions of Medicare
payments to providers of 2% per fiscal year, which went into effect on April 1, 2013 and will stay in effect through 2024 unless additional Congressional action is taken. On January 2,
2013, President Obama signed into law the American Taxpayer Relief Act of 2012, or ATRA, which among other things, further reduced Medicare payments to several types of providers, including hospitals,
imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years. We expect that
additional federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, and
in turn could significantly reduce the projected value of our product candidates and reduce our profitability.
Moreover,
the Drug Quality and Security Act imposes obligations on manufacturers of pharmaceutical products related to product tracking and tracing. Among the requirements of this
legislation, manufacturers are required to provide certain information regarding the drug product to individuals and entities to which product ownership is transferred, will be required to label drug
product with a product identifier toward the end of 2017 and are required to keep certain records regarding the drug product. The transfer of information to subsequent product owners by manufacturers
will be required to be done electronically toward the end of 2017. Manufacturers must also verify that purchasers of the manufacturers' products are appropriately licensed. Further, under this
legislation, manufactures have drug product investigation, quarantine, disposition, and FDA and trading partner notification
responsibilities related to counterfeit, diverted, stolen and intentionally adulterated products, as well as products that are the subject of fraudulent transactions or which are otherwise unfit for
distribution such that they would be reasonably likely to result in serious health consequences or death.
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Third party coverage and reimbursement and healthcare cost containment initiatives and treatment guidelines
may constrain our future revenues.
Our ability to successfully market Twirla and other product candidates, if approved, will depend in part on the level of coverage and
reimbursement that government authorities, private health insurers and other organizations provide for Twirla or our other product candidates and contraceptives in general. Countries in which Twirla
or our other product candidates are sold through reimbursement schemes under national health insurance programs frequently require that manufacturers and sellers of pharmaceutical products obtain
governmental approval of initial prices and any subsequent price increases. In certain countries, including the United States, government-funded and private medical care plans can exert significant
indirect pressure on prices. We may not be able to sell Twirla or our other product candidates profitably if adequate prices are not approved or coverage and reimbursement are unavailable or limited
in scope. Increasingly, third party payors attempt to contain healthcare costs in ways that are likely to impact our development of products including:
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Failing to approve or challenging the prices charged for healthcare products;
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Introducing reimportation schemes from lower-priced jurisdictions;
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Limiting both coverage and the amount of reimbursement for new therapeutic products;
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Denying or limiting coverage for products that are approved by the regulatory agencies but are considered to be experimental or investigational
by third party payors; and
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Refusing to provide coverage when an approved product is used for off-label indications.
Risks Related to Manufacturing and Our Reliance on Third Parties
We have no manufacturing capacity and anticipate continued reliance on Corium, our third party manufacturer,
for the development and commercialization of our product candidates in accordance with manufacturing regulations.
We rely on Corium International, Inc., or Corium, our third party manufacturer, to produce clinical supplies of Twirla and our other
product candidates, and we plan to continue relying on them for commercial supplies and samples of our product candidates, if approved. We do not own or operate, and have no plans to establish, any
manufacturing facilities for our product candidates. We lack the resources and the capabilities to manufacture Twirla or any of our product candidates on a clinical or commercial scale. The facilities
used by Corium to manufacture our product candidates must be approved by the FDA pursuant to inspections that will be conducted after submission of an NDA to the FDA. We do not control the
manufacturing process of, and are completely dependent on, our contract manufacturing partners for compliance with the regulatory requirements, known as Current Good Manufacturing Practices, or cGMPs,
for manufacture of our product candidates and our products, if and when approved. If Corium or other contract manufacturers that we may use cannot successfully manufacture material that conforms to
our specifications and the strict regulatory requirements of the FDA or others, they will not be able to secure or maintain regulatory approval for their manufacturing facilities. In addition, we have
no control over the ability of our contract manufacturer to maintain adequate quality control, quality assurance and qualified personnel. If the FDA or a comparable foreign regulatory authority does
not approve these facilities for the manufacture of our product candidates or if it withdraws any such approval in the future, we may need to find alternative manufacturing facilities that would also
require FDA approval and which would significantly impact our ability to develop, obtain regulatory approval for or market our product candidates, if
approved. Moreover, if our contract manufacturer cannot successfully manufacture materials that conform to our specifications and the strict regulatory requirements of the FDA or others, we may be
subject to other regulatory enforcement action such as adverse inspectional findings, Warning Letters, Untitled Letters, recall requests, withdrawal of product or investigational approvals, clinical
holds or
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termination,
disgorgement, restitution, exclusion from federal healthcare programs product seizures and detention, consent decrees, corporate integrity agreements, criminal and civil penalties,
including imprisonment, refusal to permit import or export of the product and injunction against or restriction of manufacture or distribution. If our contract manufacturer experiences issues in its
manufacturing process or is unable to produce clinical supplies in adequate quantity and quality, our clinical trial could be delayed or our ability to receive regulatory approval of our product
candidates could be negatively affected. Additionally, if there are changes to the manufacturing process for Twirla or to our formulation for Twirla that require a change in the manufacturing process,
we could experience significant additional cost and our ability to receive regulatory approval could be delayed.
The
machinery to produce the commercial supply of Twirla must be qualified and validated, which is time-consuming and expensive, and this machinery is located within one manufacturing
site and is customized to the particular manufacturing specifications of Twirla. If Corium is unable to qualify and validate this equipment in a timely manner and successfully produce validation
batches, our ability to launch and commercialize Twirla will be compromised and we could require additional capital to complete the validation process. If this customized equipment malfunctions at any
time during the production process, the time it may take Corium to secure replacement parts, to undertake repairs and to revalidate the equipment and process could limit our ability to meet the
commercial demand for Twirla. Similar manufacturing conditions may also apply to our other product candidates. This may increase the risk that the third party manufacturer may not manufacture Twirla
in accordance with the applicable regulatory requirements, that we may not have sufficient quantities of Twirla or our product candidates or that we may not have such quantities at an acceptable cost,
any of which could delay, prevent, or impair the commercialization of Twirla, if approved, and the development of our product candidates.
Although
we have manufacturing agreements with Corium for the clinical and commercial supply of Twirla, Corium and several of its suppliers of raw materials will be single source
providers to us for a significant period of time. In particular, Corium manufactures Twirla using EE and LNG and components that it purchases from third parties, most of which are single source
suppliers of the applicable material. We do not have any control over the process or timing of the acquisition of these raw materials by Corium. Although we generally do not begin a clinical trial
unless we believe we have a sufficient supply of a product candidate to complete the clinical trial, any significant delay in the supply of a product candidate, or the raw material components thereof,
for an ongoing clinical trial due to the need to replace a third party manufacturer could considerably delay completion of our clinical trials, product testing and potential regulatory approval of our
product candidates.
Because
we outsource all of our manufacturing processes, there is no guarantee that there will be sufficient supplies to fulfill our requirements or that we may obtain such supplies on
acceptable terms. Although Corium intends to enter into agreements with critical manufacturers, component fabricators and secondary service providers to secure commercial supply of Twirla, not all of
such suppliers and service providers will be under contract. Any delays in obtaining adequate supplies of our product candidates could limit our ability to meet commercial demand for Twirla.
In
addition, in the event Twirla is approved and achieves significant market share, Corium may not possess adequate manufacturing capabilities to meet market demand for Twirla. If it
becomes necessary to engage an additional third party manufacturer to produce Twirla, we may need to license certain manufacturing know-how from Corium, or our commercial supply will be limited while
the new third party manufacturer develops the necessary know-how to manufacture Twirla and while we obtain regulatory approval for the addition of a new manufacturer.
Reliance
on a third party manufacturer subjects us to risks that would not affect us if we manufactured the product candidates ourselves,
including:
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Reliance on the third party for regulatory compliance and quality assurance;
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Reduced control over the manufacturing process for our product candidates;
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The possible breach of the manufacturing agreements by the third party because of factors beyond our control;
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The possibility of termination or nonrenewal of the agreements by the third party because of our breach of the manufacturing agreement or based
on their own business priorities; and
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The disruption and costs associated with changing suppliers.
Our
product candidates may compete with other products and product candidates for access to manufacturing resources and facilities. There are a limited number of manufacturers that
operate under cGMP requirements and that are both capable of manufacturing for us and willing to do so. If our existing third party manufacturer, or the third parties that we may engage in the future
to manufacture a product for commercial sale or for our clinical trials, should cease to continue to manufacture our product candidates for any reason, we likely would experience delays in obtaining
sufficient quantities of our product candidates for us to meet commercial demand or to advance our clinical trials while we identify and qualify replacement suppliers. If for any reason we are unable
to obtain adequate supplies of our product candidates or the drug substances used to manufacture them, it will be more difficult for us to develop our product candidates and compete effectively.
Our
third party manufacturer is subject to regulatory requirements, covering manufacturing, testing, quality control and record keeping relating to our product candidates, and subject to
ongoing inspections by the regulatory agencies. In addition to the above-described regulatory actions, failures by our third party manufacturer to comply with applicable regulations may result in long
delays and interruptions to our manufacturing capacity while we seek to secure another third party manufacturer that meets all regulatory requirements.
We are dependent on numerous third parties in Corium's supply chain for the supply of our product candidates,
and if Corium fails to maintain supply relationships with these third parties, develop new relationships with other third parties or suffers disruptions in supply, we may be unable to continue to
develop our product candidates, or, assuming FDA approval, commercialize Twirla.
We, through our manufacturing partner Corium, rely on a number of third parties for the supply of active ingredients, other raw materials and
laboratory services for the supply of our product candidates and, assuming FDA approval, commercialization of Twirla. Our ability to develop our product candidates depends, in part, on Corium's
ability to successfully obtain the active pharmaceutical ingredients used in our product candidates, in accordance with regulatory requirements and in sufficient quantities for clinical testing and
later commercialization. If Corium fails to develop and maintain supply relationships with these third parties, we may be unable to continue to develop our product candidates or commercialize any
approved products in the future.
We,
through Corium, also rely on certain third parties as the current sole source of the materials they supply. Although many of these materials are produced in more than one location or
are available from another supplier, if any of these materials becomes unavailable to us for any reason, we likely would incur added costs and delays in identifying or qualifying replacement materials
and there can be no assurance that replacements would be available to us on acceptable terms, or at all. In certain cases we may be required to get regulatory approval to use alternative suppliers,
and this process of approval could delay development of our product candidates and, assuming FDA approval, commercial production of Twirla, indefinitely. For example, the sole manufacturer of one of
the components of the packaging of our Twirla patch notified us that it would be discontinuing manufacture of the component in 2016, although it has now extended the period during which it will
continue to manufacture the component. In conjunction with Corium, we were able to secure an amount of inventory of the packaging component that we believe will last until 2019. We are currently
evaluating sources for a replacement for this discontinued component and, assuming FDA approval of this replacement
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material,
we plan to use the replacement material in connection with the commercial production of Twirla.
