Item 1. Business
Overview
We are a leader in RNA-targeted therapeutics. We believe our medicines, which are based on our novel antisense technology, have the
potential to pioneer new markets, change standards of care and transform the lives of people with devastating diseases. We currently have three marketed medicines- SPINRAZA, TEGSEDI and WAYLIVRA. We also have a rich late-stage pipeline of medicines,
primarily focused on our cardiovascular and neurology franchises. Our late-stage pipeline consists of six medicines in Phase 3 development for eight indications.
Over the past year, we made important progress toward achieving our goal to be a leading fully integrated biotechnology company. We
advanced our commercial strategy and go-to-market plans for our near-term commercial opportunities, eplontersen, olezarsen and donidalorsen. We entered an agreement with AstraZeneca to jointly develop and commercialize eplontersen. We believe this
agreement positions eplontersen to maximize value for patients and shareholders while also enabling us to bolster our commercial organization and accelerate our preparations for our near-term product launches.
We continued to advance and expand our Phase 3 pipeline with the achievement of key enrollment milestones for eplontersen and pelacarsen,
and the addition of two new Phase 3 programs for olezarsen and donidalorsen, bringing us to 6 medicines in Phase 3 development addressing 8 indications. In 2021, we also reported data from the Phase 3 VALOR study of tofersen in patients with SOD1-ALS.
While VALOR did not achieve statistical significance in the primary endpoint, signs of reduced disease progression were observed across multiple secondary and exploratory endpoints. Biogen is actively engaged with regulators to determine the next steps
for tofersen. In addition, Roche recently announced plans to initiate a new Phase 2 study of tominersen in patients with Huntington’s disease, based on new findings from a post hoc analysis of the Phase 3 GENERATION HD1 study of tominersen.
Our mid-stage pipeline also continued to perform well, with positive data readouts from several medicines. And we invested in expanding
the reach of our technology, including obtaining exclusive rights to Bicycle Therapeutic’s peptide technology targeting transferrin receptor 1 to expand the capabilities of our Ligand Conjugated Antisense, or LICA, technology. We strengthened our
financial position and focused our resources in support of our highest priority programs through the integration of Akcea Therapeutics and our distribution agreements with Swedish Orphan Biovitrum AB, or Sobi. We accomplished all this and exceeded our
2021 financial guidance, including achieving revenues of $810 million. And we remain well capitalized with a 2021 year-end cash balance of $2.1 billion.
Our multiple sources of revenue and strong balance sheet enable us to invest in our strategic
priorities to build our commercial pipeline, expand and diversify our technology and deliver new medicines to the market. By continuing to focus on these priorities, we believe we are well positioned to drive future growth and to deliver increasing
value for patients and shareholders.
Marketed Medicines
SPINRAZA is the global foundation-of-care for the treatment of patients of all ages with spinal muscular atrophy, or SMA, a progressive,
debilitating and often fatal genetic disease. Biogen, our partner responsible for commercializing SPINRAZA worldwide, reported that as of December 31, 2021, over 11,000 patients were on SPINRAZA therapy in markets around the world. From inception
through December 31, 2021, we have earned more than $1.6 billion in revenues from our SPINRAZA collaboration, including nearly $1.2 b
illion in royalties on sales of SPINRAZA.
TEGSEDI is a once weekly, self-administered subcutaneous medicine approved in the U.S., Europe, Canada and Brazil for the treatment of
patients with polyneuropathy caused by hATTR, a debilitating, progressive, and fatal disease. We launched TEGSEDI in the U.S. and the European Union, or EU, in late 2018. In 2021, we began selling TEGSEDI in Europe through our distribution agreement
with Sobi. Additionally, in the second quarter of 2021, Sobi began distributing TEGSEDI in the U.S. and Canada. In Latin America, PTC Therapeutics International Limited, or PTC, is commercializing TEGSEDI in Brazil and is pursuing access in additional
Latin American countries through its exclusive license agreement with us.
WAYLIVRA is a once weekly, self-administered, subcutaneous medicine that received conditional marketing authorization in May 2019 from the
European Commission, or EC, as an adjunct to diet in adult patients with genetically confirmed familial chylomicronemia syndrome, or FCS, and at high risk for pancreatitis. We launched WAYLIVRA in the EU in the third quarter of 2019. In 2021, we began
selling WAYLIVRA in Europe through our distribution agreement with Sobi. Through our exclusive license agreement with PTC, PTC is working to provide access to WAYLIVRA across Latin America, beginning in Brazil. In the third quarter of 2021, the
National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária), or
ANVISA, approved WAYLIVRA in Brazil. In December 2021, PTC submitted an application to ANVISA for approval of WAYLIVRA for the
treatment of familial partial lipodystrophy, or FPL, in Brazil. If approved, Waylivra will be the first approved treatment for patients with FPL in Brazil.
Under our distribution agreements with Sobi, we retained the marketing authorizations for TEGSEDI and WAYLIVRA. We will continue to supply
commercial product to Sobi and manage regulatory and manufacturing processes, as well as relationships with key opinion leaders. We will also continue to lead the TEGSEDI and WAYLIVRA global commercial strategy. In connection with the agreements, we
restructured our European operations in the first quarter of 2021, and we restructured our North American TEGSEDI operations in the second quarter of 2021.
Medicines in Phase 3 Studies
We currently have six medicines in Phase 3 studies for eight indications, which include:
|
● |
Eplontersen: In July 2021, we achieved full enrollment in the NEURO-TTRansform Phase 3 study with data expected mid-2022. Enrollment is ongoing in the CARDIO-TTRansform
Phase 3 study
|
|
o |
In November 2021, we entered into an agreement with AstraZeneca for eplontersen, under which we will jointly develop and commercialize eplontersen in the U.S. AstraZeneca
has exclusive rights to commercialize eplontersen in the rest of the world
|
|
● |
Olezarsen: We initiated the Phase 3 CORE study in patients with severe hypertriglyceridemia, or SHTG, in October 2021. Enrollment is ongoing in the BALANCE Phase 3 study
in patients with FCS
|
|
o |
Data from the Phase 2 study of olezarsen in patients with moderate hypertriglyceridemia and at high risk for or with established cardiovascular disease were published in
the European Heart Journal
|
|
● |
Donidalorsen: Based on positive topline data from a Phase 2 study of donidalorsen in patients with hereditary angioedema which we reported in April 2021, we initiated the
Phase 3 OASIS-HAE study in November 2021
|
|
o
|
We reported additional positive results from the Phase 2 study of donidalorsen at the ACAAI annual scientific meeting in November 2021, demonstrating
rapid and sustained reductions in HAE attacks with favorable safety and tolerability
|
|
● |
ION363: In April 2021, we initiated a Phase 3 study in patients with amyotrophic
lateral sclerosis, or ALS, with mutations in the fused in sarcoma gene, or FUS, or FUS-ALS, the most common cause of juvenile-onset ALS
|
|
● |
Pelacarsen: In August 2021, Novartis achieved 50 percent enrollment in Novartis’ Lp(a) HORIZON Phase 3 cardiovascular outcome study in patients with established
cardiovascular disease and elevated lipoprotein(a), or Lp(a)
|
|
● |
Tofersen: In October 2021, Biogen reported that tofersen did not meet the primary clinical endpoint in the Phase 3 VALOR study; however, trends favoring tofersen were
seen across multiple secondary and exploratory measures of disease activity and clinical function
|
|
o |
Biogen is actively engaging with regulators, the medical community, patient advocacy groups and other key stakeholders around the world to determine potential next
steps
|
|
o |
Given the high unmet medical need, Biogen expanded its ongoing early access program, or EAP, to the broader SOD1-ALS population
|
|
o |
The Phase 3 ATLAS study in patients with presymptomatic SOD1-ALS is ongoing
|
COVID-19
As a company focused on improving the health of people around the world, our priority during the COVID-19 pandemic
is the safety of our employees, their families, the healthcare workers who work with us and the patients who rely on our medicines. We are also focused on maintaining the quality of our studies and minimizing the impact to timelines. While the
COVID-19 pandemic has impacted some areas of our business, we believe our mitigation efforts and financial strength will enable us to continue to manage through the pandemic and execute on our strategic initiatives. Because the situation is extremely
fluid, we are continuing to evaluate the impact COVID-19 could have on our business, including the impact on our commercial products and the medicines in our pipeline.
Our Marketed Medicines – Potentially Transformational Medicines Bringing Value to Patients Today
SPINRAZA –
SPINRAZA (nusinersen) injection for intrathecal use is a survival motor neuron-2, or SMN2, directed antisense medicine indicated for the treatment of SMA in pediatric and adult patients.
SPINRAZA continues to demonstrate substantial benefit in SMA patients of all ages, supporting its position as a global foundation of care
for the treatment of SMA. Biogen, our worldwide commercial partner, reported that as of December 31, 2021, there were more than 11,000 patients on SPINRAZA therapy.
SMA is characterized by loss of motor neurons
in the spinal cord and lower brain stem, People with SMA have a deletion or defect in their SMN1 gene and rely on their SMN2 gene to produce functional SMN protein, which motor neurons need to maintain motor function and muscle strength. However, the SMN2 gene can only produce approximately 10 percent of the SMN protein critical
for motor neurons, resulting in severe and progressive loss of motor function and strength.
The rate and severity of degeneration varies depending on the amount of functional SMN protein a patient can produce. Type
1, or infantile-onset, SMA is the most severe form of the disease. Type 1 SMA patients produce very little SMN protein and often progress to death or permanent ventilation by the age of 2. Patients with Type 2 or Type 3, or later-onset, SMA produce
more SMN protein, but also suffer from a progressive loss of muscle strength and function and a reduced life expectancy.
Biogen continues to expand the body of evidence supporting SPINRAZA’s durable efficacy and well-established safety
profile to address the remaining needs of SMA patients of all ages. In the Phase 2/3 DEVOTE study, Biogen is evaluating the safety and potential to achieve increased efficacy with a higher dose of SPINRAZA compared to the currently approved dose. At
the AAN 2021 Virtual Annual meeting in April 2021, Biogen reported that initial findings from the DEVOTE study suggest no new safety concerns and support continued development of a higher dose of SPINRAZA.
In January 2021, Biogen initiated the Phase
4 RESPOND study evaluating the benefit of SPINRAZA in infants and children with a suboptimal clinical response to the gene therapy, onasemnogene abeparvovec.
And in September 2021, Biogen initiated the Phase 3b ASCEND study designed to evaluate the clinical outcomes and assess
the safety of a higher dose of SPINRAZA in children, teens and adults with later-onset SMA following treatment of risdiplam.
Additionally, Biogen continues to conduct
the Phase 2 NURTURE study, an open-label study investigating the benefit of SPINRAZA when administered before symptom onset in patients genetically diagnosed with SMA, and likely to develop Type 1 or Type 2 SMA. NURTURE was the first study to
investigate the potential to slow or stop SMA disease progression in presymptomatic SMA patients. In June 2021, Biogen reported data from an interim analysis, showing that all study patients remain alive without the need for permanent ventilation.
Additionally, at the time of the interim analysis, 92 percent of patients maintained the ability to swallow.
The approval of SPINRAZA was based on efficacy and safety data from multiple clinical studies, including two randomized,
placebo-controlled Phase 3 studies, ENDEAR, in patients with infantile-onset SMA, and CHERISH, in patients with later-onset SMA as well as from SHINE, an open-label extension, or OLE, study for patients with SMA who participated in prior SPINRAZA
studies.
TEGSEDI – TEGSEDI (inotersen)
injection is an RNA-targeted medicine indicated for the treatment of polyneuropathy due to hATTR in adults. TEGSEDI prevents the creation of TTR proteins,
reducing the amount of amyloid that builds up, which damages organs and issues.
Polyneuropathy due to hATTR is caused by the accumulation of misfolded mutated TTR protein in the peripheral nerves. Patients with
polyneuropathy due to hATTR experience ongoing debilitating nerve damage throughout their body resulting in the progressive loss of motor functions, such as walking. These patients also accumulate TTR in other major organs, which progressively
compromises their function and eventually leads to death within five to fifteen years of disease onset. There are an estimated 40,000 patients with polyneuropathy due to hATTR worldwide.
TEGSEDI is commercially available in numerous countries, including the U.S., many European countries, Canada, and Latin America. In 2021, we began selling TEGSEDI in Europe through our distribution agreement with Sobi. Additionally, in the second quarter of 2021, Sobi began distributing
TEGSEDI in the U.S. and Canada. In Latin America, PTC through its exclusive license agreement with us, is commercializing TEGSEDI in Brazil and is working to achieve access in additional Latin American countries.
The approvals of TEGSEDI were based on efficacy and safety data from the Phase 3 NEURO-TTR study in patients with hATTR amyloidosis with
stage 1 and stage 2 polyneuropathy. We also conducted an OLE study in patients with hATTR treated with TEGSEDI to evaluate the long-term efficacy and safety
profile of TEGSEDI. We reported interim data from the study that demonstrated continued efficacy in patients after two years. Results also showed that patients who started treatment earlier achieved greater long-term disease stabilization
compared to those who switched from placebo to TEGSEDI in the OLE study.
WAYLIVRA – WAYLIVRA (volanesorsen)
is an antisense medicine indicated as an adjunct to diet in adult patients with genetically confirmed FCS and at high risk for pancreatitis, in whom response to diet and triglyceride lowering therapy has been inadequate. WAYLIVRA reduces triglyceride levels by inhibiting the production of apolipoprotein C-III, or apoC-III, a protein that is a key regulator of triglyceride levels.
FCS is a rare, genetic disease estimated to affect 3,000 to 5,000 people worldwide and characterized by extremely elevated triglyceride
levels. FCS can lead to many chronic health issues including severe, recurrent abdominal pain, fatigue, high risk of life-threatening pancreatitis and abnormal enlargement of the liver or spleen. In addition, people with FCS are often unable to work,
adding to their disease burden. In severe cases, patients can have bleeding into the pancreas, serious tissue damage, infection, and cyst formation, as well as damage to other vital organs such as the heart, lungs, and kidneys.
WAYLIVRA is commercially available in multiple European countries and in Brazil. In 2021, we began selling WAYLIVRA in Europe through our distribution agreement with Sobi. In Latin America, PTC through its exclusive license agreement with us, is commercializing WAYLIVRA in Brazil and is
working to achieve access in additional Latin American countries.
WAYLIVRA’s conditional marketing authorization in the EU and approval in Brazil were based on efficacy and safety data from the Phase 3
APPROACH study, the ongoing APPROACH OLE study and supported by results from the Phase 3 COMPASS study.
Drug Discovery and Development
Introduction to Drug Discovery
Proteins are essential working molecules in a cell. Almost all human diseases result from inappropriate protein
production, improper protein activity or loss of a protein. Antisense medicines can modify the production of proteins by targeting RNAs. In this way, antisense medicines can inhibit the production of a disease-causing protein, modify the protein
produced or increase the production of a protein that, when absent, causes diseases. Antisense medicines can also treat diseases by targeting and reducing RNAs that may be causing diseases (so called “toxic RNAs”). RNAs are naturally occurring
molecules in the body that primarily act as messengers that carry the information the cell needs to produce proteins from the deoxyribonucleic acid, or DNA, to the protein making complex in the cell. When antisense medicines bind to the specific RNAs
of a particular gene, they will ultimately alter the production of the protein encoded in the target gene or, in the case of disease-causing RNAs, degrade the toxic RNAs.