If
Corium's third party suppliers fail to deliver the required quantities of sub-components and starting materials, in accordance with all regulatory requirements, and on a timely basis
and at commercially reasonable prices, and we and Corium are unable to find one or more replacement suppliers capable of production at a substantially equivalent cost in substantially equivalent
volumes and quality, and on a timely basis, the continued development of our product candidates, and assuming FDA approval, commercialization of Twirla, would be impeded, delayed, limited or
prevented, which could harm our business, results of operations, financial condition and prospects.
If the manufacturing facilities of Corium are not maintained in a manner that is compliant with cGMP
requirements, we may need to find alternative manufacturers and suppliers, which could result in supply interruptions of Twirla and our other product candidates, additional costs and lost revenues.
Corium's facilities used for the manufacture of our product candidates must be maintained in a manner compliant with cGMP requirements,
including obtaining favorable inspection reports. We do not control the manufacturing process and are dependent on Corium for compliance with the FDA's requirements for manufacture of Twirla and our
other product candidates. If Corium cannot successfully manufacture material components and finished products that conform to our specifications and the FDA's strict regulatory requirements, they and
we may be subject to regulatory action, including adverse inspectional findings, Warning Letters, Untitled Letters, product recall requests, withdrawal of product or investigational approvals,
clinical holds or termination, disgorgement,
restitution, exclusion from federal healthcare programs, detentions or seizures, refusal to allow the import or export of a product, injunction against or restriction of manufacture or distribution,
consent decrees, corporate integrity agreements, criminal and civil penalties, including imprisonment, and Corium may not be able to maintain FDA approval for its manufacturing facilities or
acceptance of its manufacturing data in regulatory filings. If Corium's facilities cannot maintain compliance with FDA requirements, we may need to find and successfully qualify alternative
manufacturing facilities, which could result in supply interruptions of Twirla and our other product candidates and substantial additional costs as a result of such delays, including costs with
respect to finding alternative manufacturing facilities, and lost revenues.
We rely on third parties to conduct aspects of our clinical trials. If these third parties do not
successfully carry out their contractual duties, meet expected deadlines or comply with applicable regulatory requirements, we may be delayed in obtaining or ultimately not be able to obtain marketing
approval for our product candidates.
We currently rely on CROs for most aspects of our clinical trials, including trial conduct, data management, statistical analysis and electronic
compilation of our NDA. We may enter into agreements with CROs to obtain additional resources and expertise in an attempt to accelerate our progress with regard to new or ongoing clinical and
preclinical programs. Entering into relationships with CROs involves substantial cost and requires extensive management time and focus. In addition, typically there is a transition period between
engagement of a CRO and the time the CRO commences work. As a result, delays may occur, which may materially impact our ability to meet our desired clinical development timelines and ultimately have a
material adverse impact on our operating results, financial condition or future prospects.
As
CROs are not our employees, we cannot control whether or not they devote sufficient time and resources to our clinical trials for which they are engaged to perform, and whether they
comply with the applicable regulatory requirements, known as Current Good Clinical Practices, or cGCPs, which are regulations and guidelines enforced by the FDA, the Competent Authorities of the
Member States of the European Economic Area, or EEA, and comparable foreign regulatory authorities for all of our
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product
candidates in clinical development, which include requirements related to the conduct of the study, subject informed consent, and IRB approval. Regulatory authorities enforce these cGCPs
through periodic inspections of trial sponsors, principal investigators and trial sites. Although we may rely on third parties for the execution of our trials, we are nevertheless responsible for
ensuring that each of our studies is conducted in accordance with the applicable protocol, legal, regulatory and scientific standards and our reliance on CROs does not relieve us of our regulatory
responsibilities. If we or any of our CROs fail to comply with applicable cGCPs, the clinical data generated in our clinical trials may be deemed unreliable and the FDA, European Medicines Agency or
comparable foreign
regulatory authorities may require us to perform additional clinical trials before approving our marketing applications, in addition to SECURE. We cannot assure you that, upon inspection by a given
regulatory authority, such regulatory authority will determine that any of our clinical trials complies with cGCP regulations. In addition, our clinical trials must be conducted with product candidate
materials produced under cGMP regulations. Our failure to comply with these regulations may require us to discontinue or repeat clinical trials, which would delay the regulatory approval process. If
the CROs we engage do not successfully carry out their contractual duties or obligations, conduct the clinical trials in accordance with all regulatory requirements, or meet expected deadlines, or if
they need to be replaced, or the quality or accuracy of the data they provide is compromised due to the failure to adhere to regulatory requirements or for other reasons, then our development programs
may be extended, delayed or terminated, or we may not be able to obtain marketing approval for or successfully commercialize our product candidates. Failure to comply with clinical trial regulatory
requirements may further subject us to regulatory action, including Warning Letters, Untitled Letters, adverse inspectional findings, clinical holds or termination, criminal and civil penalties,
including imprisonment, injunction against manufacture or distribution and debarment. As a result, our financial results and the commercial prospects for our product candidates would be harmed and our
costs would increase.
Any collaboration arrangements that we may enter into in the future may not be successful, which could
adversely affect our ability to develop and commercialize our product candidates.
We may seek partnerships, collaborations and other strategic transactions to maximize the commercial potential of Twirla, our other product
candidates and our proprietary technologies in the United States and territories throughout the world. We may enter into such arrangements on a selective basis depending on the merits of retaining
commercialization rights for ourselves as compared to entering into selective collaboration arrangements with leading pharmaceutical or biotechnology companies for Twirla and each of our other product
candidates and technologies, both in the United States and internationally. We face competition in seeking appropriate collaborators. Moreover, collaboration arrangements are complex and time
consuming to negotiate, document and implement. We may not be successful in our efforts to establish and implement collaborations or other alternative arrangements should we choose to enter into such
arrangements. The terms of any collaborations or other arrangements that we may establish may not be favorable to us.
Any
future collaborations that we enter into may not be successful. The success of our collaboration arrangements will depend heavily on the efforts and activities of our collaborators.
Collaborators generally have significant discretion in determining the efforts and resources that they will apply to these collaborations.
Disagreements
between parties to a collaboration arrangement regarding clinical development and commercialization matters could lead to delays in the development process or
commercialization of our product candidates and, in some cases, termination of the collaboration arrangement. These disagreements can be difficult to resolve if neither of the parties has final
decision making authority.
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Collaborations
with pharmaceutical or biotechnology companies and other third parties often are terminated or allowed to expire by the other party. Any such termination or expiration
could adversely affect us financially and could harm our business reputation.
If we fail to establish an effective distribution process our business may be adversely affected.
We do not currently have the infrastructure necessary for distributing pharmaceutical products. We intend to contract with third party logistics
wholesalers to warehouse these products and distribute them to pharmacies. This distribution network will require significant coordination with our sales and marketing and finance organizations.
Failure to secure contracts with wholesalers could negatively impact the distribution of our products, if and when approved, and failure to coordinate financial systems could negatively impact our
ability to accurately report product revenue. If we are unable to effectively establish and manage the distribution process, the commercial launch and sales of our products, if and when approved, will
be delayed or severely compromised and our results of operations may be harmed. Distribution practices will also need to comply with the applicable regulatory requirements. If our distributors do not
comply with the applicable regulatory requirements, we could be exposed to potential enforcement actions.
Risks Related to Regulatory Matters Following Approval
Even if we obtain marketing approval for Twirla or other product candidates, we will be subject to ongoing
obligations and continued regulatory review, which may result in significant additional expense. Additionally, Twirla or other product candidates could be subject to labeling and other restrictions,
including withdrawal from the market, and we may be subject to penalties if we fail to comply with regulatory requirements or if we experience unanticipated problems.
Even if we obtain U.S. regulatory approval of Twirla or other product candidates, the FDA may still impose significant restrictions on their
indicated uses, including more limited patient populations, require that precautions, contraindications, or warnings be included on the product labeling, including black box warnings, or impose
ongoing requirements for potentially costly and time-consuming post-approval studies, including Phase 4 clinical trials, and post-market surveillance to monitor safety and efficacy. Claims that
we may make may also be restricted through our approved labeling. For example, based on the SECURE top-line data, the Pearl Index for the overall intent to treat population of subjects 35 years
of age and under was 4.80 with an upper-bound of the 95% confidence interval of 6.06, but in the obese subpopulation of subjects 35 years of age and under, the Pearl Index was 6.42 with an
upper-bound of the 95% confidence interval of 8.88. The highest Pearl Index for a hormonal contraceptive product approved by the FDA to date was 3.19 and the highest upper-bound of the 95% confidence
interval was 5.03. In the combined safety database for our three Phase 3 trials (n>3,000), there were 5 subjects with potentially study drug related DVTs or PEs, 4 of whom were obese
(BMI
³
30kg/m
2
). Although ultimate approvability of a hormonal contraceptive is based on a
risk/benefit assessment of the overall safety and efficacy profile of a product, not only a specific Pearl Index, the FDA could conclude that the Pearl Index in the overall population or a
subpopulation is too high to demonstrate efficacy and an adequate risk/benefit profile. As such, we may not obtain approval of Twirla based on these data or any other basis. Even if we receive
approval of Twirla, FDA may determine that for a specific subgroup of patients, Twirla has lower efficacy and presents a higher risk, necessitating labeling restrictions. For instance, FDA may require
labeling restrictions on the use of Twirla for patients in certain BMI categories or otherwise require labeling limitations or warnings for such subpopulation, which could limit the commercial
potential of the product, if approved. FDA may further require us to include other information and/or data in the label for Twirla that may make it more difficult for us to successfully commercialize
the product, if approved. For instance, FDA may require us to include the Pearl Index results from the previously conducted Phase 3 trials, which were higher than the SECURE trial's overall and
certain sub-group Pearl Index results. We will discuss specific labeling requirements with FDA in the future.
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If approved, Twirla and our other product candidates will also be subject to ongoing regulatory requirements governing the manufacturing, labeling, packaging,
storage, distribution, import, export, safety surveillance, advertising, marketing promotion, recordkeeping, reporting of adverse events and other post-market information, and further development.
These requirements include registration with the FDA, listing of our drug products, payment of annual fees, as well as continued compliance with cGCPs for any clinical trials that we conduct
post-approval. Application holders must notify the FDA, and depending on the nature of the change, obtain FDA pre-approval for product manufacturing changes. In addition, manufacturers of drug
products and their facilities are subject to continual review and periodic inspections by the FDA and other regulatory authorities for compliance with cGMP requirements relating to quality control,
quality assurance and corresponding maintenance of records and documents. If we are found to be noncompliant with applicable requirements, the FDA and other government authorities may issue a Warning
Letter or Untitled Letter, or take other regulatory action such as a product seizure and detention, withdrawal of product approval, request for a recall, refusal to allow the import or export of the
product, criminal or civil penalties, injunction against or restriction of manufacture or distribution, consent decrees, disgorgement, restitution, clinical holds or terminations, exclusion from
federal healthcare programs, corporate integrity agreements, or imprisonment.
The
FDA has the authority to require a REMS as part of an NDA or after approval, which may impose further requirements or restrictions on the information that patients must be provided,
distribution or use of an approved drug, such as limiting prescribing to certain physicians or medical centers that have undergone specialized training, limiting treatment to patients who meet certain
safe-use criteria or requiring treated patients to enroll in a registry.
With
respect to sales and marketing activities by us or any future collaborative partner, advertising and promotional materials must comply with the FDA's rules in addition to other
applicable federal and local laws in the United States and similar legal requirements in other countries. In the United States, the distribution of product samples to physicians must comply with the
requirements of the U.S. Prescription Drug Marketing Act. We may also be subject, directly or indirectly through our customers and partners, to various fraud and abuse laws, including, without
limitation, the U.S. Anti-Kickback Statute, U.S. False Claims Act and similar state laws, which impact, among other things, our proposed sales, marketing and scientific/educational grant programs. If
we participate in the U.S. Medicaid Drug Rebate Program, the Federal Supply Schedule of the U.S. Department of Veterans Affairs, or other government drug programs, we will be subject to complex laws
and regulations regarding reporting and payment obligations. All of these activities are also potentially subject to U.S. federal and state consumer protection and unfair competition laws. Similar
requirements exist in many of these areas in other countries.
In
addition, if Twirla and our other product candidates are approved, our product labeling, advertising and promotional materials would be subject to regulatory requirements and
continuing review by the FDA, Department of Justice, Department of Health and Human Services' Office of Inspector General, state attorneys general, members of Congress and the public. The FDA strictly
regulates the promotional claims that may be made about prescription products. In particular, a product may not be promoted for uses that are not approved by the FDA as reflected in the product's
approved labeling, a practice known as off-label promotion. If we receive marketing approval for Twirla or our other product candidates, physicians may nevertheless prescribe the products to their
patients in a manner that is inconsistent with the approved label. If we are found to have promoted such off-label uses, we may become subject to significant liability and government fines. The FDA
and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to
significant sanctions. The federal government has levied large civil and criminal fines against companies for alleged improper promotion and has enjoined several companies from engaging in off-label
promotion. The FDA has also requested that companies enter into consent decrees of permanent injunctions under which
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specified
promotional conduct is changed or curtailed. For example, we believe that Twirla, if approved, will have a label consistent with all other marketed hormonal contraceptive products, which
include class labeling that warns of risks of certain serious conditions, including venous and arterial blood clots, such as heart attacks, thromboembolism and stroke, as well as liver tumors,
gallbladder disease, and hypertension, and a black box warning regarding risks of smoking and CHC use, particularly in women over 35 years old that smoke. However, regulatory authorities may
require the inclusion of additional statements about adverse events in the label, including additional black box warnings or contraindications.
In
the United States, engaging in the impermissible promotion of our products, following approval, for off-label uses can also subject us to false claims litigation under federal and
state statutes, which can lead to civil and criminal penalties and fines, agreements with governmental authorities that materially restrict the manner in which we promote or distribute drug products
through, for example, corporate integrity agreements, and debarment, suspension or exclusion from participation in federal and state healthcare programs. These false claims statutes include the
federal civil False Claims Act, which allows any individual to bring a lawsuit against a pharmaceutical company on behalf of the federal government alleging submission of false or fraudulent claims,
or causing others to present such false or fraudulent claims, for payment by a federal program such as Medicare or Medicaid. If the government decides to intervene and prevails in the lawsuit, the
individual will share in the proceeds from any fines or settlement funds. If the government declines to intervene, the individual may pursue the case alone. Since 2004, these False Claims Act lawsuits
against pharmaceutical companies have increased significantly in volume and breadth, leading to several substantial civil and criminal settlements regarding certain sales practices promoting off-label
drug uses involving fines that are as much as $3.0 billion. This growth in litigation has increased the risk that a pharmaceutical company will have to defend a false claim action, pay
settlement fines or restitution, as well as criminal and civil penalties, agree to comply with burdensome reporting and compliance obligations, and be excluded from Medicare, Medicaid and other
federal and state healthcare programs. If we do not lawfully promote our approved products, if any, we may become subject to such litigation and, if we do not successfully defend against such actions,
those actions may have a material adverse effect on our business, financial condition, results of operations and prospects.
If
we or a regulatory agency discover previously unknown problems with a product candidate, once approved, such as adverse events of unanticipated severity or frequency, data integrity
issues with regulatory filings, problems with the facility where the product is manufactured or we or our manufacturers or others working on our behalf fail to comply with applicable regulatory
requirements before or after marketing approval, we may be subject to reporting obligations as well as the following administrative or judicial sanctions:
-
-
Restrictions on the marketing, distribution or manufacturing of the product, withdrawal of the product from the market, or requests for product
recalls;
-
-
Issuance of Warning Letters, Cyber Letters or Untitled Letters;
-
-
Mandate modification to promotional materials and labeling or require us to provide corrective information to healthcare providers;
-
-
FDA or regulatory authority issuance of safety alerts, Dear Healthcare Provider letters, press releases, or other communications containing
warnings and other safety information about the product;
-
-
Require us to enter into a consent decree or corporate integrity agreement, which can include imposition of various fines, reimbursement for
inspection costs, required due dates for specific actions and penalties for noncompliance;
-
-
Clinical holds or termination;
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-
-
Injunctions or the imposition of civil or criminal penalties, imprisonment, monetary fines disgorgement or restitution;
-
-
Suspension or withdrawal of regulatory approval;
-
-
Suspension of any ongoing clinical trials;
-
-
Refusal to approve pending applications or supplements to approved applications filed by us, or suspension or revocation of product license
approvals;
-
-
Debarment;
-
-
Exclusion from participation in federal healthcare programs or refusal of government contracts;
-
-
Suspension or imposition of restrictions on operations, including costly new manufacturing requirements; or
-
-
Product seizure or detention or refusal to permit the import or export of product.
The
occurrence of any event or penalty described above may inhibit our ability to commercialize Twirla or our other product candidates, if approved, and generate revenue. Adverse
regulatory action, whether pre- or post-approval, can also potentially lead to product liability claims and increase our product liability exposure.
Moreover,
the FDA's policies may change and additional government regulations may be enacted that could prevent, limit or delay marketing approval, and the sale and promotion of our
product candidates. If we are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory compliance, we
may lose any marketing approval that we may have obtained, which would adversely affect our business, prospects and ability to achieve or sustain profitability.
Even if Twirla receives marketing approval by the FDA in the United States, we may never receive marketing
approval for or commercialize Twirla or any other product candidates outside the United States.
In order to market Twirla or any other product candidate outside the United States, we must obtain separate marketing approvals and comply with
numerous and varying regulatory requirements of other countries regarding safety and efficacy and governing, among other things, clinical trials and commercial sales, pricing and distribution of our
product candidates. The time required to obtain approval in other countries might differ from and be longer than that required to obtain FDA approval. The marketing approval process in other countries
may include all of the risks associated with obtaining FDA approval in the United States, as well as other risks. For example, legislation analogous to Section 505(b)(2) of the FDCA in the
United States, which relates to the ability of an NDA applicant to use published data not developed by such applicant, may not exist in other countries. In territories where data is not freely
available, we may not have the ability to commercialize our products, when and if approved, without negotiating rights from third parties to refer to their clinical data in our regulatory
applications, which could require the expenditure of significant additional funds. Further, we may be unable to obtain rights to the necessary clinical data and may be required to develop our own
proprietary safety and efficacy dossiers. In addition, in many countries outside the United States, it is required that a product receive pricing and reimbursement approval before the product can be
commercialized. This can result in substantial delays in such countries. Further, the product labeling requirements outside the United States may be different and inconsistent with the U.S. labeling
and to the detriment to the product, and therefore negatively affect the ability to market in countries outside the United States.
Marketing
approval in one country does not ensure marketing approval in another, but a failure or delay in obtaining marketing approval in one country may have a negative effect on the
regulatory
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process
in others. In addition, we may be subject to fines, suspension or withdrawal of marketing approvals, product recalls, seizure of products, operating restrictions and criminal prosecution if we
fail to comply with applicable foreign regulatory requirements. If we fail to comply with regulatory requirements in international markets or to obtain and maintain required approvals, our ability to
market to our full target market will be reduced and our ability to realize the full market potential of our product candidates will be harmed.
We will need to obtain FDA approval of any proposed product names, and any failure or delay associated with
such approval may adversely affect our business.
We have received conditional approval from the FDA for the use of Twirla as the proprietary name for our lead product candidate, AG200-15.
However, this approval is conditional upon a further and final review by the FDA at the time of NDA approval. Additionally, any name we intend to use for our other product candidates will require
approval from the FDA regardless of whether we have secured a formal trademark registration from the U.S. Patent and Trademark Office, or USPTO. The FDA typically conducts a review of proposed product
names, including an evaluation of the potential for confusion with other product names. The FDA may also object to a product name if it believes the name inappropriately implies medical claims or
contributes to an overstatement of efficacy. If the FDA objects to any of our proposed product names, we may be required to adopt alternative names for our product candidates. If we adopt alternative
names, we would lose the benefit of our existing trademark applications for such product candidate and may be required to expend significant additional resources in an effort to identify a suitable
product name that would qualify under applicable trademark laws, not infringe the existing rights of third parties and be acceptable to the FDA. We may be unable to build a successful brand identity
for a new trademark in a timely manner or at all, which would limit our ability to commercialize our product candidates.
Our relationships with physicians, customers and payors will be subject to applicable anti-kickback, fraud
and abuse and other healthcare laws and regulations, which could expose us to criminal sanctions, civil penalties, exclusion from government healthcare programs, contractual damages, reputational harm
and diminished profits and future earnings.