Our Pipeline
We are a leader in the discovery and development of RNA-targeted therapeutics. We are focused on pioneering new markets
and changing standards of care with a focus on cardiovascular and neurological diseases. Additionally, we are developing a number of medicines that are outside these areas. We also have an emerging specialty rare disease pipeline comprised of medicines
which we believe represent a compelling opportunity for us. We are developing our medicines for systemic and local delivery (e.g., subcutaneous, intrathecal, intraocular, oral and aerosol). We plan to continue adding new investigational medicines to
our pipeline in the future.
We have built a rich pipeline of medicines designed to treat many serious diseases. To select the best candidates, we
efficiently screen many targets in parallel and apply our rational approach to selecting disease targets. With our expertise in discovering and characterizing novel antisense medicines, our scientists can optimize the properties of our antisense
medicines against each particular target. We have created LICA technology, which we designed to enhance the effective uptake and activity of our medicines in particular tissues. With our LICA technology we attach specific chemical structures or
molecules to our antisense medicines. With our first LICA conjugate, a complex sugar-like molecule called N-acetylgalactosamine, or GalNAc, we have shown an increase in medicinal potency of 20-30-fold for liver targets, compared to non-conjugated
antisense medicines. Many of the medicines in our pipeline are LICA medicines, including four LICA medicines currently in Phase 3 studies: eplontersen, olezarsen, donidalorsen and pelacarsen. We have utilized our chemistry advancements to expand the
therapeutic and commercial opportunities of our pipeline. Our antisense technology, along with our manufacturing and analytical processes that are the same across our medicines, shorten our timeline from initial concept to the first human dose, when
compared to early development timelines for other drug modalities like small molecule and monoclonal antibody medicines.
The table below lists the medicines in our clinical pipeline. We categorize patient studies to establish a medicine’s
safety profile as Phase 1/2 and those studies in healthy volunteers as Phase 1. The table includes the disease indication, a partner (if the medicine is partnered), and the development status of each medicine. We have included descriptions for each of
our medicines in Phase 2 and Phase 3 development below.
*China Only
Our Phase 3 Medicines
We currently have six medicines in Phase 3 studies for eight indications: eplontersen, olezarsen, donidalorsen, ION363, pelacarsen and
tofersen.
Eplontersen (TTR) – Eplontersen (formerly IONIS-TTR-LRx) is an
investigational LICA medicine we designed to inhibit the production of TTR protein. We are developing eplontersen as a monthly self-administered subcutaneous injection to treat all types of ATTR. ATTR amyloidosis is a systemic, progressive
and fatal disease in which patients experience multiple overlapping clinical manifestations caused by the inappropriate formation and aggregation of TTR amyloid deposits in various tissues and organs, including peripheral nerves, heart, intestinal
tract, eyes, kidneys, central nervous system, thyroid and bone marrow. The progressive accumulation of TTR amyloid deposits in these tissues and organs leads to organ failure and eventually death.
Polyneuropathy due to hATTR is caused by the accumulation of misfolded mutated TTR protein in the peripheral nerves. Patients with
polyneuropathy due to hATTR experience ongoing debilitating nerve damage throughout their body resulting in the progressive loss of motor functions, such as walking. These patients also accumulate TTR in other major organs, which progressively
compromises their function and eventually leads to death within five to fifteen years of disease onset. There are an estimated 40,000 patients with polyneuropathy due to hATTR worldwide.
ATTR cardiomyopathy is caused by the accumulation of misfolded TTR protein in the cardiac muscle. Patients experience ongoing
debilitating heart damage resulting in progressive heart failure, which results in death within 3 to 5 years from disease onset. ATTR cardiomyopathy includes both the genetic and wild-type form of the disease. There are an estimated 300,000 to
500,000 patients with ATTR cardiomyopathy worldwide.
Often patients with the polyneuropathy form of TTR amyloidosis will have TTR build up in the heart and experience cardiomyopathy
symptoms. Similarly, patients with the cardiomyopathy form of TTR amyloidosis may often have TTR build up in their peripheral nerves and experience nerve damage and progressive difficulty with motor functions.
In November 2019, we initiated the NEURO-TTRansform Phase 3 study of eplontersen in patients with polyneuropathy caused by hATTR
amyloidosis. NEURO-TTRansform is a global, multi-center, randomized, open-label study designed to evaluate the efficacy, safety and tolerability of
eplontersen. The NEURO-TTRansform study is fully enrolled with 168 patients. We expect data from the NEURO-TTRansform study in mid-2022. The current
study will be compared to the historical placebo arm from the TEGSEDI (inotersen) NEURO-TTR Phase 3 study. The NEURO-TTRansform study includes multiple primary endpoints, including the percent change from baseline in serum TTR concentration modified
Neuropathy Impairment Score +7, or mNIS+7, a measure of neuropathic disease progression and in the Norfolk Quality of Life Questionnaire-Diabetic
Neuropathy, or Norfolk QoL-DN.
In January 2020, we initiated the CARDIO-TTRansform Phase 3 cardiovascular outcome study of eplontersen in patients with ATTR
cardiomyopathy. CARDIO-TTRansform is a global, multi-center, randomized, double-blind, placebo-controlled study in up to 750 patients designed to
evaluate the efficacy, safety and tolerability of eplontersen. The CARDIO-TTRansform study includes co-primary outcome measures of cardiovascular death
and frequency of cardiovascular clinical events.
In September 2019, we reported results from the Phase 1 study with eplontersen in healthy volunteers at the Heart Failure Society of
America Annual Meeting. In this study, subjects treated with eplontersen achieved dose-dependent reductions of TTR protein of up to 94 percent and eplontersen had a favorable safety and tolerability profile supportive of continued development.
In January 2022, the FDA granted an Orphan Medicine Designation for eplontersen.
In December 2021, we entered into an agreement with AstraZeneca to jointly develop and commercialize eplontersen in the
U.S. AstraZeneca obtained exclusive rights to commercialize eplontersen outside the U.S, except for certain Latin American countries.
Olezarsen (ApoC-III) – Olezarsen (formerly IONIS-APOCIII-LRx) is an investigational LICA medicine we designed to inhibit
the production of apoC-III for patients who are at risk of disease due to elevated triglyceride levels. ApoC-III is a protein produced in the liver that regulates triglyceride metabolism in the blood. People with severely elevated triglycerides, such
as people with FCS, are at high risk for acute pancreatitis and an increased risk of CVD. It is estimated that there are between 3,000 to 5,000 patients with FCS worldwide and more than three million patients with severely high triglycerides in the
U.S.
In December 2020, we initiated our first Phase 3 study of olezarsen, BALANCE, in patients with FCS. BALANCE is a global,
multi-center, randomized, double-blind, placebo-controlled study enrolling up to 60 patients (age 18 and over) designed to assess the efficacy, safety and tolerability of olezarsen. The primary endpoint is percent change from baseline in fasting
triglyceride levels at six months compared to placebo.
In November 2021, we initiated a
second Phase 3 study of olezarsen, CORE, in patients with SHTG. CORE is a global, multi-center, randomized, double-blind, placebo-controlled study enrolling up to 450 patients designed to assess the efficacy, safety and tolerability of olezarsen. The
CORE study will compare olezarsen to placebo in patients with triglyceride levels equal to or greater than 500 mg/dL who are on currently available therapies for elevated triglycerides. The primary endpoint of the study is the percent change in fasting
triglycerides from baseline at month 6.
In January 2020, we reported positive
results from a Phase 2 clinical study in patients with hypertriglyceridemia and at high risk of or with established CVD. Olezarsen achieved statistically significant, dose-dependent reductions in fasting triglycerides compared to placebo at
all dose levels. Additionally, at the highest monthly dose, 91 percent of patients achieved serum triglycerides of ≤ 150 mg/dL, the recognized threshold for cardiovascular risk, compared to less than 5 percent of patients in the placebo group.
Olezarsen also achieved statistical significance in numerous key secondary endpoints, including significant reductions in apoC-III, very low-density lipoprotein cholesterol, or VLDL-C, and remnant cholesterol, and a statistically significant increase
in high-density lipoprotein cholesterol, or HDL-C. Olezarsen had a favorable safety and tolerability profile supportive of continued development.
Donidalorsen (PKK) – Donidalorsen (formerly IONIS-PKK-LRx) is an investigational LICA medicine we designed to inhibit the production of prekallikrein, or PKK,
to treat people with HAE. HAE is a rare genetic disease that is characterized by rapid and painful attacks of inflammation in the hands, feet, limbs, face, abdomen, larynx, and trachea and can be fatal if swelling occurs in the larynx. PKK plays an
important role in the activation of inflammatory mediators associated with acute attacks of HAE. By inhibiting the production of PKK, donidalorsen could be an effective prophylactic approach to preventing or reducing the severity of HAE attacks. It is
estimated that there are more than 20,000 patients with HAE in the U.S. and EU.
In November 2021, we initiated the Phase 3 study of donidalorsen, OASIS-HAE, in patients with HAE. OASIS-HAE is a multi-center,
randomized, double-blind placebo-controlled study in up to 84 patients designed to assess the efficacy, safety and tolerability of olezarsen. The primary endpoint is the time-normalized number of investigator-confirmed HAE attacks per month from Week 1
to Week 25.
In March 2021, we reported positive results
from a Phase 2 clinical study of donidalorsen in patients with HAE. Patients received either donidalorsen 80mg or placebo subcutaneously once monthly for 17 weeks. The Phase 2 study met its primary and secondary endpoints, achieving
significant reductions in the number of attacks suffered by patients with HAE compared to placebo. The study demonstrated a mean reduction of 90 percent in the number of monthly HAE attacks in weeks one to 17 of the study (p <0.001) and a mean
reduction of 97 percent in the number of monthly HAE attacks in weeks five to 17 (p=0.003). In weeks five to 17, 92 percent of patients treated with donidalorsen were attack-free compared to 0 percent in the placebo group (p <0.001). Additionally,
in November 2021 we reported additional data from the Phase 2 study, including that donidalorsen demonstrated an overall reduction in moderate to severe attacks starting with the second dose. For the final month of the study, all donidalorsen treated
patients were attack-free. Donidalorsen had a favorable safety and tolerability profile supportive of continued development.
In September 2020, results from the Phase 1 study of donidalorsen in healthy volunteers and a compassionate-use study of
IONIS-PKKRx and donidalorsen in patients living with severe angioedema were published in The New England Journal of Medicine. In the study, we observed that the medicines reduced plasma prekallikrein activity levels and showed evidence of clinical efficacy in reducing the number of
breakthrough attacks per month in patients over the course of the treatment, including complete resolution in a patient.
ION363 (FUS) – ION363 is an
investigational antisense medicine we designed to reduce the production of the FUS protein to treat people with ALS caused by mutations in the FUS gene. Because antisense-mediated reduction of mutant FUS protein in a FUS-ALS mouse model demonstrated
the ability to prevent motor neuron loss, it is hypothesized that reduction of FUS protein will reverse or prevent disease progression in FUS-ALS patients. It is estimated that there are approximately 350 patients with FUS-ALS in G7 countries
(comprised of Canada, France, Germany, Italy, Japan, the United Kingdom and the U.S.).
In April 2021, we initiated a Phase 3 study of ION363 in patients with FUS-ALS. The Phase 3 trial of ION363 is a global, multi-center,
randomized, double-blind, placebo-controlled study enrolling up to 64 patients designed to assess the efficacy, safety and tolerability of ION363. Part 1 of the trial will consist of patients randomized to receive a multi-dose regimen of ION363 or
placebo for 29 weeks, followed by Part 2, which will be an open-label period in which all patients in the trial will receive ION363 for 73 weeks. The primary endpoint is change from baseline as measured by the ALSFRS-R Total Score, time of rescue or
discontinuation from Part 1 and entering Part 2 due to a deterioration in function, and Ventilation Assistance-free survival, or VAFS.
Pelacarsen (Apo(a)) (TQJ230) – Pelacarsen (formerly IONIS-APO(a)-LRx) is an investigational LICA antisense
medicine we designed to inhibit the production of apolipoprotein(a), or Apo(a), in the liver to offer a direct approach for reducing Lp(a). Elevated Lp(a) is recognized as an independent, genetic cause of CVD. Lp(a) levels are determined at birth and
lifestyle modification, including diet and exercise, do not impact Lp(a) levels. Inhibiting the production of Apo(a) in the liver reduces the level of Lp(a) in blood, potentially slowing down or reversing cardiovascular disease in people with
hyperlipoproteinemia(a), a condition in which individuals have levels of Lp(a) greater than 50 mg/dL, the recognized threshold for risk of CVD. We believe antisense technology is well suited to address hyperlipoproteinemia(a) because antisense
technology specifically targets the RNA that codes for all forms of the Apo(a) molecule. Furthermore, we believe addressing elevated Lp(a) is the next important horizon in CVD risk reduction. It is estimated that there are more than eight million
people living with CVD and elevated levels of Lp(a).
In December 2019, Novartis initiated
the Phase 3 study of pelacarsen, Lp(a) HORIZON, in patients with elevated Lp(a) levels and a prior cardiovascular event. Lp(a) HORIZON is a global, multi-center, randomized, double-blind, placebo-controlled cardiovascular outcomes study in more than 8,000 patients designed to assess the efficacy,
safety and tolerability of pelacarsen. Patients will be treated with 80 mg of pelacarsen administered monthly by subcutaneous injection. The primary endpoint in Lp(a) HORIZON is the time to occurrence of first major adverse cardiovascular event, or MACE. In August 2021, we announced that the
Lp(a) HORIZON study had reached 50 percent enrollment.
In November 2018, we reported results of the Phase 2 study of pelacarsen in patients with hyperlipoproteinemia(a) at the American Heart
Association, or AHA, annual meeting. In the Phase 2 study, we observed statistically significant and dose dependent reductions from baseline in Lp(a) levels. Approximately 98 percent of patients who received the highest dose in the study demonstrated a
reduction in Lp(a) levels to below 50 mg/dL. Pelacarsen had a favorable safety and tolerability profile supportive of continued development.
In February 2019, Novartis exercised its option to license pelacarsen. As a result, Novartis is responsible for global
development, regulatory and commercialization activities, and costs for pelacarsen.
Tofersen (SOD1) (BIIB067) – Tofersen (formerly IONIS-SOD1Rx) is an investigational antisense medicine we designed to inhibit the production of superoxide dismutase 1,
or SOD1, which is a well understood genetic cause of ALS. SOD1-ALS is a rare, fatal, neurodegenerative disorder caused by a mutation in the SOD1 gene leading to a progressive loss of
motor neurons. As a result, people with SOD1-ALS experience increasing muscle weakness, loss of movement, difficulty breathing and swallowing and eventually succumb to the disease. Current treatment options for people with SOD1-ALS are extremely
limited, with no medicines that significantly slow disease progression. Tofersen is one of four medicines we have in development to treat ALS. It is estimated that there are approximately 1,400 patients with SOD1-ALS in G7 countries.
In October 2021, Biogen announced topline results of the Phase 3 VALOR study of tofersen in patients with SOD1-ALS
designed to assess the efficacy, safety and tolerability of tofersen. While tofersen did not meet the primary endpoint of change from baseline to 28 weeks in the ALSFRS-R, trends favoring tofersen were seen across multiple secondary and exploratory
measures of disease activity and clinical function. As a result, Biogen is actively engaged with regulators to determine next steps for the program. Additionally, in October 2021, Biogen announced that it would expand eligibility for its ongoing EAP to
all people with SOD1-ALS, where permitted.