Healthcare providers, physicians and others play a primary role in the recommendation and prescription of any product candidates that we
commercialize. Our arrangements with third-party payors, including government healthcare programs, and customers will expose us to broadly-applicable fraud and abuse and other healthcare laws and
regulations that may constrain the business or financial arrangements and relationships through which we market, sell and distribute Twirla, if approved, and any other product candidates we
commercialize. Restrictions under applicable federal and state healthcare laws and regulations include the following:
-
-
The federal healthcare anti-kickback statute prohibits, among other things, persons from knowingly and willfully soliciting, offering,
receiving or providing remuneration, directly or indirectly, in cash or in kind, to induce or reward either the referral of an individual for, or the purchase, order or recommendation of, any good or
service for which payment may be made under federal healthcare programs such as Medicare and Medicaid;
-
-
The federal False Claims Act imposes criminal and civil penalties, including civil whistleblower or qui tam actions, against individuals or
entities for knowingly presenting, or causing to be presented, to the federal government, claims for payment that are false or fraudulent or making a false statement to avoid, decrease, or conceal an
obligation to pay money to the federal government;
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-
-
The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, created federal criminal statutes that prohibit executing a
scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters;
-
-
HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, and its implementing regulations, impose
obligations on covered healthcare providers, health plans and healthcare clearinghouses, as well as their business associates that create receive, maintain or transmit individually identifiable health
information for or on behalf of a covered entity, with respect to safeguarding the privacy, security and transmission of individually identifiable health information;
-
-
The federal physician payment transparency requirements under the ACA and applicable regulations require manufacturers of drugs, devices,
biologics and medical supplies to report certain information to the Department of Health and Human Services including information related to payments and other transfers of value made to physicians
and teaching hospitals and the ownership and investment interests held by physicians and their immediate family members; and
-
-
Analogous state laws and regulations, such as state anti-kickback and false claims laws that may apply to sales or marketing arrangements and
claims involving healthcare items or services reimbursed by non-governmental third-party payors, including private insurers; state laws that require pharmaceutical companies to comply with the
pharmaceutical industry's voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government in addition to requiring drug manufacturers to report information
related to payments to physicians and other healthcare providers or marketing expenditures and drug pricing; and state laws governing the privacy and security of health information in certain
circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.
The
risk of our being found in violation of these laws and regulations is increased by the fact that many of them have not been fully interpreted by the relevant government or regulatory
authorities or the courts, and their provisions are open to a variety of interpretations. Moreover, recent healthcare reform legislation has strengthened these laws. For example, the ACA, among other
things, amended the intent requirement of the federal anti-kickback and criminal healthcare fraud statutes; such that a person or entity no longer needs to have actual knowledge of these statutes or
specific intent to violate them. In addition, the ACA provided that the government may assert that a claim including items or services resulting from a violation of the federal anti-kickback statute
constitutes a false or fraudulent claim for purposes of the false claims statutes.
Efforts
to ensure that our business arrangements with third parties will comply with applicable healthcare laws and regulations are costly. It is possible that governmental authorities
will conclude that our business practices may not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations. If our
operations, including anticipated activities conducted by our sales team in the sale of Twirla or our other product candidates, if approved, are found to be in violation of any of these laws or any
other governmental regulations that may apply to us, we may be subject to a variety of different consequences, depending upon which law we are found to have violated, including significant civil,
criminal and administrative penalties, damages, fines, exclusion from government funded healthcare programs, such as Medicare and Medicaid, corporate integrity agreements, refusal of government
contracts, contract debarment and the curtailment or restructuring of our operations. If any of the physicians or other providers or entities with whom we expect to do business is found to not be in
compliance with applicable laws, they may be subject to criminal, civil or administrative sanctions, including exclusions from government funded healthcare programs.
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Risks Related to Intellectual Property Rights
We may not be able to protect our proprietary technology in the marketplace.
We depend on our ability to protect our proprietary technology. We rely on trade secret, patent, copyright and trademark laws, and
confidentiality, licensing and other agreements with employees and third parties, all of which offer only limited protection. Our success depends in large part on our ability and any future licensee's
ability to maintain our patents and to obtain additional patent protection in the United States and other countries with respect to our proprietary technology and products. We believe we will be able
to obtain, through prosecution of our pending patent applications, additional patent protection for our proprietary technology. If we are compelled to spend significant time and money protecting or
enforcing our patents, designing around patents held by others or licensing or acquiring, potentially for large fees, patents or other proprietary rights held by others, our business and financial
prospects may be harmed. If we are unable to effectively protect the intellectual property that we own, other companies may be able to offer for sale the same or similar products containing the
generically available active pharmaceutical ingredients in our product candidates, which could materially adversely affect our competitive business position and harm our business prospects. Our
patents may be challenged, narrowed, invalidated or circumvented, which could limit our ability to stop competitors from marketing the same or similar products or limit the length of term of patent
protection that we may have for our product candidates. Even if our patents are unchallenged, they may not adequately protect our intellectual property, provide exclusivity for our product candidates
or prevent others from designing around our claims. Any of these outcomes could impair our ability to prevent competition from third parties, which may have an adverse impact on our business.
The
patent positions of pharmaceutical products are often complex and uncertain. The breadth of claims allowed in pharmaceutical patents in the United States and many jurisdictions
outside of the United States is not consistent. For example, in many jurisdictions the support standards for pharmaceutical patents are becoming increasingly strict. Some countries prohibit method of
treatment claims in patents. Changes in either the patent laws or interpretations of patent laws in the United States and other countries may diminish the value of our intellectual property or create
uncertainty. In addition, publication of information related to our current product candidates and potential products may prevent us from obtaining or enforcing patents relating to these product
candidates and potential products, including without limitation transdermal delivery systems and methods of using such transdermal delivery systems. Our product candidates contain generically
available active pharmaceutical ingredients. As a result, new chemical entity patents directed to the active pharmaceutical ingredients in our product candidates, which are generally believed to offer
the strongest form of patent protection, are not available for our product candidates.
Patents
that we own or may license in the future do not necessarily ensure the protection of our intellectual property for a number of reasons, including without limitation the
following:
-
-
The active pharmaceutical ingredients in our product candidates are generic and therefore our patents do not include claims directed solely to
the active pharmaceutical ingredients;
-
-
Our patents may not be broad or strong enough to prevent competition from other products that are identical or similar to our product
candidates using the same active pharmaceutical ingredients;
-
-
There can be no assurance that the term of patent protection will be long enough for our company to realize sufficient economic value under the
patents following commercialization of our product candidates;
-
-
We do not expect, upon approval of our NDA, to receive patent term restoration under the Hatch-Waxman Act for the patents that have been, or
will be, submitted to the FDA for listing in the Orange Book;
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-
-
Our issued patents and pending patent applications that may issue as patents in the future may not prevent entry into the U.S. market or other
markets of generic versions of our Twirla and AG890 product candidates;
-
-
Our patents may face paragraph IV challenges from potential generic of 505(b)(2) applicants, asserting that our applicable patents are
invalid, enforceable, or will not be infringed by the manufacture, use, or sale of the competitive drug product;
-
-
We do not at this time own or control issued foreign patents in all markets that would prevent generic entry into some markets for our product
candidates;
-
-
We may be required to disclaim part of the term of one or more patents;
-
-
There may be prior art of which we are not aware that may affect the validity or enforceability of one or more patent claims;
-
-
There may be prior art of which we are aware, which we do not believe affects the validity or enforceability of a patent claim, but which,
nonetheless, ultimately may be found to affect the validity or enforceability of a patent claim;
-
-
There may be other patents issued to others that will affect our freedom to operate;
-
-
If our patents are challenged, a patent office or a court could determine that they are invalid or unenforceable;
-
-
There might be changes in the law that governs patentability, validity and infringement of our patents that adversely affects the scope or
enforceability of our patent rights;
-
-
A court could determine that a competitor's technology or product that is the same as or similar to, our product candidates does not infringe
our patents; and
-
-
Our patents could irretrievably lapse due to failure to pay fees or otherwise comply with regulations or could be subject to compulsory
licensing.
If
we encounter delays in our development or clinical trials, the period of time during which we could market our product candidates under patent protection would be reduced.
Our
competitors may be able to circumvent our patents by developing similar or alternative technologies or products in a non-infringing manner. Our competitors may seek to market generic
versions of any approved products by submitting abbreviated new drug applications to the FDA in which our competitors claim that our patents are invalid, unenforceable or not infringed. Alternatively,
our competitors may seek approval to market their own products that are the same as, similar to or otherwise competitive with our product candidates. In these circumstances, we may need to defend or
assert our patents, by means including filing lawsuits alleging patent infringement. In any of these types of proceedings, a court or government agency with jurisdiction may find our patents invalid,
unenforceable or not infringed. We may also fail to identify patentable aspects of our research and development before it is too late to obtain patent protection. Even if we have valid and enforceable
patents, these patents still may not provide protection against competing products or processes sufficient to achieve our business objectives.
The
issuance of a patent is not conclusive as to its inventorship, scope, ownership, priority, validity or enforceability. In that regard, third parties may challenge our patents in the
courts or patent offices in the United States and abroad. Such challenges may result in loss of exclusivity or freedom to operate or in patent claims being narrowed, invalidated or held unenforceable,
in whole or in part, which could limit our ability to stop others from using or commercializing similar or identical technology and products, or limit the duration of the patent protection of our
technology and potential products. In addition, given the amount of time required for the development, testing and regulatory review of new
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product
candidates, patents protecting such candidates might expire or be held invalid or unenforceable before our company can realize sufficient economic value following commercialization of our
product candidates.
Our intellectual property portfolio is currently comprised of issued patents and pending patent applications.
If our issued patents are found to be invalid, not enforceable or not infringed by competitor products, or pending patent applications fail to issue or fail to issue with a scope that is meaningful to
our product candidates, our business will be adversely affected.
There can be no assurance that our pending patent applications will result in issued patents in the United States or foreign jurisdictions in
which such applications are pending. Even if patents do issue on any of these applications, there can be no assurance that a third party will not challenge their validity or enforceability, that we
will obtain sufficient claim scope or term in those patents to prevent a third party from competing successfully with our product candidates, or that, even if our patents are found to be valid,
enforceable, and infringed, a legal tribunal would enjoin infringing activity.
We may not be able to enforce our intellectual property rights throughout the world.
The laws of some foreign countries do not protect intellectual property rights to the same extent as the laws of the United States. Many
companies have encountered significant problems in protecting and defending intellectual property rights in certain foreign jurisdictions. The legal systems of some countries, particularly developing
countries, do not favor the enforcement of patents and other intellectual property protection, especially those relating to life sciences. To the extent that we have obtained or are able to obtain
patents or other intellectual property rights in any foreign jurisdictions, it may be difficult for us to stop the infringement of our patents or the misappropriation of other intellectual property
rights. For example, some foreign countries have compulsory licensing laws under which a patent owner must grant licenses to third parties. In addition, many countries limit the availability of
certain types of patent rights and enforceability of patents against third parties, including government agencies or government contractors. In these countries, patents may provide limited or no
benefit.
Proceedings
to enforce our patent rights in foreign jurisdictions could result in substantial costs and divert our efforts and attention from other aspects of our business. Accordingly,
our efforts to protect our intellectual property rights in such countries may be inadequate. In addition, changes in the law
and legal decisions by courts in the United States and foreign countries may affect our ability to obtain adequate protection for our technology and product candidates, and the enforcement of
intellectual property.
Recent patent reform legislation could increase the uncertainties and costs surrounding the prosecution of
our patent applications and the enforcement or defense of our issued patents.
On September 16, 2011, the Leahy-Smith America Invents Act, or the Leahy-Smith Act, was signed into law. The Leahy-Smith Act includes a
number of significant changes to U.S. patent law. These include provisions that affect the way patent applications will be prosecuted and may also affect patent litigation. In particular, under the
Leahy-Smith Act, the United States transitioned in March 2013 to a "first to file" system in which the first inventor to file a patent application will be entitled to the patent. Third parties
are allowed to submit prior art before the issuance of a patent by the USPTO, and may become involved in post-grant proceedings including reexamination, post-grant review, inter-partes review, or
derivation or interference proceedings challenging our patent rights or the patent rights of others. An adverse determination in any such submission, proceeding or litigation could reduce the scope or
enforceability of, or invalidate, our patent rights, which could adversely affect our competitive position.
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The USPTO has developed regulations and procedures to govern administration of the Leahy-Smith Act, and many of the substantive changes to patent law associated
with the Leahy-Smith Act, and in particular, the first to file provisions, did not become effective until March 16, 2013. However, the full impact of the Leahy-Smith Act and the courts' review
of any appeals to related proceedings, is in its early stages. Accordingly, the full impact that the Leahy-Smith Act will have on the operation of our business is not clear. However, the Leahy-Smith
Act and its implementation could increase the uncertainties and costs surrounding the prosecution of our patent applications and the enforcement or defense of our issued patents, as well as our
ability to bring about timely favorable resolution of any disputes involving our patents and the patents of others.
Obtaining and maintaining our patent protection depends on compliance with various procedural, documentary,
fee payment and other requirements imposed by governmental patent agencies, and our patent protection could be reduced or eliminated for noncompliance with these requirements.
Periodic maintenance fees on any issued patent are due to be paid to the USPTO and foreign patent agencies in several stages over the lifetime
of the patent. The USPTO and various foreign governmental patent agencies require compliance with a number of procedural, documentary, fee payment and other similar provisions during the patent
application process. While an inadvertent lapse can in many cases be cured by payment of a late fee or by other means in accordance with the applicable rules, there are situations in which
noncompliance can result in unenforceability, invalidity, abandonment or lapse of the patent or patent application, resulting in partial or complete loss of patent rights in the relevant jurisdiction.
Noncompliance events that could result in unenforceability, invalidity, abandonment or lapse of a patent or patent application include, but are not limited to, failure to respond to official actions
within prescribed time limits, non-payment of fees and failure to properly legalize and submit formal documents. If we or any future licensors fail to maintain the patents and patent applications
covering our product candidates, our competitive position would be adversely affected.
We may infringe the intellectual property rights of others, which may prevent or delay our product
development efforts and stop us from commercializing or increase the costs of commercializing our products, when and if approved.
Our commercial success depends significantly on our ability to operate without infringing the patents and other intellectual property rights of
third parties. For example, there could be issued patents of which we are not aware that our current or future product candidates infringe. There also could be patents that we believe we do not
infringe, but that we may ultimately be found to infringe.
Moreover,
patent applications are in some cases maintained in secrecy until patents are issued. The publication of discoveries in the scientific or patent literature frequently occurs
substantially later than the date on which the underlying discoveries were made and patent applications were filed. There may be currently pending applications of which we are unaware that may later
result in issued patents that our current or future product candidates infringe. For example, pending applications may exist that claim or can be amended to claim subject matter that our current or
future product candidates infringe. Competitors may file continuing patent applications claiming priority to already issued patents in the form of continuation, divisional or continuation-in-part
applications, in order to maintain the pendency of a patent family and attempt to cover our product candidates.
Third
parties may assert that we are employing their proprietary technology without authorization and may sue us for patent or other intellectual property infringement or
misappropriation. These lawsuits
are costly and could adversely affect our results of operations and divert the attention of managerial and scientific personnel. If we are sued for patent infringement, we would need to demonstrate
that our product candidates or methods either do not infringe the claims of the relevant patent or that the patent claims are invalid or unenforceable, and we may not be able to do this.
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Proving
invalidity or unenforceability is difficult. For example, in the United States, proving invalidity requires a showing of clear and convincing evidence to overcome the presumption of validity
enjoyed by issued patents. Even if we are successful in these proceedings, we may incur substantial costs and the time and attention of our management and scientific personnel could be diverted in
pursuing these proceedings, which could have a material adverse effect on us. In addition, we may not have sufficient resources to bring these actions to a successful conclusion. If a court holds that
any third-party patents are valid, enforceable and cover our product candidates or their use, the holders of any of these patents may be able to block our ability to commercialize our product
candidates unless we acquire or obtain a license under the applicable patents or until the patents expire. We may not be able to enter into licensing arrangements or make other arrangements at a
reasonable cost or on reasonable terms. Any inability to secure licenses or alternative technology could result in delays in the introduction of our product candidates or lead to prohibition of the
manufacture or sale of product candidates by us. Even if we are able to obtain a license, it may be non-exclusive, thereby giving our competitors access to the same technologies licensed to us. We
could be forced, including by court order, to cease commercializing the infringing technology or product. In addition, in any such proceeding or litigation, we could be found liable for monetary
damages, including treble damages and attorneys' fees if we are found to have willfully infringed a patent. A finding of infringement could prevent us from commercializing our product candidates or
force us to cease some of our business operations, which could materially harm our business. Any claims by third parties that we have misappropriated their confidential information, know-how or trade
secrets could have a similar negative impact on our business. In addition, any uncertainties resulting from the initiation and continuation of any litigation could have a material adverse effect on
our ability to raise the funds necessary to continue our operations.
We may be subject to claims that we or our employees have misappropriated the intellectual property,
including know-how or trade secrets, of a third party, or that claim ownership of what we regard as our own intellectual property.
Many of our employees, consultants and contractors were previously employed at or engaged by biotechnology companies or other pharmaceutical
companies, including our competitors or potential competitors. Some of these employees, consultants and contractors, including each member of our senior management, executed proprietary rights,
non-disclosure and non-competition agreements in connection with such previous employment. Although we try to ensure that our employees, consultants and contractors do not use the intellectual
property and other proprietary information or know-how or trade secrets of others in their work for us, we may be subject to claims that we or these
employees, consultants and contractors have used or disclosed such intellectual property, including know-how, trade secrets or other proprietary information. Litigation may be necessary to defend
against these claims. We are not aware of any threatened or pending claims related to these matters or concerning agreements with our senior management, or other of our employees, consultants and
contractors, but litigation may be necessary in the future to defend against such claims. If we fail in defending any such claims, in addition to paying monetary damages, we may lose valuable
intellectual property rights, or personnel or access to consultants and contractors. Even if we are successful in defending against such claims, litigation could result in substantial costs and be a
distraction to management.
In
addition, while we typically require our employees, consultants and contractors who may be involved in the development of intellectual property to execute agreements assigning such
intellectual property to us, we may be unsuccessful in executing such an agreement with each party who in fact develops intellectual property that we regard as our own, which may result in claims by
or against us related to the ownership of such intellectual property. If we fail in prosecuting or defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual
property rights. Even if we are successful in prosecuting or defending against such claims, litigation could result in substantial costs and be a distraction to our management and scientific
personnel.
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We may be unable to adequately prevent disclosure of trade secrets and other proprietary information.
We rely on trade secrets to protect our proprietary technological advances and know-how, especially where we do not believe patent protection is
appropriate or obtainable. However, trade secrets are difficult to protect. We rely in part on confidentiality agreements with our employees, consultants, contractors, outside scientific
collaborators, sponsored researchers and other advisors, including the third parties we rely on to manufacture our product candidates, to protect our trade secrets and other proprietary information.
However, any party with whom we have executed such an agreement may breach that agreement and disclose our proprietary information, including our trade secrets. Accordingly, these agreements may not
effectively prevent disclosure of confidential information and may not provide an adequate remedy in the event of unauthorized disclosure of confidential information. Costly and time-consuming
litigation could be necessary to enforce and determine the scope of our proprietary rights. In addition, others may independently discover our trade secrets and proprietary information. Further, the
FDA, as part of its Transparency Initiative, a proposal to increase disclosure and make data more accessible to the public, is currently considering whether to make additional information publicly
available on a routine basis, including information that we may consider to be trade secrets or other proprietary information, and it is not clear at the present time how the FDA's disclosure policies
may change in the future, if at all. Failure to obtain or maintain trade secret protection could enable competitors to use our proprietary information to develop
products that compete with our products or cause additional, material adverse effects upon our competitive business position and financial results.
Any lawsuits relating to infringement of intellectual property rights brought by or against us will be costly
and time consuming and may adversely impact the price of our common stock.
We may be required to initiate litigation to enforce or defend our intellectual property rights. These lawsuits can be very time consuming and
costly. There is a substantial amount of litigation involving patent and other intellectual property rights in the pharmaceutical industry generally. Such litigation or proceedings could substantially
increase our operating expenses and reduce the resources available for development activities or any future sales, marketing or distribution activities.
In
infringement litigation, any award of monetary damages we receive may not be commercially valuable. Furthermore, because of the substantial amount of discovery required in connection
with intellectual property litigation, there is a risk that some of our confidential information and trade secrets could be compromised by disclosure during litigation. Moreover, there can be no
assurance that we will have sufficient financial or other resources to file and pursue such infringement claims, which typically last for years before they are resolved. Further, any claims we assert
against a perceived infringer could provoke these parties to assert counterclaims against us alleging that we have infringed their patents. Some of our competitors may be able to sustain the costs of
such litigation or proceedings more effectively than we can because of their greater financial resources. Uncertainties resulting from the initiation and continuation of patent litigation or other
proceedings could have a material adverse effect on our ability to compete in the marketplace.
In
addition, our patents and patent applications in the United States and other jurisdiction could face other challenges, such as derivation or interference proceedings, opposition
proceedings,
inter partes
review, reexamination proceedings, third party submissions of prior art, and other forms of post-grant challenges. In the
United States, for example, post-grant review, which is similar to opposition proceedings available in many countries other than the U.S., was newly established by the Leahy-Smith Act. Any of these
challenges, if successful, could result in the invalidation of, or in a narrowing of the scope or preventing the issuance of, any of our patents and patent applications subject to challenge. Any of
these challenges, regardless of their success, would likely be time consuming and expensive to defend and resolve and would divert our management and scientific personnel's time and attention.
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In
addition, there could be public announcements of the results of hearings, motions or other interim proceedings or developments, and if securities analysts or investors perceive these
results to be negative, it could have a material adverse effect on the market price of our common stock.
Intellectual property disputes could cause us to spend substantial resources and distract our personnel from
their normal responsibilities.
Even if resolved in our favor, litigation or other legal proceedings relating to intellectual property claims may cause us to incur significant
expenses and could distract our technical and management personnel from their normal responsibilities. In addition, there could be public announcements of the results of hearings, motions or other
interim proceedings or developments and if securities analysts or investors perceive these results to be negative, it could have a substantial adverse effect on the market price of our common stock.