In April 2021, Biogen initiated a second Phase 3 study of tofersen, ATLAS, in presymptomatic individuals with a SOD1
genetic mutation and biomarker evidence of disease activity. ATLAS is a multi-center, randomized, double-blind, placebo-controlled study enrolling up to 150 subjects designed to assess the efficacy, safety and tolerability of tofersen in presymptomatic
individuals with a SOD1 genetic mutation and biomarker evidence of disease activity.
Biogen conducted a Phase 1/2 study that demonstrated proof of biology and proof of concept. At the highest dose tested, treatment with
tofersen over a three month period resulted in a statistically significant lowering of SOD1 protein levels in the cerebrospinal fluid, or CSF, and positive numerical trends across three efficacy endpoints compared to placebo, including slowing of
clinical decline as measured by the ALSFRS-R. Tofersen had a favorable safety and tolerability profile supportive of continued development.
In December 2018, Biogen exercised its option to license tofersen, as a result, Biogen is responsible for global
development, regulatory and commercialization activities, and costs for tofersen.
Our Cardiovascular Medicines in Development
According to the World Health Organization, or WHO, CVD remains the number one cause of death globally. An estimated 17.9 million people
died from CVD in 2019, representing approximately 30 percent of all deaths globally. Our cardiovascular medicines target the major risk factors of cardiovascular disease, including cholesterol, triglycerides, and hypertension.
Eplontersen – See the medicine
description under “Our Phase 3 Medicines” section above.
Olezarsen – See the medicine
description under “Our Phase 3 Medicines” section above.
Pelacarsen – See
the medicine description under “Our Phase 3 Medicines” section above.
ION449 (PCSK9) (AZD8233) – ION449 (formerly IONIS-AZ4-2.5-L-Rx) is an investigational LICA medicine we designed to reduce the production of proprotein convertase subtilisin/kexin type 9, or PCSK9, in the liver. PCSK9 is integrally involved in the regulation of LDL-cholesterol. Genetic studies
have shown that individuals with life-long reductions of LDL-C due to reduced function of PCSK9 have substantially reduced risk of CVD.
In November 2020, AstraZeneca initiated the Phase 2b study of ION449 in patients with LDL-C levels between 70 and 190 mg/dl and receiving statin therapy. The study is a randomized, double-blind, placebo-controlled clinical study in approximately 110 patients to assess the efficacy, safety
and tolerability of ION449. The primary objective is to assess the effect of different doses of ION449 on LDL-C compared to placebo at Week 12 in patients taking baseline statin therapy. The study will evaluate three dose levels of ION449 versus
placebo, all administered once a month by subcutaneous injection.
In November 2021, we reported positive results from the Phase 1 study of ION449 in patients with dyslipidemia. Participants were treated
with multiple ascending subcutaneous doses and ION449 demonstrated dose-dependent mean reductions in circulating plasma PCSK9 and LDL-C levels and had a favorable safety and tolerability profile supportive of continued development.
In October 2020, we reported positive results from the Phase 1 study of ION449 in healthy volunteers. Participants were treated with a
single subcutaneous dose and ION449 demonstrated dose-dependent mean reductions in circulating plasma PCSK9 and LDL-C levels and had a favorable safety and tolerability profile supportive of continued development.
We licensed ION449 to AstraZeneca under our cardiovascular, renal and metabolic diseases collaboration. As a result,
AstraZeneca is responsible for global development, regulatory and commercialization activities, and costs for ION449.
Fesomersen (FXI)
(BAY2976217) – Fesomersen (formerly IONIS-FXI-LRx) is an investigational LICA medicine we designed to inhibit the production of Factor XI. Factor XI is a clotting factor produced in the liver that is important in the growth of blood clots.
Thrombosis, characterized by the formation of a blood clot inside blood vessels, can cause heart attacks and strokes. People who are deficient in Factor XI have a lower incidence of thromboembolic events with minimal increase in bleeding risk. Although
currently available anticoagulants reduce the risk of thrombosis, physicians associate these anticoagulants with increased bleeding, which can be fatal. By inhibiting Factor XI production, we believe that fesomersen can be used broadly as an
anti-thrombotic in many different therapeutic settings for which additional safe and well tolerated anti-thrombotic medicines are needed.
In August 2020, Bayer initiated the RE-THINc Phase 2b study of fesomersen in patients with end-stage renal disease, or
ESRD, on hemodialysis. RE-THINc is a randomized, blinded, placebo-controlled study in approximately 290 patients to assess the efficacy, safety and tolerability of fesomersen. The study is designed to evaluate multiple monthly doses administered
subcutaneously. The primary endpoint is incidence of major bleeding and clinically relevant non-major bleeding.
We conducted a Phase 1, blinded, randomized, placebo-controlled, dose-escalation study of fesomersen in healthy
volunteers. In this study, fesomersen produced significant reductions in FXI activity and FXI antigen, without evidence of increased bleeding and had a favorable safety and tolerability profile supportive of continued development.
In February 2017, we licensed fesomersen to Bayer. As a result, Bayer is responsible for global development, regulatory and
commercialization activities, and costs for fesomersen.
IONIS-AGT-LRx – IONIS-AGT-LRx is an investigational LICA medicine we designed to inhibit the production of
angiotensinogen to decrease blood pressure in people with treatment resistant hypertension, or TRH. Despite the availability of antihypertensive agents, TRH is still a major contributor to cardiovascular and renal disease. Approximately 140 million
adults globally and approximately 10 million adults in the U.S. have resistant hypertension, defined as failure to achieve a blood pressure goal of 140/90 (systolic/diastolic) despite the use of three or more antihypertensive medications. People with
TRH have been found to have a three-fold higher chance of having fatal and non-fatal cardiovascular events relative to those with controlled hypertension.
We are also studying IONIS-AGT-LRx in patients with chronic heart failure with reduced ejection fraction.
Heart failure, or HF, afflicts approximately 6.5 million patients in the United States, or U.S., and 26 million worldwide. As the population ages, HF incidence is increasing, and more than 550,000 patients are diagnosed with HF each year. HF is
responsible for more hospitalizations than all forms of cancer combined and is the most common diagnosis in hospital patients 65 years and older. Every year over 1 million patients are hospitalized for HF in the U.S. and Europe, accounting for 6.5
million hospital days. High rates of hospitalizations with frequent readmission (almost 25 percent of patients with HF are readmitted within 30 days) along with other direct and indirect costs, also place an enormous economic burden on healthcare
systems. Despite new advances in medical therapy, the residual risk for patients with HF is still high.
In January 2021, we initiated a Phase 2b clinical study of IONIS-AGT-LRx in patients with hypertension
uncontrolled with three or more antihypertensive medications, including angiotensin-converting enzyme, or ACE, inhibitors or angiotensin II receptor blockers, or ARBs. The study is a randomized, double-blinded, placebo-controlled study in approximately
150 patients to assess the efficacy, safety and tolerability of IONIS-AGT-LRx. We designed the study to evaluate multiple doses administered subcutaneously. The primary endpoint is the change in systolic blood pressure, or SBP, from
baseline.
In September 2021, we initiated a Phase 2 clinical study of IONIS-AGT-LRx in patients with chronic HF with
reduced ejection fraction. The study is a randomized, double-blind, placebo-controlled study in approximately 75 patients to assess the safety, tolerability, and efficacy of IONIS-AGT-LRx. We designed the study to evaluate multiple doses
administered subcutaneously. The primary endpoint is the percent change in plasma AGT concentration from baseline.
We evaluated IONIS-AGT-LRx in two randomized, double-blinded, placebo-controlled Phase 2 studies. The first study was in
people with mild hypertension and the second was in people with TRH who were on two or three antihypertensive medications, including ACE inhibitors or ARBs.
IONIS-AGT-LRx significantly reduced AGT levels compared with placebo in both studies. Although not
powered for this endpoint, trends were noted in blood pressure reduction and IONIS-AGT-LRx had a favorable safety and tolerability profile supportive of continued development.
Our Neurological Medicines in Development
Our neurological medicines address a broad range of diseases in major regions of the brain and in the central nervous system, or CNS,
cell types. Our antisense medicines aim to address both large and rare patient populations. We are currently investigating potential disease-modifying treatments for common neurological diseases including Alzheimer’s disease and Parkinson’s disease. We
also have multiple investigational medicines in clinical trials for rare neurological diseases, including ALS and hATTR polyneuropathy. According to the National Institute of Neurological Disorders and Stroke, or NINDS, at the National Institutes of
Health, or NIH, a third of the 7,000 known rare diseases are neurological disorders or thought to include a neurological component.
Eplontersen – See the medicine
description under “Our Phase 3 Medicines” section above.
ION363 – See the medicine
description under “Our Phase 3 Medicines” section above.
Tofersen – See the medicine
description under “Our Phase 3 Medicines” section above.
ION373 (GFAP) – ION373 is an
investigational antisense medicine targeting glial fibrillary acidic protein, or GFAP, mRNA we designed to inhibit the production of GFAP. We are developing ION373 as a potential therapy for Alexander disease, or AxD. AxD is a rare progressive and
fatal neurological disease that affects the myelin sheath which protects nerve fibers. AxD is caused by a gain-of-function mutation in the GFAP gene and is characterized by progressive deterioration, including loss of skills and independence, generally
leading to death in childhood or early adulthood.
Two major types of AxD have been defined. Type I onset typically occurs before 4 years of age and patients can experience head
enlargement, seizures, limb stiffness, delayed or declining cognition, and lack of growth. Type II onset typically occurs after the age of 4 and symptoms can include difficulty speaking, swallowing, and making coordinated movements. AxD is most often
fatal. There are treatments that can relieve symptoms, but there is no disease modifying therapy yet available to patients.
In April 2021, we initiated a pivotal study of ION373 in patients with AxD. The Phase 2/3 study of ION373 is a multi-center,
double-blind, placebo-controlled, multiple-ascending dose study in up to 58 patients with AxD designed to assess the efficacy, safety and tolerability of ION373. Patients will receive ION373 or placebo for a 60-week period, after which all patients in
the study will receive ION373 for a 60-week open-label treatment period. The primary endpoint is the change from baseline in the 10-Meter Walk Test, or 10MWT.
IONIS-C9Rx (BIIB078) – IONIS-C9Rx is an investigational antisense medicine we designed to selectively inhibit the production of the mutated chromosome 9 open reading frame 72, or C9ORF72, gene. A mutation in this gene results in an inherited form of ALS, referred to as C9ORF72-ALS, or C9-ALS, the most prevalent genetic cause of ALS worldwide. This
mutation can lead to rapid progressive loss of motor neurons and is a fatal disease characterized by muscle weakness, loss of movement, and difficulty breathing and swallowing. IONIS-C9Rx is one of four medicines we have in development to
treat ALS.
In August 2018, Biogen initiated a Phase 1/2 clinical study of IONIS-C9Rx in adult patients with C9-ALS. The
Phase 1/2 study is a global, multi-center, randomized, double-blinded, placebo-controlled study designed to assess safety, tolerability and activity of multiple ascending doses of IONIS-C9Rx administered intrathecally.
IONIS-C9Rx is being developed under our 2013 Strategic Neurology collaboration with Biogen.
IONIS-MAPTRx (BIIB080) – IONIS-MAPTRx is an investigational antisense medicine we designed to selectively inhibit production of the microtubule-associated protein tau, or tau, protein in the brain. We are developing
IONIS-MAPTRx to treat people with Alzheimer’s disease, or AD, and potentially other neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain, such as certain forms of frontotemporal degeneration, or
FTD, and progressive supranuclear palsy, or PSP.
AD and FTD are characterized predominantly by memory impairment and behavioral changes, resulting in a person’s inability to independently
perform daily activities. PSP is characterized by problems with walking and control of movement, sleep disorder and loss of memory and ability to reason. AD generally occurs late in life and may progress to death in five to 20 years after the onset of
the disease. FTD and PSP have a more rapid disease progression. In the U.S., there are approximately five million people living with AD, approximately 55,000 people living with FTD and approximately 20,000 people living with PSP.
In July 2021, we and Biogen reported positive topline data from our Phase 1/2 study of IONIS-MAPTRx in
patients with mild Alzheimer’s disease at the Alzheimer’s Association International Conference, or AAIC. The Phase 1/2 study was a blinded, randomized, placebo-controlled, dose-escalation of IONIS-MAPTRx to evaluate the safety and activity
of once-monthly intrathecal injections of IONIS-MAPTRx in patients with mild AD. The study showed that IONIS-MAPTRx met its primary objective of safety and tolerability in patients with mild Alzheimer’s disease. The study
demonstrated robust time and dose dependent lowering of tau protein in cerebrospinal fluid over the three-month treatment period and sustained reductions during the six-month post-treatment period and IONIS-MAPTRx had a favorable safety and
tolerability profile supportive of continued development.
In December 2019, Biogen exercised its option to license IONIS-MAPTRx. We were responsible for completing the Phase 1/2 study
in patients with mild AD and a one-year long-term extension study. Biogen has responsibility for global development, regulatory and commercialization activities, and costs for IONIS-MAPTRx.
ION859 (LRRK2) (BIIB094) –
ION859 is an investigational antisense medicine we designed to inhibit the production of the Leucine Rich Repeat Kinase 2, or LRRK2, protein as a potential therapy for Parkinson’s disease, or PD. The most common genetic mutations in PD are found in the
LRRK2 protein. It is believed that increased LRRK2 protein activity could be one of the key drivers for developing PD. PD is a progressive neurodegenerative disease characterized by loss of neurons in the motor system. Patients with PD can experience
tremors, loss of balance and coordination, stiffness, slowing of movement, changes in speech and in some cases cognitive decline. PD is ultimately fatal. There are treatments that can relieve symptoms, but there is no disease modifying therapy.
In August 2019, Biogen initiated a Phase 1/2 study evaluating ION859 in adult patients with PD. The Phase 1/2 study is a global,
multi-center, randomized, double-blinded, placebo-controlled study designed to assess the safety, tolerability and activity of multiple ascending doses of ION859 administered intrathecally.
ION859 is being developed under our 2013 Strategic Neurology collaboration with Biogen.
ION464 (SNCA) (BIIB101) – ION464
is an investigational antisense medicine we designed to inhibit the production of the alpha-synuclein protein as a potential therapy for PD, Multiple System Atrophy, or MSA, and related synucleinopathies. Alpha-synuclein protein abnormally accumulates
in the brains of PD and MSA patients and is thought to be one of the key drivers of these diseases. It is believed that decreasing the production of the alpha-synuclein protein will reduce the toxic effects of gain-of-function mutations.
In July 2020, we initiated a Phase 1/2 study evaluating ION464 in patients with MSA. The current study is a multi-center, randomized,
double-blinded, placebo-controlled study designed to assess the safety and tolerability of multiple doses of ION464 administered intrathecally.
ION464 is being developed under our 2013 Strategic Neurology collaboration with Biogen.
ION541 (ATXN2) (BIIB105)
– ION541 is an investigational antisense medicine we designed to reduce the production of the ataxin-2, or ATXN2, protein for the potential treatment of ALS. The reduction of ATXN2 has been shown to decrease aggregation of TDP-43, a toxic RNA binding
protein found in most patients with ALS, including the approximately 90 percent of the ALS population with no known family history of ALS. ION541 is one of four medicines we have in development to treat ALS.
In October 2020, Biogen initiated a Phase 1/2 clinical study evaluating ION541 in this broad ALS population. The current
study is a randomized, blinded, placebo-controlled study designed to assess the safety, tolerability, and pharmacokinetics of multiple ascending doses of ION541 administered intrathecally.