Such litigation or proceedings could substantially increase our operating losses and reduce the resources available for development activities or any future sales, marketing or distribution
activities. We may not have sufficient financial or other resources to adequately conduct such litigation or proceedings.
Risks Related to the Development of Our Additional Product Candidates
If we fail to develop and commercialize Twirla and our current pipeline of additional product candidates, our
prospects for future growth and our ability to reach or sustain profitability may be limited.
A key element of our strategy is to develop, obtain regulatory approval for and commercialize our portfolio of product candidates in addition to
Twirla. To do so, we plan to utilize our proprietary transdermal delivery technology, Skinfusion, to develop additional product candidates. We may not be successful in our efforts to develop our
portfolio of additional product candidates, and any product candidates we do develop may not produce commercially viable products that safely and effectively treat their indicated conditions. To date,
our efforts have identified three additional product candidates in addition to Twirla, including AG200-ER, which is a regimen designed to allow a woman to extend the length of her cycle, AG200-SP,
which is a regimen designed to provide shorter, lighter periods, and AG890, which is a progestin-only contraceptive patch intended for use by women who are unable or unwilling to take estrogen.
AG200-SP and AG200-ER are intended to be Twirla line extensions that would expand the use of Twirla beyond its initial approved use. In July 2016, we began preparations for an initial Phase 2
clinical trial examining the use of AG200-SP along with a smaller
lower dose combination ethinyl estradiol/levonorgestrel patch (SmP) in the fourth week of the woman's cycle. The Phase 2 clinical trial is designed to identify the optimal dose of the SmP, and
will evaluate bleeding profiles, pharmacokinetic parameters, ovulation inhibition and safety over 3 cycles of treatment with AG200-SP. We expect to initiate dosing of the AG200-SP (SmP) clinical trial
in the first quarter of 2017. Our planned Phase 2 clinical trial of AG200-SP (SmP) is only the initial clinical trial in this program and AG200-SP (SmP) may require additional clinical trials
to establish the safety and efficacy of this product candidate. The other product candidates in our pipeline will likely require additional product development efforts to optimize patch formulations
and dosing. In addition, we will need to conduct additional clinical trials to establish the safety and efficacy of these product candidates which will require additional capital. Our ability to
develop these product candidates, in particular AG200-SP and AG200-ER could be significantly affected by our inability to get Twirla approved.
Our
development programs may initially show promise in identifying potential product leads, yet fail to produce product candidates for clinical development. In addition, identifying new
treatment needs and product candidates requires substantial technical, financial and human resources on our part. If we are unable to obtain development partners or additional development program
funding, or to continue to devote substantial technical and human resources to such programs, we may have to delay or abandon these programs. Any product candidate that we successfully identify may
require substantial additional development efforts prior to commercial sale, including preclinical studies, extensive clinical
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and approval by the FDA and applicable foreign regulatory authorities. All product candidates are susceptible to the risks of failure that are inherent in pharmaceutical product development.
We may be unable to license or acquire suitable additional product candidates or technologies from third
parties for a number of reasons.
The licensing and acquisition of pharmaceutical products is competitive. A number of more established companies are also pursuing strategies to
license or acquire products. These established companies may have a competitive advantage over us due to their size, cash resources or greater clinical development and commercialization capabilities.
In addition, we expect competition in acquiring product candidates to increase, which may lead to fewer suitable acquisition opportunities for us as well as higher acquisition prices.
Other
factors that may prevent us from licensing or otherwise acquiring suitable product candidates include the following:
-
-
We may be unable to license or acquire the relevant technology on terms that would allow us to make an appropriate return on our investment in
such product;
-
-
Companies that perceive us to be their competitor may be unwilling to assign or license their product rights to us;
-
-
We may be unable to identify suitable products or product candidates within our areas of expertise; or
-
-
We may not have sufficient funds to acquire, develop or commercialize additional product candidates or technologies.
Risks Related to Our Business Operations and Industry
In order to establish our sales and marketing infrastructure, we will need to grow the size of our
organization, and we may experience difficulties in managing this growth.
As of December 31, 2016, we had a total of 19 full-time employees, and we use third-party consultants to assist with our current sales
and marketing functions. As our development and commercialization plans and strategies develop, we expect to need to expand the size of our employee base for managerial, operational, sales, marketing,
financial and other resources. Future growth would impose significant added responsibilities on members of management, including the need to identify, recruit, maintain, motivate and integrate
additional employees. In addition, our
management may have to divert a disproportionate amount of its attention away from our day-to-day activities and devote a substantial amount of time to managing these growth activities. Our future
financial performance and our ability to commercialize Twirla, if approved, and any other future product candidates and our ability to compete effectively will depend, in part, on our ability to
effectively manage any future growth.
If we are not successful in attracting and retaining highly qualified personnel, we may not be able to
successfully implement our business strategy.
Our ability to compete in the highly competitive pharmaceuticals industry depends in large part upon our ability to attract and retain highly
qualified managerial, scientific and medical personnel. We are highly dependent on our management, scientific and medical personnel. In order to induce valuable employees to remain with us, we have
provided these employees with stock options that vest over time. The value to employees of stock options that vest over time is significantly affected by movements in our stock price that we cannot
control and may at any time be insufficient to counteract more lucrative offers from other companies.
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Our
management team has expertise in many different aspects of drug development and commercialization. Competition for skilled personnel in our market is intense and competition for
experienced personnel may limit our ability to hire and retain highly qualified personnel on acceptable terms. Despite our efforts to retain valuable employees, members of our management, scientific
and medical teams may terminate their employment with us on short notice. We have an employment agreement with only one of our employees, Alfred Altomari, our President and Chief Executive Officer.
The employment agreement provides for at-will employment, which means that Mr. Altomari or any of our other employees could leave our employment at any time, with or without notice. The loss of
the services of any of our executive officers or other key employees could potentially harm our business, operating results or financial condition. In particular, we believe that the loss of the
services of Mr. Altomari, or Dr. Elizabeth Garner, our Chief Medical Officer, may have a material adverse effect on our business. We do not currently carry "key person" insurance on the
lives of members of executive management. Our success also depends on our ability to continue to attract, retain and motivate highly skilled junior, mid-level and senior managers as well as junior,
mid-level and senior scientific and medical personnel.
Other
pharmaceutical companies with which we compete for qualified personnel have greater financial and other resources, different risk profiles and a longer history in the industry than
we do. They also may provide more diverse opportunities and better chances for career advancement. Some of these characteristics may be more appealing to high-quality candidates than those that we
have to offer. If we
are unable to continue to attract and retain high-quality personnel, the rate of and success with which we can develop and commercialize product candidates would be limited.
If product liability lawsuits are brought against us, we may incur substantial liabilities and may be
required to limit commercialization of Twirla or our other product candidates, if approved.
We face a potential risk of product liability as a result of the clinical testing of Twirla and our other product candidates and will face an
even greater risk if we commercialize Twirla or our other product candidates, if approved or any other current or future product candidate. For example, we may be sued if any product candidate we
develop allegedly causes injury or is found to be otherwise unsuitable during product testing, manufacturing, marketing or sale. Any such product liability claims may include allegations of defects in
manufacturing, defects in design, a failure to warn of dangers inherent in the product, negligence, strict liability and a breach of warranties. Claims could also be asserted under state consumer
protection acts. If we cannot successfully defend ourselves against product liability claims, we may incur substantial liabilities or be required to limit commercialization of the product candidate
subject to such claims. Even successful defense would require significant financial and management resources. Regardless of the merits or eventual outcome, liability claims may result
in:
-
-
Decreased demand for Twirla or any future product candidates that we may develop;
-
-
Injury to our reputation;
-
-
Withdrawal of clinical trial participants;
-
-
Costs to defend any related litigation;
-
-
A diversion of management's time and our resources;
-
-
Substantial monetary awards to trial participants or patients;
-
-
Product recalls, withdrawals or labeling, marketing or promotional restrictions;
-
-
Loss of revenue;
-
-
The inability to commercialize Twirla or our other product candidates, if approved;
-
-
A decline in our stock price; and
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-
-
Exposure to adverse publicity.
We
have obtained limited product liability insurance coverage for our products and our clinical trials with a $10.0 million annual aggregate coverage limit. Our inability to
obtain and retain sufficient product liability insurance at an acceptable cost to protect against potential product liability claims could prevent or inhibit the commercialization of product
candidates we develop. Although we maintain such insurance, any claim that may be brought against us could result in a court judgment or settlement in an amount that is not covered, in whole or in
part, by our insurance or that is in excess of the limits of our insurance coverage. Our insurance policies also have various exclusions, and we may be subject to a product liability claim for which
we have no coverage. We may have to pay any amounts awarded by a court or negotiated in a settlement that exceed our coverage limitations or that are not covered by our insurance, and we may not have,
or be able to obtain, sufficient capital to pay such amounts.
We may acquire businesses or products, or form strategic alliances in the future, and we may not realize the
benefits of such acquisitions or alliances.
We may acquire additional businesses or products, form strategic alliances or create joint ventures with third parties that we believe will
complement or augment our existing business. If we acquire businesses with promising markets or technologies, we may not be able to realize the benefit of acquiring such businesses if we are unable to
successfully integrate them with our existing operations and company culture. We may encounter numerous difficulties in developing, manufacturing and marketing any new products resulting from a
strategic alliance or acquisition that delay or prevent us from realizing their expected benefits or enhancing our business. We cannot assure you that, following any such acquisition, we will achieve
the expected synergies to justify the transaction.
Our business is affected by macroeconomic conditions.
Various macroeconomic factors could adversely affect our business and the results of our operations and financial condition, including changes
in inflation, interest rates and foreign currency exchange rates, and overall economic conditions and uncertainties, including those resulting from political instability and the current and future
conditions in the global financial markets. For instance, if inflation or other factors were to significantly increase our business costs, it may not be feasible to pass through price increases to
patients. Interest rates, the liquidity of the credit markets and the volatility of the capital markets could also affect the value of our investments and our ability to liquidate our investments in
order to fund our operations, if necessary.
Interest
rates and the ability to access credit markets could also adversely affect the ability of patients, payors and distributors to purchase, pay for and effectively distribute our
products if and when approved. Similarly, these macroeconomic factors could affect the ability of our current or potential
future contract manufacturers, sole-source or single-source suppliers, or licensees to remain in business or otherwise manufacture or supply our product candidates. Failure by any of them to remain in
business could affect our ability to manufacture product candidates.
We continue to incur significant increased costs as a result of operating as a public company, and our
management is required to devote substantial time to compliance initiatives.
As a public company, we continue to incur significant legal, accounting and other expenses that we did not incur as a private company. In
addition, the Sarbanes-Oxley Act, as well as rules subsequently implemented by the SEC and the NASDAQ Global Market, impose various requirements on public companies, including requiring establishment
and maintenance of effective disclosure controls and internal control over financial reporting and changes in corporate governance practices. Our management and other personnel devote a substantial
amount of time to these compliance initiatives.
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Moreover,
these rules and regulations have increased our legal and financial compliance costs and have made some activities more time-consuming and costly. We estimate that we will annually incur
approximately $2.0 million in expenses in response to these requirements.
Section 404(a)
of the Sarbanes-Oxley Act requires annual management assessments of the effectiveness of our internal control over financial reporting, starting with the second
annual report that we would expect to file with the SEC. However, for as long as we remain an "emerging growth company" as defined in the Jumpstart Our Business Startups Act of 2012, or JOBS Act, we
intend to take advantage of certain exemptions from various reporting requirements that are applicable to other public companies that are not "emerging growth companies" including, but not limited to,
not being required to comply with the auditor attestation requirements of Section 404(b) of the Sarbanes-Oxley Act. We may take advantage of these reporting exemptions until we are no longer an
"emerging growth company." We will remain an "emerging growth company" until the earliest of (i) the last day of the fiscal year in which we have total annual gross revenues of
$1.0 billion or more; (ii) the last day of our fiscal year following the fifth anniversary of the date of the completion of our initial public offering; (iii) the date on which we
have issued more than $1.0 billion in nonconvertible debt during the previous three years; or (iv) the date on which we are deemed to be a large accelerated filer under the rules of the
SEC.
Our
testing, or the subsequent testing by our independent registered public accounting firm, may reveal deficiencies in our internal control over financial reporting that are deemed to
be material weaknesses.
We will incur substantial accounting expense and expend significant management efforts to comply with internal control over financial reporting requirements. We currently do not have an internal audit
group, and we may need to hire additional accounting and financial staff with appropriate public company experience and technical accounting knowledge. Moreover, if we are not able to comply with
these requirements in a timely manner or if we or our independent registered public accounting firm identifies deficiencies in our internal control over financial reporting that are deemed to be
material weaknesses, the market price of our stock could decline, and we could be subject to sanctions or investigations by the NASDAQ Global Market, the SEC or other regulatory authorities, which
would require additional financial and management resources.
Business interruptions could delay us in the process of developing our product candidates and could disrupt
our sales.
Our headquarters are located in Princeton, New Jersey, and Corium, our contract manufacturer, is located in Grand Rapids, Michigan. We are
vulnerable to natural disasters, such as severe storms and other events that could disrupt our or Corium's operations. We do not carry insurance for natural disasters and we may not carry sufficient
business interruption insurance to compensate us for losses that may occur. Any losses or damages we incur could have a material adverse effect on our business operations.
Our business and operations would suffer in the event of system failures.
Despite the implementation of security measures, our internal computer systems, and those of our CROs and other third parties on which we rely,
are vulnerable to damage from computer viruses, unauthorized access, natural disasters, terrorism, war and telecommunication and electrical failures. If such an event were to occur and cause
interruptions in our operations, it could result in a material disruption of our drug development programs. For example, the loss of clinical trial data from completed or ongoing or planned clinical
trials could result in delays in our regulatory approval efforts and significantly increase our costs to recover or reproduce the data. To the extent that any disruption or security breach were to
result in a loss of or damage to our data or applications, or inappropriate disclosure of confidential or proprietary information, we could incur liability and the further development of our product
candidates could be delayed.
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Our employees, independent contractors, principal investigators, CROs, consultants, commercial partners and
vendors may engage in misconduct or other improper activities, including noncompliance with regulatory standards and requirements and insider trading, which could significantly harm our business.
We are exposed to the risk that employees, independent contractors, principal investigators, CROs, consultants, commercial partners and vendors
may engage in fraudulent or other illegal activity, fraud or other misconduct. Misconduct by these parties could include intentional, reckless or negligent conduct or disclosure of unauthorized
activities to us that violates: (i) the law and regulations of the FDA and non-U.S. regulators, including those laws that require the reporting of true, complete and accurate information to the
FDA and non-U.S. regulators, (ii) healthcare fraud and abuse laws and regulations in the United States and abroad and (iii) laws that require the true, complete and accurate reporting of
financial information or data. In particular, sales, marketing and business arrangements in the healthcare industry are subject to extensive laws and regulations intended to prevent fraud, misconduct,
kickbacks, self-dealing and other abusive practices. These laws and regulations may restrict or prohibit a wide range of pricing, discounting, marketing and promotion, sales commission, customer
incentive programs and other business arrangements. Misconduct in violation of these laws may also involve the improper use of information obtained in the course of
clinical trials, which could result in regulatory sanctions and serious harm to our reputation. We have adopted a code of conduct, but it is not always possible to identify and deter misconduct by our
employees and other third parties, and the precautions we take to detect and prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from
governmental investigations or other actions or lawsuits stemming from a failure to comply with these laws or regulations. If any such actions are instituted against us, and we are not successful in
defending ourselves or asserting our rights, those actions could have a significant impact on our business, including regulatory enforcement actions, the imposition of significant civil, criminal and
administrative penalties, damages, monetary fines, possible exclusion from participation in Medicare, Medicaid and other federal healthcare programs, corporate integrity agreements, contractual
damages, reputational harm, diminished profits and future earnings and curtailment of our operations, any of which could adversely affect our ability to operate our business and our results of
operations.
Our ability to use net operating loss and tax credit carryforwards and certain built-in losses to reduce
future tax payments may be limited by provisions of the Internal Revenue Code, and may be subject to further limitation as a result of our initial public offering.
Sections 382 and 383 of the Internal Revenue Code of 1986, as amended, or the Code, contain rules that limit the ability of a company
that undergoes an ownership change, which is generally any change in ownership of more than 50% of its stock over a three-year period, to utilize its net operating loss and tax credit carryforwards
and certain built-in losses recognized in years after the ownership change. These rules generally operate by focusing on ownership changes involving stockholders owning, directly or indirectly, 5% or
more of the stock of a company and any change in ownership arising from a new issuance of stock by the company. Generally, if an ownership change occurs, the yearly taxable income limitation on the
use of net operating loss and tax credit carryforwards and certain built-in losses is equal to the product of the applicable long-term tax exempt rate and the value of the company's stock immediately
before the ownership change. We may be unable to offset future taxable income, if any, with losses, or our tax liability with credits, before such losses and credits expire and therefore would incur
larger federal income tax liability.
In
addition, it is possible that the transactions relating to our initial public offering, either on a standalone basis or when combined with future transactions, has caused us to
undergo one or more additional ownership changes. In that event, we generally would not be able to use our pre-change loss or credit carryovers or certain built-in losses prior to such ownership
change to offset future taxable income in excess of the annual limitations imposed by Sections 382 and 383. We have not completed a
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study
to assess whether an ownership change has occurred, or whether there have been multiple ownership changes since our inception.
Risks Related to Ownership of Our Common Stock
An active trading market for our common stock may not be sustained.
In May 2014, we closed our initial public offering. Prior to our initial public offering, there was no public market for shares of our common
stock. Although we have completed our initial public offering and shares of our common stock are listed and trading on The NASDAQ Global Market, an active trading market for our shares may not be
sustained. If an active market for our common stock does not continue, it may be difficult for our stockholders to sell their shares without depressing the market price for the shares or sell their
shares at or above the prices at which they acquired their shares or sell their shares at the time they would like to sell. Any inactive trading market for our common stock may also impair our ability
to raise capital to continue to fund our operations by selling shares.
We expect that our stock price may fluctuate significantly.
Prior to our initial public offering, you could not buy or sell our common stock publicly. The trading price of our common stock is highly
volatile and is subject to wide fluctuations in response to various factors, some of which are beyond our control, including limited trading volume. In addition to the factors discussed in this "Risk
Factors" section and elsewhere in this quarterly report, these factors include:
-
-
Any delay in filing our response to the CRL received from the FDA with respect to Twirla and any adverse development or perceived adverse
development with respect to the FDA's review of our response;
-
-
Adverse results in our SECURE Phase 3 clinical trial for Twirla;
-
-
Our failure to commercialize Twirla, if approved, or develop and commercialize additional product candidates;
-
-
Unanticipated efficacy, safety or tolerability concerns related to the use of Twirla;
-
-
Regulatory actions with respect to Twirla;
-
-
Inability to obtain adequate product supply of Twirla or inability to do so at acceptable prices;
-
-
Adverse results or delays in our clinical trials for our other product candidates;
-
-
Changes in laws or regulations applicable to Twirla or any future product candidates, including but not limited to clinical trial requirements
for approvals;
-
-
Actual or anticipated fluctuations in our financial condition and operating results;
-
-
Actual or anticipated changes in our growth rate relative to our competitors;
-
-
Competition from existing products or new products that may emerge;
-
-
Announcements by us, our collaborators or our competitors of significant acquisitions, strategic partnerships, joint ventures, collaborations
or capital commitments;
-
-
Failure to meet or exceed financial estimates and projections of the investment community or that we provide to the public;
-
-
Issuance of new or updated research or reports by securities analysts;
-
-
Fluctuations in the valuation of companies perceived by investors to be comparable to us;
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Share price and volume fluctuations attributable to inconsistent trading volume levels of our shares;
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-
Additions or departures of key management or scientific personnel;
-
-
Disputes or other developments related to proprietary rights, including patents, litigation matters and our ability to obtain patent protection
for our technologies;
-
-
Announcement or expectation of additional debt or equity financing efforts;
-
-
Sales of our common stock by us, our insiders or our other stockholders; and
-
-
General economic and market conditions.
These
and other market and industry factors may cause the market price and demand for our common stock to fluctuate substantially, regardless of our actual operating performance, which
may limit or prevent investors from readily selling their shares of common stock and may otherwise negatively affect the liquidity of our common stock. In addition, the stock market in general, and
the NASDAQ Global Market and the stock prices of pharmaceutical companies in particular, have experienced extreme price and volume fluctuations that have often been unrelated or disproportionate to
the operating performance of these companies. In the past, when the market price of a stock has been volatile, holders of that stock have instituted securities class action litigation against the
company that issued the stock. If any of our stockholders brought a lawsuit against us, we could incur substantial costs defending the lawsuit. Such a lawsuit could also divert the time and attention
of our management. For example, two complaints have been filed in federal court in the District of New Jersey on January 6, 2017 and January 20, 2017, titled
Peng
v. Agile Therapeutics, Inc., Alfred Altomari, and Elizabeth Garner
, No. 17-cv-119 (D.N.J.), and
Lichtenthal v. Agile
Therapeutics, Inc., Alfred Altomari, and Elizabeth Garner
,
No. 17-cv-405 (D.N.J.), respectively, on behalf of a putative class of investors who purchased stock from March 9, 2016 through January 3, 2017. The complaints allege violations
of the federal securities laws based on public statements made regarding the Company's Phase 3 "SECURE" clinical trial. We deny all allegations in the complaints and we plan to vigorously
defend the complaints that have been filed.