ION541 is being developed under our 2013 Strategic Neurology collaboration with Biogen.
ION582 (UBE3A) (BIIB121) – ION582
is an investigational antisense medicine we designed to inhibit the expression of the UBE3A transcript, or UBE3A-ATS for the potential treatment of Angelman Syndrome, or AS. AS is a rare, genetic neurological disease caused by the loss of function of
the maternally inherited UBE3A gene. Angelman syndrome typically presents in infancy and is characterized by intellectual disability, balance
issues, motor impairment, and debilitating seizures. Some patients are unable to walk or speak. Some symptoms can be managed with existing drugs; however, there is no disease modifying therapy. It is estimated that there are more than 60,000 patients
with AS in the U.S. and EU.
In December 2021, we initiated the Phase 1/2 study, HALOS, of ION582 in patients with Angelman syndrome. The study is an open label
dose-escalation study enrolling up to 44 participants to assess the safety, tolerability and activity of multiple ascending doses of ION582.
ION582 is being developed under our 2012 Neurology collaboration with Biogen.
Tominersen (HTT) (RG6042) – Tominersen (formerly IONIS-HTTRx)
is an investigational antisense medicine we designed to target the underlying cause of Huntington’s disease, or HD, by reducing the production of all forms of the huntingtin protein, or HTT, including its mutated variant, or mHTT. HD is an inherited
genetic brain disorder that results in the progressive loss of both mental faculties and physical control. It is caused by the expansion of the CAG trinucleotide sequence in the HTT gene. The resulting mutant HTT protein is toxic and gradually destroys
neurons. Symptoms usually appear between the ages of 30 and 50 and worsen over a 10 to 25-year period. Ultimately, the weakened individual succumbs to pneumonia, heart failure or other complications. Presently, there is no effective treatment or cure
for the disease, and currently available medicines only mask the patient’s symptoms but do not slow down the underlying loss of neurons.
In January 2022, Roche announced plans to initiate a new Phase 2 trial to evaluate tominersen in patients with HD based on findings from a
post-hoc analysis of the Phase 3 GENERATION HD1 study. The findings from the post-hoc analysis suggested tominersen may benefit younger adult patients with lower disease burden. As a result, Roche is in the early stages of designing a Phase 2 clinical
trial to explore different doses of tominersen in this patient population.
Roche conducted the Phase 3 study, GENERATION HD1,of tominersen in patients with HD. The Phase 3 study was a randomized, multicenter,
double-blind, placebo-controlled study that recruited 791 participants from 18 countries around the world. In March 2021, Roche announced that dosing would be stopped in the study following a recommendation from the independent data monitoring
committee, or iDMC, based on an overall benefit/risk assessment. The study is ongoing without dosing to allow participants to be followed for safety and clinical outcomes. Roche anticipates the study will complete in March/April 2022.
Roche is also conducting the GEN-EXTEND study, an OLE study for participants coming from any prior Roche HD study. The study is ongoing
without dosing to allow participants to be followed for safety and clinical outcomes. Roche anticipates the study will complete in March/April 2022. In parallel with the OLE, Roche initiated a natural history study in a similar patient population to
the OLE aimed at further understanding the natural progression of HD.
We completed a randomized, placebo-controlled, dose escalation, Phase 1/2 clinical study of tominersen in patients with early-stage HD. In
this study, we observed dose-dependent reductions of mHTT among patients treated with tominersen and a favorable safety and tolerability profile supporting continued development. The data from this study were published in The New England Journal of Medicine in May 2019.
The European Medicines Agency, or EMA, granted PRIority MEdicines scheme, or PRIME, designation to tominersen. EMA PRIME status is granted
to medicines that may offer a major therapeutic advantage over existing treatments, or benefit patients without treatment options. The FDA and EMA granted Orphan Medicine Designation for tominersen to treat people with HD.
In December 2017, Roche exercised its option to license tominersen. As a result, Roche is responsible for global
development, regulatory and commercialization activities, and costs for tominersen.
IONIS-DNM2-2.5Rx (DYN101) – IONIS-DNM2-2.5Rx is an investigational antisense medicine we designed to inhibit the production of Dynamin 2, or DNM2, protein for the treatment of centronuclear myopathy, or CNM. CNM is a
group of rare, potentially fatal disorders of the skeletal muscle cells. It is characterized by muscle weakness, decreased muscle tone and muscle atrophy, ranging from severe to mild, and potentially life-threatening. DNM2 reduction demonstrated
improved muscle mass and muscle force, and extended lifespan in animal models of the most severe form of CNM.
In November 2019, Dynacure initiated a Phase 1/2 clinical study evaluating IONIS-DNM2-2.5Rx in patients with CNM. The current
study is an open-label study designed to assess the safety and tolerability of multiple doses of IONIS-DNM2-2.5Rx administered intravenously.
In the fourth quarter of 2017, we licensed IONIS-DNM2-2.5Rx to Dynacure. As a result, Dynacure is responsible
for global development, regulatory and commercialization activities, and costs for IONIS-DNM2-2.5Rx.
Specialty Rare Medicines in Development
Our emerging specialty rare disease pipeline is comprised of medicines that are outside of our cardiovascular and
neurological franchises, but we believe could represent a compelling opportunity for us.
Sapablursen (TMPRSS6)
– Sapablursen (formerly IONIS-TMPRSS6-LRx) is an investigational LICA medicine we designed to target the TMPRSS6 gene to modulate the production of hepcidin, which is the key regulator of iron homeostasis. By modulating hepcidin expression,
sapablursen has the potential to positively impact diseases characterized by iron excess, such as β-thalassemia, and iron deficiency, such as polycythemia vera, or PV.
β-thalassemia is a rare, genetic and potentially fatal form of chronic anemia resulting in hepcidin deficiency, severely
reduced red blood cell production and iron toxicity. In some cases, iron accumulates in major organs, such as the heart and liver, which can be fatal. The current standard-of-care involves symptom management, including blood transfusions and iron
chelation. There are no approved disease-modifying treatments for β-thalassemia.
PV is a rare, non-genetic and potentially fatal disease caused by overproduction of red blood cells. This overproduction
leads to a thickening of the blood, which increases patients’ risk of life-threatening blood clots, including in the lungs, heart and brain. Patients with PV also experience severe iron deficiency due to hepcidin overexpression. The current
standard-of-care for PV involves symptom management. There are no approved disease-modifying treatments for PV.
In August 2020, we initiated a Phase 2 study evaluating sapablursen in patients with non-transfusion dependent, or
NTDT, β-thalassemia intermedia. The Phase 2 study is multi-center, randomized, open-label study in approximately 36 patients we designed assess the efficacy, safety, and tolerability of sapablursen administered monthly subcutaneously. The primary
endpoint is the percentage of participants with a greater than or equal to 1.0 g/dl increase from baseline in hemoglobin at week 27.
In January 2022 we initiated a Phase 2 study evaluating sapablursen in patients with Phlebotomy Dependent Polycythemia
Vera, or PD-PV. The Phase 2 study is a multi-center, randomized, open-label study in approximately 40 patients designed to assess the efficacy, safety and tolerability of sapablursen. The primary endpoint is Change in the frequency of phlebotomy
comparing baseline with the last 20 weeks of the 37-week treatment period.
In December 2018, we presented positive data from our Phase 1 study of sapablursen in healthy volunteers at the American
Society of Hematology Annual Meeting. The Phase 1 study demonstrated dose-dependent reductions of serum iron and serum transferrin saturation with sapablursen. Additionally, we observed an increase in serum hepcidin and predicted changes in hemoglobin
and sapablursen had a favorable safety and tolerability profile supportive of continued development.
Cimdelirsen (GHR) –
Cimdelirsen (formerly IONIS-GHR-LRx) is an investigational LICA medicine we designed to inhibit the production of growth hormone receptor, or GHr, to decrease the circulating level of insulin-like growth factor-1, or IGF-1. Elevated levels
of IGF-1 results in acromegaly, a chronic, slowly progressing and potentially fatal disease. Patients with acromegaly experience multiple chronic conditions, such as type 2 diabetes, hypertension, and respiratory complications and premature death.
Current treatments to block IGF-1 are often unsuccessful. Drug treatments to normalize IGF-1 levels are also available but are associated with potentially serious side effects.
In January 2021, we initiated a Phase 2
study of cimdelirsen evaluating cimdelirsen as a monotherapy in patients with acromegaly. The Phase 2 study is a multi-center, randomized, open label
study in approximately 40 patients to assess the efficacy, safety and tolerability of cimdelirsen. The primary endpoint is the percent change
from baseline in IGF-1 to week 27.
We completed a Phase 2 study evaluating
cimdelirsen as an add-on therapy in patients with uncontrolled acromegaly despite stable therapy with long-acting somatostatin receptor ligands, or SRL. Based on the results of this Phase 2 study and a preliminary analysis of the ongoing open-label
study, proof of mechanism was achieved with a strong indication of proof of concept supporting the continued development of cimdelirsen. Due to enrollment difficulties associated with the COVID-19 pandemic, the study closed early, resulting in
smaller cohort sizes than planned. While no longer powered to assess the primary endpoint (percentage of IGF- lowering at Day 141) in accordance with the protocol, the study did permit placebo-controlled evaluation of safety and efficacy. Cimdelirsen
had a favorable safety and tolerability profile supportive of continued development.
We also completed a Phase 1, blinded,
placebo-controlled, dose-escalation study of cimdelirsen in healthy volunteers. In this study, cimdelirsen demonstrated a favorable safety and tolerability profile supporting continued development.
Other Medicines in Development
We continue to advance other medicines in
clinical development targeting metabolic diseases, infectious diseases, renal diseases, ophthalmic diseases and cancer.
*China Only
ION224 (DGAT) – ION224 is an investigational LICA medicine designed to reduce the production of DGAT2, or diacylglycerol acyltransferase 2, to treat patients with nonalcoholic steatohepatitis,
or NASH. NASH is a common liver disease characterized by liver steatosis, inflammation and scarring and can lead to increased risk of cardiovascular disease, liver cancer, need for liver transplantation and early death. DGAT2 is an enzyme that
catalyzes the final step in triglyceride synthesis in the liver. Reducing the production of DGAT2 should therefore decrease triglyceride synthesis in the liver. In animal studies, antisense inhibition of DGAT2 significantly improved liver steatosis,
lowered blood lipid levels and reversed diet-induced insulin resistance.
NASH is sometimes considered a “silent” liver disease because people with early-stage NASH feel well, even though they are starting to
accumulate fat in their livers and may not be aware that they have the disease. However, NASH can develop into more severe diseases such as liver cirrhosis and liver failure. Currently, liver transplant is the only therapeutic option for patients with
liver cirrhosis. In addition, NASH has been shown to be a major risk factor for the development of liver cancer.
Nonalcoholic fatty liver disease, or NAFLD, describes the full spectrum of liver disease progression from fatty liver to NASH to
cirrhosis to hepatocellular carcinoma. NASH epidemiology studies have estimated 13 to 32 percent of the global population has NAFLD, 1.5 to 6.5 percent have NASH, and approximately 9 percent of NASH patients progress to advanced liver disease. There
are currently no commercially available medications to treat NASH.
In June 2021, we initiated a Phase 2 study of ION224 in patients with confirmed non-alcoholic steatohepatitis. The Phase 2 study is a multi-center, randomized, double-blind, placebo-controlled clinical study enrolling approximately 150 patients designed to assess the efficacy, safety and tolerability of multiple subcutaneous
doses of ION224 on NASH histologic improvement.
Bepirovirsen (HBV) (GSK3228836) – Bepirovirsen (formerly IONIS-HBVRx) is an investigational antisense medicine we designed to inhibit the production of viral proteins
associated with hepatitis B virus, or HBV. These include proteins associated with infection and replication, including the hepatitis B surface antigen, or HBsAg, which is present in both acute and chronic infections and is associated with a poor
prognosis in people with chronic HBV infection.
HBV infection is a serious health problem that can lead to significant and potentially fatal health conditions,
including cirrhosis, liver failure and liver cancer. Chronic HBV infection is one of the most common persistent viral infections in the world. Currently available therapies, although effective in reducing circulating HBV in the blood, do not
effectively inhibit HBV antigen production and secretion, which are associated with poor prognosis and increased risk of liver cancer.
GSK is conducting a broad Phase 2 program for bepirovirsen. The B-Clear study is a Phase 2b randomized, double-blinded,
placebo-controlled study in approximately 440 patients with chronic HBV. The primary endpoint is the percentage of patients achieving HBV surface antigen and HBV DNA less than the lower limit of quantitation. Additionally, GSK is conducting two open label Phase 2 studies and a long-term follow up study in patients with chronic HBV.
In November 2019, GSK reported results of the Phase 2a study of bepirovirsen in patients with chronic HBV infection at the American Association for the Study of Liver Diseases annual meeting. In the Phase 2a study, bepirovirsen demonstrated target engagement with dose
dependent declines in HBsAg with up to 3-log reductions in HBsAg at one month, including two patients who achieved reductions in HBsAg and HBV DNA below levels of detection. Additionally, bepirovirsen had a favorable safety and tolerability profile supportive of continued development.
In August 2019, GSK exercised its option to license our HBV program following the positive Phase 2 results described above. As a result,
GSK is responsible for global development, regulatory and commercialization activities, and costs for the HBV program.
IONIS-FB-LRx – IONIS-FB-LRx is an investigational LICA medicine we designed to inhibit the production of complement factor B, or FB. Genetic association studies have shown that overaction of this cascade has been associated with the development
of several complement-mediated diseases, including IgA nephropathy, or IgAN, and dry age-related macular degeneration, or AMD.
IgAN is one of the most common causes of inflammation that impairs the filtering ability of kidneys and is an important
cause of chronic kidney disease and renal failure. Also known as Berger’s disease, IgAN is characterized by deposits of IgA in the kidneys, resulting in inflammation and tissue damage.
AMD is the leading cause of central vision loss in developed countries. It is estimated that the disease will affect
more than three million people in the U.S. by 2026. AMD is believed to be a systemic disease with local disease manifestation at the aging retinal macula. AMD gradually destroys vision in the center of the visual field due to progressive damage of the
retina. Geographic atrophy, or GA, is an advanced form of AMD and accounts for approximately fifteen percent of all patients with cases of AMD.
In September 2019, we initiated a Phase 2
study of IONIS-FB-LRx in patients with IgA nephropathy. The Phase 2 study is a single-arm, open-label study
designed to assess the efficacy, safety and tolerability of IONIS-FB-LRx administered subcutaneously in adults with
primary IgA nephropathy. The primary endpoint is the percent reduction in 24-hour urine protein excretion from baseline to week 29.
In May 2017, we reported data from a Phase
1 study evaluating IONIS-FB-LRx in 54 healthy volunteers. The Phase 1 study was a randomized, placebo-controlled,
dose-escalation study. Subjects were treated with a single dose of IONIS-FB-LRx achieved dose-dependent reductions
in plasma FB of up to 50 percent. Treatment with multiple doses of IONIS-FB-LRx during a six-week period resulted
in greater reductions in circulating FB levels. IONIS-FB-LRx had a favorable safety and tolerability profile
supportive of continued development.
In June 2019, we initiated a Phase 2 study
evaluating IONIS-FB-LRx in patients with GA secondary to age-related macular degeneration. The study is a
randomized, masked, placebo-controlled study designed to assess the efficacy, safety and tolerability of multiple ascending doses of IONIS-FB-LRx administered subcutaneously in adults with GA. The primary endpoint is the absolute change from baseline in GA area at week 49.