Future sales of shares of our common stock by existing stockholders could cause our stock price to decline.
If our existing stockholders sell substantial amounts of our common stock in the public market, or if the public perceives that such sales could
occur, this could have an adverse impact on the market price of our common stock, even if there is no relationship between such sales and the performance of our business.
As
of March 10, 2017, we had 28,776,398 shares of common stock outstanding. Of these shares, 25,150,683 shares of common stock are freely tradeable, without restriction, in the
public market. Moreover, a relatively small number of our stockholders own large blocks of shares. We cannot predict the effect, if any, that public sales of these shares or the availability of these
shares for sale will have on the market price of our common stock
In
addition, the 3,983,387 shares subject to outstanding options under our stock option plans and the 724,030 shares reserved for future issuance under our stock option plans will become
eligible for sale in the public market in the future, subject to certain legal and contractual limitations.
We may be subject to securities litigation, which is expensive and could divert management attention.
Our market price of our common stock may be volatile, and in the past companies that have experienced volatility in the market price of their
stock have been subject to securities class action litigation. We may be the target of this type of litigation. Litigation of this type could result in substantial costs and diversion of management's
attention and resources, which could adversely impact
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our
business. Any adverse determination in litigation could also subject us to significant liabilities. For example, two complaints have been filed in federal court in the District of New Jersey on
January 6, 2017 and January 20, 2017, titled
Peng v. Agile Therapeutics, Inc., Alfred Altomari, and Elizabeth Garner
,
No. 17-cv-119 (D.N.J.), and
Lichtenthal v. Agile Therapeutics, Inc., Alfred Altomari, and Elizabeth Garner
, No. 17-cv-405 (D.N.J.),
respectively, on behalf of a putative class of investors who purchased stock from March 9, 2016 through January 3, 2017. The complaints allege violations of the federal securities laws
based on public statements made regarding the Company's Phase 3 "SECURE" clinical trial. We deny all allegations in the complaints and we plan to vigorously defend the complaints that have been
filed.
Our existing principal stockholders, executive officers and directors own a significant percentage of our
common stock and will be able to exert a significant control over matters submitted to our stockholders for approval.
As of December 31, 2016, our executive officers, directors, director nominees, holders of 5% or more of our capital stock and their
respective affiliates together beneficially owned approximately 66.9% of our outstanding voting stock.
This
significant concentration of share ownership may adversely affect the trading price for our common stock because investors often perceive disadvantages in owning stock in companies
with controlling stockholders. As a result, these stockholders, if they acted together, could significantly influence all matters requiring approval by our stockholders, including the election of
directors and the approval of mergers or other business combination transactions. These stockholders may be able to determine all matters requiring stockholder approval. The interests of these
stockholders may not always coincide with our interests or the interests of other stockholders. This may also prevent or discourage unsolicited acquisition proposals or offers for our common stock
that other stockholders may feel are in their best interest and our large stockholders may act in a manner that advances their best interests and not necessarily those of other stockholders, including
seeking a premium value for their common stock, and might affect the prevailing market price for our common stock.
We will have broad discretion in how we use the net proceeds from our initial public offering, our private
placement and our recently completed public offering. We may not use these proceeds effectively, which could affect our results of operations and cause our stock price to decline.
We will have considerable discretion in the application of the net proceeds from our initial public offering, our private placement and our
recently completed public offering. We intend to use the majority of the net proceeds from our initial public offering, our private placement and our
recently completed public offering to conduct a Phase 3 clinical trial for Twirla, obtain marketing approval and begin preparations for the U.S. commercial launch of Twirla, continue the
equipment qualification and validation related to the expansion of Corium's manufacturing capabilities, develop our product pipeline, and for working capital and other general corporate purposes,
which may include funding for the hiring of additional personnel, validation of capital equipment and the costs of operating as a public company. As a result, investors will be relying upon
management's judgment with only limited information about our specific intentions for the use of the balance of the net proceeds from our initial public offering, our private placement and our
recently completed public offering. We may use the net proceeds for purposes that do not yield a significant return or any return at all for our stockholders. In addition, pending their use, we may
invest the net proceeds from our initial public offering, our private placement and our recently completed public offering in a manner that does not produce income or that loses value.
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We are an "emerging growth company" and will be able to avail ourselves of reduced disclosure requirements
applicable to emerging growth companies, which could make our common stock less attractive to investors.
We are an "emerging growth company," as defined in the JOBS Act, and we intend to take advantage of certain exemptions from various reporting
requirements that are applicable to other public companies that are not "emerging growth companies" including not being required to comply with the auditor attestation requirements of
Section 404(b) of the Sarbanes-Oxley Act, reduced disclosure obligations regarding executive compensation in our periodic reports and proxy statements, and exemptions from the requirements of
holding a nonbinding advisory vote on executive compensation and shareholder approval of any golden parachute payments not previously approved. We cannot predict if investors will find our common
stock less attractive because we may rely on these exemptions. If some investors find our common stock less attractive as a result, there may be a less active trading market for our common stock and
our stock price may be more volatile. We may take advantage of these reporting exemptions until we are no longer an "emerging growth company." We will remain an "emerging growth company" until the
earliest of (i) the last day of the fiscal year in which we have total annual gross revenues of $1.0 billion or more; (ii) the last day of our fiscal year following the fifth
anniversary of the date we completed our initial public offering; (iii) the date on which we have issued more than $1.0 billion in nonconvertible debt during the previous three years; or
(iv) the date on which we are deemed to be a large accelerated filer under the rules of the SEC.
Our status as an "emerging growth company" under the JOBS Act may make it more difficult to raise capital as
and when we need it.
Because of the exemptions from various reporting requirements allowed to us as an "emerging growth company" we may be less attractive to
investors and it may be difficult for us to raise additional capital as and when we need it. Investors may be unable to compare our business with other companies in our industry if they believe that
our financial accounting is not as transparent as other companies in our industry. If we are unable to raise additional capital as and when we need it, our financial condition and results of
operations may be materially and adversely affected.
If we fail to maintain an effective system of internal control over financial reporting in the future, we may
not be able to accurately report our financial condition, results of operations or cash flows, which may adversely affect investor confidence in us and, as a result, the value of our common stock.
Effective internal controls over financial reporting are necessary for us to provide reliable financial reports and, together with adequate
disclosure controls and procedures, are designed to prevent fraud. Any failure to implement required new or improved controls, or difficulties encountered in their implementation, could cause us to
fail to meet our reporting obligations. In addition, any testing by us conducted in connection with Section 404 of the Sarbanes-Oxley Act, or the subsequent testing by our independent
registered public accounting firm, may reveal deficiencies in our internal controls over financial reporting that are deemed to be material weaknesses or that may require prospective or retroactive
changes to our financial statements or identify other areas for further attention or improvement. If we are unable to conclude that our internal control over financial reporting is effective, or if
our independent registered public accounting firm determines we have a material weakness or significant deficiency in our internal control over financial reporting once that firm begin its
Section 404 reviews, we could lose investor confidence in the accuracy and completeness of our financial reports, the market price of our common stock could decline, and we could be subject to
sanctions or investigations by the NASDAQ Global Market, the SEC or other regulatory authorities. Failure to remedy any material weakness in our internal control over financial reporting, or to
implement or maintain other effective control systems required of public companies, could also restrict our future access to the capital markets.
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Our disclosure controls and procedures may not prevent or detect all errors or acts of fraud.
We are subject to the periodic reporting requirements of the Securities Exchange Act of 1934, as amended, or the Exchange Act. Our disclosure
controls and procedures are designed to reasonably assure that information required to be disclosed by us in reports we file or submit under the Exchange Act is accumulated and communicated to
management, recorded, processed, summarized and reported within the time periods specified in the rules and forms of the SEC. We believe that any disclosure controls and procedures or internal
controls and procedures, no matter how well conceived and operated, can provide only reasonable, not absolute, assurance that the objectives of the control system are met.
These
inherent limitations include the realities that judgments in decision-making can be faulty, and that breakdowns can occur because of simple error or mistake. Additionally, controls
can be circumvented by the individual acts of some persons, by collusion of two or more people or by an unauthorized override of the controls. Accordingly, because of the inherent limitations in our
control system, misstatements or insufficient disclosures due to error or fraud may occur and not be detected.
We have never paid dividends on our common stock and we do not anticipate paying any dividends in the
foreseeable future. Consequently, any gains from an investment in our common stock will likely depend on whether the price of our common stock increases.
We have not paid dividends on our common stock to date and we currently intend to retain our future earnings, if any, to fund the development
and growth of our business. As a result, capital appreciation, if any, of our common stock will be your sole source of gain for the foreseeable future. Consequently, in the foreseeable future, you
will likely only experience a gain from your investment in our common stock if the price of our common stock increases.
If equity research analysts do not publish research or reports about our business or if they issue
unfavorable commentary or downgrade our common stock, the price of our common stock could decline.
The trading market for our common stock relies in part on the research and reports that equity research analysts publish about us and our
business. We do not control these analysts. The price of our common stock could decline if one or more equity analysts downgrade our common stock or if analysts issue other unfavorable commentary or
cease publishing reports about us or our business.
Anti-takeover provisions in our organizational documents and Delaware law may discourage or prevent a change
of control, even if an acquisition would be beneficial to our stockholders, which could affect our stock price adversely and prevent attempts by our stockholders to replace or remove our current
management.
Our amended and restated certificate of incorporation and amended and restated bylaws contain provisions that could delay or prevent a change of
control of our company or changes in our board of directors that our stockholders might consider favorable. Some of these provisions:
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Authorize the issuance of preferred stock which can be created and issued by the board of directors without prior stockholder approval, with
rights senior to those of our common stock;
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Provide for a classified board of directors, with each director serving a staggered three-year term;
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Prohibit our stockholders from filling board vacancies, calling special stockholder meetings or taking action by written consent;
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Provide for the removal of a director only with cause and by the affirmative vote of the holders of 75% or more of the shares then entitled to
vote at an election of our directors;
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Require advance written notice of stockholder proposals and director nominations; and
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Require any action instituted against our officers or directors in connection with their service to the Company to be brought in the state of
Delaware.
In
addition, we are subject to the provisions of Section 203 of the Delaware General Corporation Law, which may prohibit certain business combinations with stockholders owning 15%
or more of our outstanding voting stock. These and other provisions in our amended and restated certificate of incorporation, amended and restated bylaws and Delaware law could make it more difficult
for stockholders or potential acquirers to obtain control of our board of directors or initiate actions that are opposed by our then-current board of directors, including a merger, tender offer or
proxy contest involving our company. This provision could have the effect of delaying or preventing a change of control, whether or not it is desired by or beneficial to our stockholders. Any delay or
prevention of a change of control transaction or changes in our board of directors could cause the market price of our common stock to decline.