IONIS-FB-LRx is being developed under our collaboration with Roche.
IONIS-GCGRRx – IONIS-GCGRRx is an investigational antisense medicine designed to inhibit the production of the glucagon receptor, or GCGR, to treat patients with type 2 diabetes. GCGR is a receptor for the hormone
glucagon. Glucagon is a hormone that opposes the action of insulin and stimulates the liver to produce glucose, particularly in type 2 diabetes. In patients with advanced diabetes, uncontrolled glucagon action can lead to significant increase in blood
glucose level. In addition, reducing GCGR produces more active glucagon-like peptide, or GLP-1, a hormone that preserves pancreatic function and enhances insulin secretion.
Diabetes is a chronic disease in which the blood glucose levels are too high. Although glucose is an important source of energy for your
body and is vital to your health, uncontrolled increases in glucose can lead to serious health problems, such as diabetes. Diabetes is separated into type 1 and type 2. In type 1 diabetes, the body does not make insulin. In type 2 diabetes, the more
common type, the body does not respond properly to insulin and, therefore, blood glucose levels are not adequately controlled.
In October 2019, Suzhou-Ribo initiated a Phase 2 clinical study evaluating IONIS-GCGRRx in patients with type 2 diabetes.
ION357 (RHO) (QR-1123)
– ION357 (formerly IONIS-RHO-2.5Rx), is an investigational antisense medicine we designed to treat patients with a genetic form of
autosomal dominant retinitis pigmentosa by inhibiting the production of the rhodopsin P23H mutant protein in the eye while allowing normal protein to be expressed.
Retinitis pigmentosa, or RP, is a group of rare inherited eye disorders causing photoreceptor degeneration that leads to
progressive vision loss. Photoreceptors are cells in the eye’s retina responsible for converting light into signals that are sent to the brain. Photoreceptors provide us our color and night vision. Affected patients first experience defective dark
adaptation during adolescence or young adulthood, followed by loss of peripheral visual field. Patients eventually have limited residual central vision, which ultimately leads to complete blindness around the age of 60.
In November 2019, ProQR initiated a Phase 1/2 clinical study evaluating ION357 in patients with RP. The Phase 1/2 study is a randomized, masked, placebo-controlled study designed to assess the safety, tolerability and activity of ION357 in adult patients with RP.
In the fourth quarter of 2018, we licensed ION357 to ProQR. As a result, ProQR is responsible for global development,
regulatory and commercialization activities, and costs for ION357.
ION736 (FOXP3)
(AZD8701) – ION736, is an investigational antisense medicine designed to reduce the production of Forkhead Box P3, or FOXP3, for the treatment of patients with cancer. FOXP3 is a protein involved in the function of immuno-suppressive T regulatory cells
(Tregs). Tregs, which are found at high levels in various types of cancers, often predict poor survival and poor response to immune checkpoint therapeutics. Preclinical studies have demonstrated that FOXP3 downregulation resulted in an increased immune
response and anti-tumor activity. Moreover, the combination of antisense inhibition of FOXP3 with other immuno-oncology drugs led to enhanced anti-tumor activity.
In August 2020, AstraZeneca initiated a first-in-human open label study of ION736 in patients with select advanced solid
tumors. The study is a multi-center, open label multi-arm study in approximately 123 patients designed to evaluate the efficacy, safety and tolerability of ION736 administered intravenously as monotherapy and in combination with durvaluamb (MEDI4736)
in patients with advanced solid tumors.
In the second quarter of 2020, we licensed ION736 to AstraZeneca. As a result, AstraZeneca is responsible for global
development, regulatory and commercialization activities, and costs for ION736.
IONIS-AR-2.5Rx – IONIS-AR-2.5Rx is an investigational antisense medicine we designed to treat people with prostate
cancer by reducing the production of all known forms of androgen receptor, or AR, including variants of the AR gene. Prostate cancer is the second
leading cause of cancer deaths in American men. Prostate cancer growth, proliferation and progression are all androgen-dependent and AR function is involved in disease progression at all stages of prostate cancer. For patients diagnosed with metastatic
prostate cancer, current treatments largely involve opposing the action of androgens by blocking the androgen receptor or removing circulating androgens. Resistance to current therapies is frequent.
An open-label, dose-escalation, Phase 1/2 clinical study of IONIS-AR-2.5Rx was completed in people with
advanced tumors for which the androgen receptor pathway is potentially a contributing factor. The study was primarily conducted in prostate cancer patients, and it showed durable responses in a number of those patients. IONIS-AR-2.5Rx had a
safety and tolerability profile supportive of continued development.
In March 2017, we licensed IONIS-AR-2.5Rx to Suzhou-Ribo to develop and commercialize the medicine in China.
In the third quarter of 2021, we entered into a license agreement with Flamingo Therapeutics for the development and commercialization of certain programs from Ionis’ oncology pipeline, including IONIS-AR-2.5Rx outside of China.
Danvatirsen (STAT3) – Danvatirsen
(formerly IONIS-STAT3-2.5Rx) is an investigational antisense medicine we designed to inhibit the production of signal transducer and activator of transcription 3, or STAT3, to treat people with cancer. STAT3 is a protein involved in the
translation of key factors critical for tumor cell growth and survival. STAT3 is over-active in a variety of cancers, including brain, lung, breast, bone, liver, and multiple myeloma. Overactivity in STAT3 prevents cancer cell death and promotes tumor
cell growth.
In October 2018, we reported data from a Phase 1/2 study of danvatirsen in combination with durvalumab in recurrent
metastatic head and neck cancer. The combination treatment resulted in seven percent of patients achieving a complete tumor response and 23 percent achieving either a partial or complete tumor response. This response rate is estimated to be double that
with durvalumab alone, based on previous studies in this difficult to treat patient population. Danvatirsen had a safety and tolerability profile supportive of continued development.
In the third quarter of 2021, we entered into a license agreement with Flamingo Therapeutics for the development and
commercialization of certain programs from Ionis’ oncology pipeline, including danvatirsen.
Phase 1 Medicines in Clinical Development
Our early-stage pipeline is comprised of medicines to treat a number of diseases, including from our cardiovascular franchise. It includes
medicines based on our latest technology advancements. As we continue to add new investigational medicines to our pipeline, we believe these medicines have the potential to expand our mid and late-stage pipelines.
Antisense Technology
Our antisense technology is an innovative platform for discovering first-in-class and/or best-in-class medicines.
Antisense medicines target RNA, the intermediary that conveys genetic information from a gene to the protein synthesis machinery in the cell. By targeting RNA instead of proteins, we can use antisense technology to increase, decrease or alter the
production of specific proteins. The unique properties of antisense technology provide several advantages over other drug discovery technologies.
These advantages include:
|
● |
Direct intervention in the disease process at the genetic level by targeting RNA: antisense technology represents a direct route from gene to drug. The
explosion in genomic information and RNA biology has led to the discovery of many new disease-causing proteins and RNAs and has created new opportunities that are uniquely accessible by antisense technology.
|
|
● |
Precise specificity: we design antisense medicines to target a single RNA, minimizing the possibility of binding to unintended targets, which can cause
unwanted side effects.
|
|
● |
Good drug properties: antisense medicines distribute well throughout the body. They also have a long half-life, in the range of weeks to months, which
means patients and/or healthcare providers can dose our medicines weekly, monthly or even less frequently depending on the medicine and target tissue.
|
|
● |
Ability to combine with other medicines: because antisense medicines do not interact with the enzymes that metabolize or break down other medicines,
physicians can use our medicines in combination with other medicines.
|
|
● |
Broad applications to multiple disease targets, multiple tissues and multiple mechanisms: there are virtually no “undruggable” targets with antisense
technology.
|
|
● |
Efficient discovery and early development: because of the efficiency of our antisense technology, our drug discovery and early development costs and
success rates compare favorably to small molecule or antibody drug discovery and development.
|
We develop antisense medicines we believe will pioneer new markets and change standards of care. Our areas of focus
include cardiovascular and neurological diseases.
Technology Overview
We use our core technology platform to discover and develop medicines that affect targets in the body at the genetic
level. Genes contain the information necessary to produce proteins. A gene is made up of nucleotides containing the nucleoside bases: adenine, thymine, guanine, and cytosine, commonly known as A, T, G and C, which are linked together to form a
two-stranded structure that resembles a twisted ladder, known as DNA. The nucleotides on one side of the ladder bind weakly to complementary nucleotides on the other strand according to specific rules; for example, A pairs with T and G pairs with C,
creating the ladder’s rungs (Figure 1). Scientists call this highly specific nucleotide pairing hybridization. The sequence or order of these nucleotides establishes the cell’s recipes for making proteins. Each protein’s instructions reside in a
corresponding segment of DNA known as a gene.
Figure 1: Illustration of DNA.
The instructions for making a protein are transcribed from a gene, or DNA, into a different genetic molecule called
messenger RNA. This process starts with the partial uncoiling of the two complementary strands of the DNA. One strand acts as a template and information stored in the DNA template strand is copied into a complementary RNA (Figure 2) by an enzyme called
RNA polymerase, or RNAP. Messenger RNA, or mRNA, are mature, fully processed RNA that code for proteins.
Figure 2: Transcription of information contained in a gene, or DNA, to RNA.
Ribosomes, the cell’s factories for manufacturing proteins, translate mRNA into proteins. The ribosome reads the encoded
information, the mRNA’s nucleotide sequence, and in doing so, strings together amino acids to form a specific protein (Figure 3).
Figure 3: Translation of the protein-coding information contained in mRNA to protein.
We primarily use our antisense technology to interrupt the cell’s protein production process by preventing the mRNA
instructions from reaching the ribosome, thus inhibiting the production of the protein. We can also design antisense medicines to increase protein production for diseases caused by the lack of a particular protein or modify the processing (or splicing)
of the mRNA, which can alter the composition of the protein. The mRNA sequence of nucleotides that carries the information for protein production is called the ‘sense’ strand. Scientists call the complementary nucleotide chain that binds specifically
to the sense strand the “antisense” strand. We use the information contained in mRNA to design chemical structures, that we call antisense oligonucleotides, or ASOs, or antisense medicines, which resemble DNA and RNA and are the complement of RNA. Our
antisense medicines bind with high selectivity to the mRNA they were designed to target. Since each mRNA codes for a specific protein, we can design antisense medicines that selectively inhibit the disease-causing member of a protein family without
interfering with other members of the protein family that might be necessary for normal cellular or bodily functions. This unique specificity means that antisense medicines may be less toxic than traditional medicines because we can design them to
minimize the impact on unintended targets.
We have developed the majority of the medicines in our pipeline using our advanced screening methods to produce medicines with what we
believe have strong safety and tolerability profiles. We continue to advance our antisense technology to create even more potent medicines that we can use in more tissues and against more targets. These advances allow us to expand the mechanisms
through which we can use our medicines and provide us with greater opportunities to use our antisense medicines to treat a greater number of diseases and reach more patients. Today our medicines and those entering our pipeline utilize our key
technology advances, including our Generation 2.5 and our LICA technology.
Generation 2.5 chemistry, used in several medicines in our pipeline, enables up to 10-fold greater potency compared to
our medicines using our earlier chemistries. This increased potency enables broad distribution throughout the body and target engagement to multiple tissues including liver, kidney, lung, muscle, adipose, adrenal gland, peripheral nerves and tumor
tissues.
LICA is a chemical technology we developed that involves attaching a molecule called a ligand that binds with receptors
on the surfaces of cells in a highly specific manner. Because these receptors are often found only on certain cell types, LICA allows us to increase effective delivery of our antisense medicines with higher specificity to certain cell types that
express these receptors relative to non-conjugated antisense medicines. As of December 2021, we have an integrated assessment of data from multiple LICA medicines and clinical programs which demonstrates that our LICA technology for liver targets can
increase potency by 20-30-fold over our non-LICA antisense medicines.
In addition to the increase in potency, our LICA platform has consistently demonstrated favorable safety and
tolerability. Pelacarsen exemplifies these improvements. We designed this medicine to reduce the production of Apo(a) protein in the liver to offer a direct approach for reducing Lp(a). Pelacarsen was the first medicine to selectively and robustly
reduce Lp(a) levels below threshold levels associated with CVD in nearly all patients and demonstrated a favorable safety and tolerability profile in the Phase 2 study. The study included more than 280 patients, with 98 percent of patients in the high
dose group achieving levels below 50 mg/dL, the recognized risk threshold for CVD.
We can also combine our LICA technology with our Generation 2.5 chemistry, further increasing potency. In addition to
the LICA technology for liver targets, we are also developing LICA conjugation technology that we can use to target other tissues, such as pancreas and muscle, and initial results in animals are promising.
Antisense Targets and Mechanisms
There are more than a dozen different antisense mechanisms that we can utilize with our antisense technology. The
majority of the medicines in our pipeline bind to mRNAs and inhibit the production of disease-causing proteins. However, our antisense technology is broadly applicable to many different antisense mechanisms, including modulation of RNA splicing, RNA
interference, or RNAi, and enhancing protein translation to increase protein production.
When using antisense technology to inhibit the production of disease-causing proteins or reduce levels of harmful RNAs,
our antisense medicines bind to the target RNA via highly specific nucleotide pairing, or hybridization, and recruit a cellular enzyme called ribonuclease H1, or RNase H1, to degrade the target RNA. The antisense medicine itself remains intact during
this process, so it can remain active against additional target RNA molecules and repeatedly trigger their degradation (Figure 4). Examples of our antisense medicines that use the RNase H1 mechanism to reduce disease protein production include,
TEGSEDI, WAYLIVRA, eplontersen, olezarsen, donidalorsen, ION363, pelacarsen, tofersen and others.
Figure 4: Antisense medicine using the RNase H mechanism of action.
SPINRAZA is an example of an antisense medicine that modulates RNA splicing to increase protein production of the SMN protein (Figure 5),
which is critical to the health and survival of nerve cells in the spinal cord that are responsible for neuro-muscular function. The SMN protein is deficient in people with SMA.
Figure 5: Antisense medicine altering splicing of the SMN2 mRNA.
We are also making progress in designing antisense medicines to target long, non-coding RNAs, or lncRNAs and RNAs that
possess a toxic function in human diseases. Many of these RNAs, such as lncRNAs, do not make proteins but often cause disease by regulating the function of other genes or proteins. In 2014, we published a paper in Nature in which we were the first to show that targeted reduction of a lncRNA with an antisense compound can ameliorate certain cognitive deficits in a mouse model of Angelman
syndrome, or AS. In 2021, we initiated the HALOS study, a Phase 1/2a study of ION582 in patients with AS.
Because the efficiency of our core technology platform can support multiple target-based antisense research programs, we
can develop antisense medicines to target a broad range of diseases, efficiently producing a large and broad proprietary portfolio of medicines. We are currently pursuing antisense drug discovery programs focused on neurological, cardiovascular, and
other diseases.
Collaborative Arrangements
We have established alliances with a cadre of leading global pharmaceutical companies. Our partners include the
following companies, among others: AstraZeneca, Bayer, Biogen, GSK, Novartis, and Roche. Through our partnerships, we have earned both commercial revenue and a broad and sustaining base of R&D revenue in the form of license fees, upfront payments
and milestone payments. In 2021, we recognized $810 million in revenue, the majority of which was from our partnered medicines and programs. We have the potential to earn more than $24 billion in future milestone payments, licensing fees and other
payments from our current partnerships. In addition, we are eligible to receive up to mid-20 percent royalties under certain partnerships. Below, we include the significant terms of our collaboration agreements. For additional details, including
other financial information, see Note 6, Collaborative Arrangements and Licensing Agreements, in the Notes to the Consolidated Financial
Statements.
Strategic Partnership
We have several strategic collaborations with Biogen focused on using antisense technology to advance the treatment of
neurological disorders. These collaborations combine our expertise in creating antisense medicines with Biogen’s expertise in developing therapies for neurological disorders. We developed and licensed to Biogen SPINRAZA, our approved medicine to treat
people with SMA. We and Biogen are currently developing nine investigational medicines to treat neurodegenerative diseases under these collaborations, including medicines in development to treat people with ALS, SMA, AS, Alzheimer’s disease and
Parkinson’s disease. In addition to these medicines, our collaborations with Biogen include a substantial research pipeline that addresses a broad range of neurological diseases. From inception through December 2021, we have received $3.2 billion from
our Biogen collaborations.
Spinal Muscular Atrophy Collaborations
SPINRAZA
In January 2012, we entered into a
collaboration agreement with Biogen to develop and commercialize SPINRAZA, an RNA-targeted therapy for the treatment of SMA. From inception through
December 2021, we generated more than $1.6
billion in total revenue under our SPINRAZA collaboration, including nearly $1.2 billion in revenue from SPINRAZA royalties and more than $435 million in R&D revenue. We are receiving tiered royalties ranging from 11 percent to 15 percent on
sales of SPINRAZA. We have exclusively in-licensed patents related to SPINRAZA from Cold Spring Harbor Laboratory and the University of Massachusetts. We pay Cold Spring Harbor Laboratory and the University of Massachusetts a low single digit royalty
on net sales of SPINRAZA. Biogen is responsible for global development, regulatory and commercialization activities and costs for SPINRAZA.
New antisense medicines for the treatment of SMA
In December 2017, we entered into a collaboration agreement with Biogen to identify new antisense medicines for the
treatment of SMA. Biogen has the option to license therapies arising out of this collaboration following the completion of preclinical studies. Upon licensing, Biogen will be responsible for global development, regulatory and commercialization
activities and costs for such therapies. Under the collaboration agreement, we received a $25 million upfront payment in December 2017. In December 2021, we earned a $60 million license fee payment when Biogen exercised its option to license ION306. Biogen is solely responsible for the costs and expenses related to the development, manufacturing and potential future commercialization of ION306 following the option exercise.
We will receive development and regulatory milestone payments from Biogen if new medicines advance towards marketing
approval. In total over the term of our collaboration, we are eligible to receive up to $1.2 billion in license fees, milestone payments and other payments, including up to $555 million if Biogen advances ION306. In addition, we are eligible to receive
tiered royalties from the mid-teens to mid-20 percent range on net sales from any product that Biogen successfully commercializes under this collaboration.
Neurology Collaborations
2018 Strategic Neurology
In April 2018, we and Biogen entered into a strategic collaboration to develop novel antisense medicines for a broad range
of neurological diseases and entered into a Stock Purchase Agreement, or SPA. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies for these diseases for 10 years. We are responsible
for the identification of antisense drug candidates based on selected targets. Biogen is responsible for conducting IND-enabling toxicology studies for the selected medicine. Biogen will have the option to license the selected medicine after it
completes the IND-enabling toxicology study. If Biogen exercises its option to license a medicine, it will assume global development, regulatory and commercialization responsibilities and costs for that medicine.
In June 2018, we received $1 billion from Biogen, comprised of $625 million to purchase our stock at an approximately 25
percent cash premium and $375 million in an upfront payment. We are eligible to receive up to $270 million in milestone payments for each medicine that achieves marketing approval. In addition, we are eligible to receive tiered royalties up to the 20
percent range on net sales from any product that Biogen successfully commercializes under this collaboration. We are currently advancing nine programs under this collaboration and through December 2021, we have generated nearly $1.1 billion in
payments, including $23 million in milestone payments generated in 2021 when Biogen advanced three programs under this collaboration.
2013 Strategic Neurology
In September 2013, we and Biogen entered into a long-term strategic relationship focused on applying antisense technology
to advance the treatment of neurodegenerative diseases. As part of the collaboration, Biogen gained exclusive rights to the use of our antisense technology to develop therapies for neurological diseases and has the option to license medicines resulting
from this collaboration. We will usually be responsible for drug discovery and early development of antisense medicines and Biogen will have the option to license antisense medicines after Phase 2 proof-of-concept. In October 2016, we expanded our
collaboration to include additional research activities we will perform. If Biogen exercises its option to license a medicine, it will assume global development, regulatory and commercialization responsibilities and costs for that medicine. We are
currently advancing six investigational medicines in development under this collaboration, including a medicine for Parkinson’s disease, three medicines for ALS, a medicine for multiple system atrophy and a medicine for an undisclosed target. In
December 2018, Biogen exercised its option to license our most advanced ALS medicine, tofersen, and as a result Biogen is now responsible for global development, regulatory and commercialization activities and costs for tofersen.
Under the terms of the agreement, we received an upfront payment of $100 million and are eligible to receive milestone
payments, license fees and royalty payments for all medicines developed under this collaboration, with the specific amounts dependent upon the modality of the molecule advanced by Biogen. For each antisense molecule that is chosen for drug discovery
and development under this collaboration, we are eligible to receive up to approximately $260 million in a license fee and milestone payments. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales from any product
that Biogen successfully commercializes under this collaboration. Through December 2021, we have generated over $280 million under this collaboration, including $10 million we received from Biogen in 2021 when Biogen advanced ION541, an investigational
medicine targeting ATXN2 to treat patients with ALS.
2012 Neurology
In December 2012, we and Biogen entered into a collaboration agreement to develop and commercialize novel antisense
medicines to treat neurodegenerative diseases. We are responsible for the development of each of the medicines through the completion of the initial Phase 2 clinical study for such medicine. Biogen has the option to license a medicine from each of the
programs through the completion of the first Phase 2 study for each program. Under this collaboration, we are currently advancing IONIS-MAPTRx for Alzheimer’s disease and ION582 for AS. If Biogen exercises its option to license a medicine,
it will assume global development, regulatory and commercialization responsibilities and costs for that medicine. In December 2019, Biogen exercised its option to license IONIS-MAPTRx and as a result Biogen is now responsible for global
development, regulatory and commercialization activities and costs for IONIS-MAPTRx.
Under the terms of the agreement, we received an upfront payment of $30 million. Over the term of the collaboration, we
are eligible to receive up to $210 million in a license fee and milestone payments per program, plus a mark-up on the cost estimate of the Phase 1 and 2 studies. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales
from any product that Biogen successfully commercializes under this collaboration. Through December 2021, we have generated over $165 million under our collaboration, including $10 million we received from Biogen for advancing ION582 during 2021.
Joint Development and Commercialization Arrangement
AstraZeneca
Eplontersen Collaboration
In December 2021, we entered into a joint development and commercialization agreement with AstraZeneca to develop and
commercialize eplontersen for the treatment of ATTR. We are jointly developing and preparing to commercialize eplontersen with AstraZeneca in the U.S. AstraZeneca obtained exclusive rights to commercialize eplontersen outside the U.S., except certain
countries in Latin America. Under the terms of the agreement, we received a $200 million upfront payment. We are eligible to receive up to $485 million in development and approval milestones, and up to $2.9 billion in sales-related milestone payments.
In addition, we are eligible to receive up to mid-20 percent royalties for sales in the U.S. and tiered royalties up to the high teens for sales outside the U.S.
The collaboration also includes
territory-specific development, commercial and medical affairs cost-sharing provisions. AstraZeneca will pay 55 percent of the costs associated with the ongoing global Phase 3 development program. As we will continue to lead the Phase 3 development
program, we will recognize as revenue the 55 percent of cost-share funding AstraZeneca is responsible for in the same period we incur the related development expenses. As AstraZeneca is responsible for the majority of the commercial and medical
affairs costs in the U.S. and all costs associated with bringing eplontersen to market outside the U.S., we will recognize cost-share funding we receive from AstraZeneca related to these activities as a reduction of our commercial and medical affairs
expenses. Through December 2021, we have generated $200 million in payments under this collaboration.
Research and Development Partners
AstraZeneca
In addition to our collaboration for eplontersen, we have two other collaborations with AstraZeneca. One is focused on the
treatment of cardiovascular, renal and metabolic diseases and the other is focused on the treatment of oncology diseases. We and AstraZeneca are currently developing six medicines under these collaborations. From inception through December 2021, we
have generated nearly $425 million from our AstraZeneca research and development collaborations.
Cardiovascular, Renal and Metabolic Diseases Collaboration
In July 2015, we and AstraZeneca formed a collaboration to discover and develop antisense therapies for treating
cardiovascular, renal and metabolic diseases. Under our collaboration, AstraZeneca has licensed five medicines from us. AstraZeneca is responsible for global development, regulatory and commercialization activities and costs for each of the medicines
it has licensed.
Under the terms of the agreement, we received a $65 million upfront payment. We are eligible to receive license fees and
milestone payments of up to more than $5.5 billion as medicines under this collaboration advance. In addition, we are eligible to receive tiered royalties up to the low teens on net sales from any product that AstraZeneca successfully commercializes
under this collaboration agreement. Through December 2021, we have generated over $280 million in payments, including $40 million we earned in 2021 for two targets that AstraZeneca is advancing for a metabolic disease.
In December 2012, we entered into a collaboration agreement with AstraZeneca to discover and develop antisense medicines
to treat cancer. We and AstraZeneca also established an oncology research program. In 2020, AstraZeneca licensed ION736, an investigational medicine in development targeting FOXP3 for the treatment of cancer. AstraZeneca is responsible for global
development, regulatory and commercialization activities and costs for ION736.
Under the terms of this agreement, we
received $31 million in upfront payments. We are eligible to receive license fees and milestone payments of up to more than $265 million as this collaboration advances. In addition, we are eligible to receive tiered royalties up to the low teens on
net sales from any product that AstraZeneca successfully commercializes under this collaboration agreement. Through December 2021, we have generated over $140 million in payments under this collaboration, including $13 million we earned in 2020 when
AstraZeneca licensed ION736.
In May 2015, we entered into an exclusive license agreement with Bayer to develop and commercialize IONIS-FXIRx
for the prevention of thrombosis and we received a $100 million upfront payment. In February 2017, we amended our agreement with Bayer to advance IONIS-FXIRx and to initiate development of fesomersen (formerly IONIS-FXI-LRx),
which Bayer licensed. In conjunction with the amendment, we received a $75 million payment. In October 2019, Bayer decided to advance fesomersen following positive clinical results. Bayer is now responsible for all global development, regulatory and
commercialization activities and costs for the FXI program. We are eligible to receive additional milestone payments as the FXI program advances toward the market. Over the term of the collaboration, we are eligible to receive up to $385 million in
license fees, milestone payments and other payments. In addition, we are eligible to receive tiered royalties in the low to high 20 percent range on gross margins of both medicines combined. Through December 2021, we have generated over $190 million
under this collaboration.
In March 2010, we entered into an alliance with GSK using our antisense drug discovery platform to discover and develop
new medicines against targets for serious and rare diseases, including infectious diseases and some conditions causing blindness. Under the collaboration, we received upfront payments of $35 million. Our collaboration with GSK covers bepirovirsen,
an investigational antisense medicine we designed to reduce the production of viral proteins associated with HBV infection. In 2019, following positive Phase 2 results, GSK licensed our HBV program. GSK is responsible for all global development,
regulatory and commercialization activities and costs for the HBV program.
Under our agreement, if GSK successfully develops bepirovirsen and achieves pre-agreed sales targets, we could receive
license fees and milestone payments of more than $260 million. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales from any product that GSK successfully commercializes under this alliance. Through December 2021,
we have generated over $185 million in payments under our collaboration.
In January 2017, we initiated a collaboration
with Novartis to develop and commercialize pelacarsen. We received a $75 million upfront payment in February 2017. In February 2019, Novartis
licensed pelacarsen and we earned a $150 million license fee. Novartis is responsible for conducting and funding future development and regulatory activities for pelacarsen, including a global Phase 3 cardiovascular outcomes study, which
Novartis initiated in December 2019. In connection with Novartis’ license of pelacarsen, we and Novartis established a more definitive framework under
which the companies would negotiate the co-commercialization of pelacarsen in selected markets. Included in this framework is an option by which Novartis could solely commercialize pelacarsen in exchange for Novartis paying us increased sales milestone
payments based on sales of pelacarsen.
Under the collaboration, we are eligible to receive up to $675 million in milestone payments related to pelacarsen. We are also eligible
to receive tiered royalties in the mid-teens to low 20 percent range on net sales of pelacarsen. Through December 2021, we have generated nearly $425 million
under our collaboration including an upfront payment, license fee, milestone payments and other payments from this collaboration, including a $25 million milestone payment we earned in 2021 when Novartis achieved 50 percent enrollment in the Lp(a)
HORIZON Phase 3 cardiovascular outcome study of pelacarsen.
In conjunction with this collaboration, we entered into a SPA with Novartis. As part of the SPA, Novartis purchased 1.6
million shares of our common stock for $100 million in the first quarter of 2017.
Roche
Huntington’s Disease
In April 2013, we formed an alliance with Hoffman-La Roche Inc. and F. Hoffmann-La Roche Ltd., collectively Roche, to
develop treatments for HD based on our antisense technology. Under the agreement, we discovered and developed tominersen, an investigational medicine targeting HTT protein. We developed tominersen through completion of our Phase 1/2 clinical study in
people with early stage HD. In December 2017, upon completion of the Phase 1/2 study, Roche exercised its option to license tominersen and is now responsible for the global development, regulatory and commercialization activities and costs
for tominersen. In March 2021, Roche discontinued dosing in the Phase 3 GENERATION HD1 study of tominersen in patients with manifest Huntington’s disease based on the results of a pre-planned review of data from the Phase 3 study conducted by an
unblinded Independent Data Monitoring Committee. In January 2022, Roche announced it is actively preparing to initiate a new Phase 2 study of tominersen in patients with HD. Post-hoc analyses from the GENERATION HD1 study suggested tominersen may
benefit younger adult patients with lower disease burden.
Under the terms of the agreement, we received an upfront payment of $30 million in April 2013. We are eligible to
receive up to $365 million in a license fee and milestone payments as tominersen advances. In addition, we are eligible to receive up to $136.5 million in milestone payments for each additional medicine successfully developed. We are also eligible to
receive tiered royalties up to the mid-teens on net sales from any product resulting from this alliance. Through December 2021, we have generated $150 million under our collaboration.
IONIS-FB-LRx for Complement-Mediated Diseases
In October 2018, we entered into a collaboration agreement with Roche to develop IONIS-FB-LRx for the treatment
of complement-mediated diseases. We are currently conducting Phase 2 studies in two disease indications for IONIS-FB-LRx, one for the treatment of patients with GA, the advanced stage of dry AMD, and a second for the treatment of patients
with IgA nephropathy. Roche has the option to license IONIS-FB-LRx at the completion of these studies. Upon licensing, Roche will be responsible for global development, regulatory and commercialization activities and costs.
Under the terms of this agreement, we received a $75 million upfront payment in October 2018. We are eligible to receive
more than $680 million including a license fee and milestone payments. In addition, we are also eligible to receive tiered royalties from the high teens to twenty percent on net sales. Through December 2021, we have generated over $75 million under our
collaboration.
Commercialization Partnerships
Swedish Orphan Biovitrum AB (Sobi)
We began commercializing TEGSEDI and WAYLIVRA in Europe in January 2021 and TEGSEDI in North America in April 2021 through
distribution agreements with Sobi. Under our agreements, we are responsible for supplying finished goods inventory to Sobi and Sobi is responsible for selling each medicine to the end customer. In exchange, we earn a distribution fee on net sales from
Sobi for each medicine.
PTC Therapeutics
In August 2018, we entered into an exclusive
license agreement with PTC Therapeutics to commercialize TEGSEDI and WAYLIVRA in Latin America and certain Caribbean countries. Under the license agreement, we are eligible to receive royalties from PTC in the mid-20 percent range on net sales for each medicine. In
December 2021, we started receiving royalties from PTC for TEGSEDI sales.
Technology Enhancement Collaboration
Bicycle License Agreement
In December 2020, we entered into a collaboration agreement with Bicycle and obtained an option to license its peptide
technology to potentially increase the delivery capabilities of our LICA medicines. In July 2021, we paid $42 million when we exercised our option to license Bicycle’s technology, which included an equity investment in Bicycle. As part of our stock
purchase, we entered into a lockup agreement with Bicycle that restricts our ability to trade our Bicycle shares for one year. In 2021, we recorded a $7 million equity investment for the shares we received in Bicycle. We recognized the remaining $35
million as R&D expense in 2021. From inception through December 2021, we have paid Bicycle $47 million under this collaboration agreement.
Alnylam Pharmaceuticals, Inc.
Under the terms of our agreement with Alnylam, we co-exclusively (with ourselves) licensed to Alnylam our patent estate
relating to antisense motifs and mechanisms and oligonucleotide chemistry for double-stranded RNAi therapeutics, with Alnylam having the exclusive right to grant platform sublicenses for double-stranded RNAi. In exchange for such rights, Alnylam
gave us a technology access fee, participation in fees from Alnylam’s partnering programs, as well as future milestone and royalty payments from Alnylam. We retained exclusive rights to our patents for single-stranded antisense therapeutics and for a
limited number of double-stranded RNAi therapeutic targets and all rights to single-stranded RNAi, or ssRNAi, therapeutics. In turn, Alnylam nonexclusively licensed to us its patent estate relating to antisense motifs and mechanisms and
oligonucleotide chemistry to research, develop and commercialize single-stranded antisense therapeutics, ssRNAi therapeutics, and to research double-stranded RNAi compounds. We also received a license to develop and commercialize double-stranded RNAi
therapeutics targeting a limited number of therapeutic targets on a nonexclusive basis. Additionally, in 2015, we and Alnylam entered into an alliance in which we cross-licensed intellectual property. Under this alliance, we and Alnylam each obtained
exclusive license rights to four therapeutic programs. Alnylam granted us an exclusive, royalty-bearing license to its chemistry, RNA targeting mechanism and target-specific intellectual property for oligonucleotides against four targets, including
FXI and Apo(a) and two other targets. In exchange, we granted Alnylam an exclusive, royalty-bearing license to our chemistry, RNA targeting mechanism and target-specific intellectual property for oligonucleotides against four other targets. Alnylam
also granted us a royalty-bearing, non-exclusive license to new platform technology arising from May 2014 through April 2019 for single-stranded antisense therapeutics. In turn, we granted Alnylam a royalty-bearing, non-exclusive license to new
platform technology arising from May 2014 through April 2019 for double-stranded RNAi therapeutics.
In the fourth quarter of 2020, we completed an arbitration process with Alnylam. The arbitration panel awarded us $41
million for payments owed to us by Alnylam related to Alnylam’s agreement with Sanofi Genzyme. We recognized the $41 million payment from Alnylam as R&D revenue in the fourth quarter of 2020.
The Ludwig Institute; Center for Neurological Studies
We have a collaboration with the Ludwig Institute, the Center for Neurological Studies and researchers to discover and
develop antisense medicines for ALS and other neurodegenerative diseases. Under this agreement, we agreed to pay the Ludwig Institute and the Center for Neurological Studies modest milestone payments and royalties on any antisense medicines resulting
from the collaboration.
Manufacturing
We manufacture most of the drug product we use for our research and development activities ourselves. We have also
manufactured API and commercial supply for our approved medicines. We have dedicated significant resources to develop ways to improve manufacturing efficiency and capacity. Since we can use variants of the same nucleotide building blocks and the same
type of equipment to produce our oligonucleotide medicines, we found that the same techniques we used to efficiently manufacture one oligonucleotide medicine could help improve the manufacturing processes for our other antisense medicines. By
developing several proprietary chemical processes to scale up our manufacturing capabilities, we have greatly reduced the cost of producing oligonucleotide medicines. For example, we have significantly reduced the cost of raw materials through improved
yield efficiency, while at the same time increasing our capacity to make our medicines. Through both our internal research and development programs and collaborations with outside vendors we may achieve even greater efficiency and further cost
reductions.
Our manufacturing facility is located in a 26,800 square foot building in Carlsbad, California. We purchased this building
in 2017. In addition, we have a 25,800 square foot building that houses support functions for our manufacturing activities. We lease this facility under a lease that has a term ending in August 2026 with an option to extend the lease for an additional
five-year period. Our manufacturing facility is subject to periodic inspections by the FDA and foreign equivalents to ensure that it is operating in compliance with current Good Manufacturing Practices, or cGMP, requirements.
As part of our collaborations we may agree to manufacture clinical trial materials and/or commercial supply for our
partners. For example, in the past we have manufactured clinical supply materials for AstraZeneca, Bayer, Biogen, GSK and Novartis and commercial supply materials for Biogen.
We believe we have sufficient manufacturing capacity at our own facility or at contract manufacturing organizations, or
CMOs, to meet our current internal research, development and potential commercial needs, as well as our obligations under existing agreements with our partners for research, development and commercial material. As we continue to advance our wholly
owned medicines through Phase 3 development, we will begin to manufacture process performance qualification batches and pre-approval inspection batches of our Phase 3 medicines that may be used for regulatory submissions and, pending regulatory
approval, commercial sale. We believe our current network of CMO partners are capable of providing sufficient quantities to meet anticipated commercial demands. Additionally, we continue to evaluate relationships with additional suppliers to increase
overall capacity and diversify our supply chain. While we believe that there are alternate sources of supply that can satisfy our commercial requirements, it is possible that identifying and establishing relationships with such sources, if necessary,
could result in significant delay or material additional costs. We also could experience a disruption in supply from our current CMO partners.
CMOs are subject to the FDA’s cGMP requirements and other rules and regulations prescribed by foreign regulatory
authorities. We depend on our CMO partners for continued compliance with cGMP requirements and applicable foreign standards.
Specifically, we have the following in place for our approved medicines, SPINRAZA, TEGSEDI and WAYLIVRA and our medicines
in Phase 3 development: eplontersen, olezarsen, donidalorsen, ION363, pelacarsen and tofersen.
SPINRAZA
Biogen is responsible for SPINRAZA drug supply.
TEGSEDI and WAYLIVRA
For TEGSEDI’s commercial drug supply, we are using CMOs to produce custom raw materials, active pharmaceutical ingredient,
or API, and finished goods. For WAYLIVRA’s commercial drug supply, we have manufactured custom raw materials and API. We are using CMOs to produce the finished goods for WAYLIVRA. Our CMO partners have extensive technical expertise and cGMP experience.
We believe our we and our current network of CMO partners are capable of manufacturing sufficient quantities to meet anticipated commercial demands.
Eplontersen
Our CMO partner supplied the API and the finished drug product for eplontersen’s Phase 3 program. Pursuant to our collaboration with
AstraZeneca, we will manufacture and supply eplontersen through a CMO for the ongoing clinical trials and process qualifications. AstraZeneca is responsible for commercial supply.
Olezarsen, Donidalorsen, ION363
We have supplied the API and the finished
drug product for olezarsen, donidalorsen and ION363 that we believe will be sufficient through the completion of the Phase 3 programs for each
medicine. We plan to leverage our relationships with CMOs to procure long-term raw material and drug supplies at competitive prices in the future.
Pelacarsen
We supplied the API and the finished drug product for pelacarsen’s Phase 3 study. Pursuant to our collaboration with
Novartis, Novartis is responsible for any further pelacarsen drug supply.
Tofersen
We manufactured the first batch of API for tofersen in 2015 to support the first in human studies under our collaboration
agreement with Biogen. Pursuant to our collaboration with Biogen, Biogen is responsible for tofersen drug supply. Biogen has an oligonucleotide synthesis manufacturing facility that gives it the capability to manufacture tofersen for all subsequent
clinical studies and potential commercialization, including supplying the API for the current Phase 3 study.
Patents and Proprietary Rights
Our success depends, in part, on our ability to obtain patent protection for our products in the U.S. and other countries.
We own or have exclusively licensed a substantial patent estate with numerous issued patents worldwide protecting our products and, more generally, our platform for development and commercialization of oligonucleotide therapeutics. We focus our
resources on patents and new patent applications that drive value for our company.
We own or control patents that provide exclusivity for products in our pipeline and patents that provide exclusivity for
our core technology in the field of antisense more generally. Our core technology patents include claims to chemically modified nucleosides and oligonucleotides as well as antisense medicine designs utilizing these chemically modified nucleosides.
These core claims are independent of specific therapeutic target, nucleic acid sequence, or clinical indication. We also own a large number of patents claiming antisense compounds having nucleic acid sequences complementary to therapeutic target
nucleic acids, independent of the particular chemical modifications incorporated into the antisense compound. Most importantly, we seek and obtain issued patent claims to specifically protect each of our medicines. For example, we file and seek to
obtain claims covering each drug’s nucleic acid sequence and precise drug design. In sum, we maintain our competitive advantage in the field of antisense technology by protecting our core platform technology and by creating multiple layers of patent
protection for each of our specific medicines in development.
|
Type of Patent Claim
(Broadly Applicable to Specific)
|
|
|
|
● Chemically Modified Nucleosides and Oligonucleotides (target and sequence independent)
● Antisense Drug Design Motifs (target and sequence independent)
● Therapeutic Methods (sequence and chemistry independent)
● Antisense Sequence (chemistry independent)
● Drug Composition
|
|
|
Chemically Modified Nucleosides and Oligonucleotides
The most broadly applicable of our patents are those that claim modified nucleosides and oligonucleotides comprising the
modified nucleosides that we incorporate into our antisense medicines to increase their therapeutic efficacy. Nucleosides and chemically modified nucleosides are the basic building blocks of our antisense medicines. Therefore claims that cover any
oligonucleotide incorporating one of our proprietary modified nucleosides can apply to a wide array of antisense mechanisms of action as well as several therapeutic targets. Of particular note are our patents covering our proprietary 2’-O-(2-methoxy)
ethyl, or “MOE,” modified nucleosides, incorporated into many of our second-generation development compounds, as well as our constrained-ethyl nucleosides, or “cEt” nucleosides incorporated into our Generation 2.5 compounds. The following are some of
our patents in this category in key jurisdictions (U.S., Europe and Japan):
|
Jurisdiction
|
|
Patent No.
|
|
Title
|
|
Expiration
|
|
Description of Claims
|
|
United States
|
|
7,101,993
|
|
OLIGONUCLEOTIDES CONTAINING 2’-O-MODIFIED PURINES
|
|
2023
|
|
Certain MOE nucleosides and oligonucleotides containing these nucleotides
|
|
United States
|
|
7,399,845
|
|
6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS
|
|
2027
|
|
cEt nucleosides and oligonucleotides containing these nucleoside analogs
|
|
United States
|
|
7,741,457
|
|
6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS
|
|
2027
|
|
cEt nucleosides and oligonucleotides containing these nucleoside analogs
|
|
United States
|
|
8,022,193
|
|
6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS
|
|
2027
|
|
Oligonucleotides containing cEt nucleoside analogs
|
|
Europe
|
|
1984381
|
|
6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS
|
|
2027
|
|
cEt nucleosides and oligonucleotides containing these nucleoside analogs
|
|
Europe
|
|
2314594
|
|
6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS
|
|
2027
|
|
Oligonucleotides containing cEt nucleoside analogs and methods of use
|
|
Japan
|
|
5342881
|
|
6-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS
|
|
2027
|
|
cEt nucleosides and oligonucleotides containing these nucleoside analogs
|
|
United States
|
|
7,569,686
|
|
COMPOUNDS AND METHODS FOR SYNTHESIS OF BICYCLIC NUCLEIC ACID ANALOGS
|
|
2027
|
|
Methods of synthesizing cEt nucleosides
|
Antisense Drug Design Motifs
We also have patents that claim oligonucleotides comprising antisense drug design motifs, or patterns of nucleoside
modifications at specified positions in the oligonucleotide. Patent claims covering our antisense drug design motifs are independent of nucleic acid sequence, so they cover oligonucleotides having the recited motif, regardless of cellular target or
clinical indication. The claimed motifs generally confer properties that optimize oligonucleotides for a particular antisense mechanism of action, such as ribonuclease H (RNase H), RNAi, or splicing. We have designed oligonucleotides incorporating
motifs, which we refer to as chimeric compounds or gapmers, to exploit the RNase H mechanism to achieve target RNA reduction. Almost all of our medicines in clinical development, including TEGSEDI and WAYLIVRA, but excluding SPINRAZA, contain this
gapmer antisense drug design motif. We own a U.S. patent that covers all of our second-generation MOE gapmer antisense medicines until March of 2023.
In addition, we have patent claims to antisense drug design motifs incorporating bicyclic nucleosides, which include both
locked nucleic acids, or “LNA” and cEt. In Europe, we have been granted claims drawn to certain gapmer oligonucleotides with bicyclic nucleosides, which include locked nucleic acids in the wings. We have also successfully obtained issued patent claims
covering our Generation 2.5 gapmer antisense drug design motifs that incorporate our cEt modified nucleosides. The following patents are some examples of our issued patents in this category in key jurisdictions (U.S., Europe and Japan):
|
Jurisdiction
|
|
Patent No.
|
|
Title
|
|
Expiration
|
|
Description of Claims
|
|
United States
|
|
7,015,315
|
|
GAPPED OLIGONUCLEOTIDES
|
|
2023
|
|
Gapmer oligonucleotides having 2’-O-alkyl-O-alkyl nucleosides
|
|
United States
|
|
7,750,131
|
|
5’-MODIFIED BICYCLIC NUCLEIC ACID ANALOGS
|
|
2027
|
|
Oligonucleotides having 5’-methyl BNA nucleosides
|
|
Europe
|
|
2092065
|
|
ANTISENSE COMPOUNDS
|
|
2027
|
|
Gapmer oligonucleotides having 2’-modifed and LNA nucleosides
|
|
Europe
|
|
2410053
|
|
ANTISENSE COMPOUNDS
|
|
2027
|
|
Gapmer oligonucleotides having wings comprised of 2’-MOE and bicyclic nucleosides
|
|
Europe
|
|
2410054
|
|
ANTISENSE COMPOUNDS
|
|
2027
|
|
Gapmer oligonucleotides having a 2’-modifed nucleoside in the 5’-wing and a bicyclic nucleoside in the 3’-wing
|
|
Japan
|
|
5665317
|
|
ANTISENSE COMPOUNDS
|
|
2027
|
|
Gapmer oligonucleotides having wings comprised of 2’-MOE and bicyclic nucleosides
|
|
United States
|
|
9,550,988
|
|
ANTISENSE COMPOUNDS
|
|
2028
|
|
Gapmer oligonucleotides having BNA nucleosides and 2’-MOE nucleosides
|
|
United States
|
|
10,493,092
|
|
ANTISENSE COMPOUNDS
|
|
2028
|
|
Gapmer oligonucleotides having BNA nucleosides and 2’-MOE nucleosides and/or 2’-OMe nucleosides
|
|
Europe
|
|
3067421
|
|
OLIGOMERIC COMPOUNDS COMPRISING BICYCLIC NUCLEOTIDES AND USES THEREOF
|
|
2032
|
|
Gapmer oligonucleotides having at least one bicyclic, one 2’-modified nucleoside and one 2’-deoxynucleoside
|
LIgand-Conjugated Antisense (LICA) Technology
We also have patent claims to new chemistries created to enhance targeting of antisense medicines to specific tissues and
cells to improve a drug’s properties. We designed our GalNAc LICA medicines to provide an increase in potency for targets in the liver. We have successfully obtained issued patent claims covering our LICA technology conjugated to any modified
oligonucleotide, including gapmers, double-stranded siRNA compounds, and fully modified oligonucleotides. The following patents are some examples of our issued patents in this category:
|
Jurisdiction
|
|
Patent
|
|
Title
|
|
Expiration
|
|
Description of Claims
|
|
United States
|
|
9,127,276
|
|
CONJUGATED ANTISENSE COMPOUNDS AND THEIR USE
|
|
2034
|
|
Preferred THA LICA conjugated to any group of nucleosides, including gapmers, double-stranded siRNA compounds, and fully modified
oligonucleotides
|
|
United States
|
|
9,181,549
|
|
CONJUGATED ANTISENSE COMPOUNDS AND THEIR USE
|
|
2034
|
|
Preferred THA conjugate having our preferred linker and cleavable moiety conjugated to any oligomeric compound or any nucleoside having
a 2’-MOE modification or a cEt modification
|
|
Europe
|
|
2991661
|
|
CONJUGATED ANTISENSE COMPOUNDS AND THEIR USE
|
|
2034
|
|
Preferred THA LICA conjugated to any group of nucleosides, including gapmers, double-stranded siRNA compounds, and fully modified
oligonucleotides
|
Therapeutic Methods of Treatment and Antisense Drug Sequences
In addition to our broad core patents, we also own hundreds of patents, worldwide, with claims to antisense compounds
having particular sequences and compounds directed to particular therapeutically important targets or methods of achieving cellular or clinical endpoints using these antisense compounds. These “Target” patents also include claims reciting the specific
nucleic acid sequences utilized by our products, independent of chemical modifications and motifs. In addition, our product-specific patents typically include claims combining specific nucleic acid sequences with nucleoside modifications and motifs. In
this way, we seek patent claims narrowly tailored to protect our products specifically, in addition to the broader core antisense patents described above.
SPINRAZA and Survival Motor Neuron
We believe SPINRAZA is protected from generic competition in the U.S. until at least 2035 and in Europe until at least
2030 by a suite of patents. These issued patents include: (i) patents licensed from the University of Massachusetts drawn to antisense compounds having the sequence of SPINRAZA, independent of chemical modification and uses of such compounds for
treating SMA, and (ii) joint patents with Cold Spring Harbor Laboratory claiming fully modified 2’MOE compositions targeting SMN2, including the precise composition of matter of SPINRAZA and methods of using such compositions. We have filed for patent
term extension, to potentially extend the term beyond 2030. With Biogen’s license of SPINRAZA, we assigned our interest in these patents to Biogen. The table below lists some key issued patents protecting SPINRAZA in the U.S. and Europe:
|
Jurisdiction
|
|
Patent No.
|
|
Title
|
|
Expiration
|
|
Description of Claims
|
|
United States
|
|
10,266,822
|
|
SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES
|
|
2025
|
|
Methods of increasing exon-7 containing SMN2 mRNA in a cell using an oligonucleotide having the sequence of SPINRAZA
|
|
United States
|
|
8,110,560
|
|
SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES
|
|
2025
|
|
Methods of using antisense oligonucleotides having sequence of SPINRAZA to alter splicing of SMN2 and/or to treat SMA
|
|
Europe
|
|
1910395
|
|
COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING
|
|
2026
|
|
Sequence and chemistry (full 2’-MOE) of SPINRAZA
|
|
Europe
|
|
3308788
|
|
COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING
|
|
2026
|
|
Pharmaceutical compositions that include SPINRAZA
|
|
United States
|
|
7,838,657
|
|
SPINAL MUSCULAR ATROPHY (SMA) TREATMENT VIA TARGETING OF SMN2 SPLICE SITE INHIBITORY SEQUENCES
|
|
2027
|
|
Oligonucleotides having sequence of SPINRAZA
|
|
United States
|
|
8,361,977
|
|
COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING
|
|
2030
|
|
Sequence and chemistry (full 2’-MOE) of SPINRAZA
|
|
United States
|
|
8,980,853
|
|
COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT
|
|
2030
|
|
Methods of administering SPINRAZA
|
|
United States
|
|
9,717,750
|
|
COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT
|
|
2030
|
|
Methods of administering SPINRAZA to a patient
|
|
Europe
|
|
3449926
|
|
COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT
|
|
2030
|
|
Pharmaceutical compositions that include SPINRAZA for treating SMA
|
|
Europe
|
|
3305302
|
|
COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT
|
|
2030
|
|
Antisense compounds including SPINRAZA for treating SMA
|
|
United States
|
|
9,926,559
|
|
COMPOSITIONS AND METHODS FOR MODULATION OF SMN2 SPLICING IN A SUBJECT
|
|
2034
|
|
SPINRAZA doses for treating SMA
|
|
United States
|
|
10,436,802
|
|
METHODS FOR TREATING SPINAL MUSCULAR ATROPHY
|
|
2035
|
|
SPINRAZA dosing regimen for treating SMA
|
TEGSEDI and Transthyretin
We believe TEGSEDI is protected from generic competition in the U.S. and Europe until at least 2031. Additional patent
applications designed to protect TEGSEDI in other foreign jurisdictions are being pursued. The table below lists some key issued patents protecting TEGSEDI in the U.S. and Europe:
|
Jurisdiction
|
|
Patent No.
|
|
Title
|
|
Expiration
|
|
Description of Claims
|
|
United States
|
|
8,101,743
|
|
MODULATION OF TRANSTHYRETIN EXPRESSION
|
|
2025
|
|
Antisense sequence and chemistry of TEGSEDI
|
|
United States
|
|
8,697,860
|
|
DIAGNOSIS AND TREATMENT OF DISEASE
|
|
2031
|
|
Composition of TEGSEDI
|
|
United States
|
|
9,061,044
|
|
MODULATION OF TRANSTHYRETIN EXPRESSION
|
|
2031
|
|
Sodium salt composition of TEGSEDI
|
|
United States
|
|
9,399,774
|
|
MODULATION OF TRANSTHYRETIN EXPRESSION
|
|
2031
|
|
Methods of treating transthyretin amyloidosis by administering TEGSEDI
|
|
Europe
|
|
2563920
|
|
MODULATION OF TRANSTHYRETIN EXPRESSION
|
|
2031
|
|
Composition of TEGSEDI
|
WAYLIVRA and Apolipoprotein C-III
We have obtained patent claims in the U.S. and Europe drawn to the use of antisense compounds complementary to a broad
active region of human ApoC-III, including the site targeted by WAYLIVRA. We have also obtained issued patents claiming the specific sequence and chemical composition of WAYLIVRA in the U.S. and Europe. We believe the issued claims protect WAYLIVRA
from generic competition in the U.S. and Europe until at least 2023 and 2024, respectively. We are pursuing additional patent applications designed to protect WAYLIVRA worldwide. The table below lists some key issued patents protecting WAYLIVRA in the
U.S. and Europe:
|
Jurisdiction
|
|
Patent No.
|
|
Title
|
|
Expiration
|
|
Description of Claims
|
|
United States
|
|
9,624,496
|
|
MODULATION OF APOLIPOPROTEIN C-III EXPRESSION
|
|
2023
|
|
Antisense compounds specifically hybridizable within the nucleotide region of ApoCIII targeted by WAYLIVRA
|
|
United States
|
|
7,598,227
|
|
MODULATION OF APOLIPOPROTEIN C-III EXPRESSION
|
|
2023
|
|
Methods of treating hyperlipidemia, lowering cholesterol levels or lowering triglyceride levels with WAYLIVRA
|
|
United States
|
|
7,750,141
|
|
MODULATION OF APOLIPOPROTEIN C-III EXPRESSION
|
|
2023
|
|
Antisense sequence and chemistry of WAYLIVRA
|
|
Europe
|
|
1622597
|
|
MODULATION OF APOLIPOPROTEIN C-III EXPRESSION
|
|
2024
|
|
Antisense sequence and chemistry of WAYLIVRA
|
|
Europe
|
|
2441449
|
|
MODULATION OF APOLIPOPROTEIN C-III EXPRESSION
|
|
2024
|
|
Antisense compounds specifically hybridizable within the nucleotide region of ApoCIII targeted by WAYLIVRA
|
|
Europe
|
|
3002007
|
|
MODULATION OF APOLIPOPROTEIN C-III EXPRESSION
|
|
2024
|
|
Compounds complementary to an ApoCIII nucleic acid for use in therapy
|
|
United States
|
|
9,157,082
|
|
MODULATION OF APOLIPOPROTEIN C-III (APOCIII) EXPRESSION
|
|
2032
|
|
Methods of using ApoCIII antisense oligonucleotides for reducing pancreatitis and chylomicronemia and increasing HDL
|
|
United States
|
|
9,593,333
|
|
MODULATION OF APOLIPOPROTEIN C-III (APOCIII) EXPRESSION IN LIPOPROTEIN LIPASE DEFICIENT (LPLD) POPULATIONS
|
|
2034
|
|
Methods of treating lipoprotein lipase deficiency with an ApoCIII specific inhibitor wherein triglyceride levels are reduced
|
|
Europe
|
|
2956176
|
|
MODULATION OF APOLIPOPROTEIN C-III (APOCIII) EXPRESSION IN LIPOPROTEIN LIPASE DEFICIENT (LPLD) POPULATIONS
|
|
2034
|
|
ApoCIII specific inhibitors including WAYLIVRA for treating lipoprotein lipase deficiency or familial chylomicronemia syndrome
|
Eplontersen and Transthyretin
We believe eplontersen is protected from
generic competition in the U.S. and Europe until at least 2034. Additional patent applications to protect eplontersen in other foreign jurisdictions are being pursued. The table below lists some key issued patents protecting eplontersen in the U.S. and Europe:
|
Jurisdiction
|
|
Patent No.
|
|
Title
|
|
Expiration
|
|
Description of Claims
|
|
United States
|
|
10,683,499
|
|
COMPOSITIONS AND METHODS FOR MODULATING TTR EXPRESSION
|
|
2034
|
|
Composition of eplontersen
|
|
Europe
|
|
3524680
|
|
COMPOSITIONS AND METHODS FOR MODULATING TTR EXPRESSION
|
|
2034
|
|
Composition of eplontersen
|
Olezarsen and ApoC-III
We believe olezarsen is protected from generic competition in the U.S. and Europe until at least 2034. Additional patent
applications to protect olezarsen in other foreign jurisdictions are being pursued. The table below lists some key issued patents protecting olezarsen in the U.S. and Europe.
|
Jurisdiction
|
|
Patent No.
|
|
Title
|
|
Expiration
|
|
Description of Claims
|
|
United States
|
|
9,163,239
|
|
COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN C-III EXPRESSION
|
|
2034
|
|
Composition of olezarsen
|
|
Europe
|
|
2991656
|
|
COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN C-III EXPRESSION
|
|
2034
|
|
Composition of olezarsen
|
Donidalorsen and PKK
We believe donidalorsen is protected from generic competition in the U.S. and Europe until at least 2035. Additional
patent applications to protect donidalorsen in other foreign jurisdictions are being pursued. The table below lists some key issued patents protecting donidalorsen in the U.S. and Europe.
|
Jurisdiction
|
|
Patent No.
|
|
Title
|
|
Expiration
|
|
Description of Claims
|
|
United States
|
|
9,315,811
|
|
METHODS FOR MODULATING KALLIKREIN (KLKB1) EXPRESSION
|
|
2032
|
|
Methods of treating HAE
|
|
Europe
|
|
2717923
|
|
METHODS FOR MODULATING KALLIKREIN (KLKB1) EXPRESSION
|
|
2032
|
|
Compounds for use in treating an inflammatory condition, including HAE
|
|
United States
|
|
10,294,477
|
|
COMPOSITIONS AND METHODS FOR MODULATING PKK EXPRESSION
|
|
2035
|
|
Composition of donidalorsen
|
|
Europe
|
|
3137091
|
|
COMPOSITIONS AND METHODS FOR MODULATING PKK EXPRESSION
|
|
2035
|
|
Composition of donidalorsen
|
ION363 and FUS
Patent applications designed to protect ION363 from generic competition are being pursued in the U.S. and Europe; patents issuing from
these applications would have term until at least 2040. The table below lists some key pending patent applications designed to protect ION363 in the
U.S. and Europe:
|
Jurisdiction
|
|
Application No.
|
|
Title
|
|
Expiration
|
|
Description of Claims
|
|
United States
|
|
17/613,183
|
|
COMPOUNDS AND METHODS FOR REDUCING FUS EXPRESSION
|
|
2040
|
|
Composition of ION363
|
|
Europe
|
|
20815459.1
|
|
COMPOUNDS AND METHODS FOR REDUCING FUS EXPRESSION
|
|
2040
|
|
Composition of ION363
|
Pelacarsen and Apo(a)
We believe pelacarsen is protected from
generic competition in the U.S. and Europe until at least 2034. Additional patent protection designed to protect pelacarsen in other foreign jurisdictions is being pursued. The table below lists some key issued patents protecting pelacarsen in the U.S. and Europe:
|
Jurisdiction
|
|
Patent No.
|
|
Title
|
|
Expiration
|
|
Description of Claims
|
|
United States
|
|
9,574,193
|
|
METHODS AND COMPOSITIONS FOR MODULATING APOLIPOPROTEIN (A) EXPRESSION
|
|
2033
|
|
Methods of lowering Apo(a) and/or Lp(a) levels with an
oligonucleotide complementary within the nucleotide region of Apo(a) targeted by pelacarsen
|
|
United States
|
|
10,478,448
|
|
METHODS AND COMPOSITIONS FOR MODULATING APOLIPOPROTEIN (A) EXPRESSION
|
|
2033
|
|
Methods of treating hyperlipidemia with an oligonucleotide
complementary within the nucleotide region of Apo(a) targeted by pelacarsen
|
|
United States
|
|
9,884,072
|
|
METHODS AND COMPOSITIONS FOR MODULATING APOLIPOPROTEIN (A) EXPRESSION
|
|
2033
|
|
Oligonucleotides complementary within the nucleotide region of Apo(a) targeted by pelacarsen
|
|
Europe
|
|
2855500
|
|
METHODS AND COMPOSITIONS FOR MODULATING APOLIPOPROTEIN (A) EXPRESSION
|
|
2033
|
|
Oligonucleotides complementary within the nucleotide region of Apo(a) targeted by pelacarsen for decreasing Apo(a) expression
|
|
United States
|
|
9,181,550
|
|
COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN (a) EXPRESSION
|
|
2034
|
|
Composition of pelacarsen
|
|
Europe
|
|
2992009
|
|
COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN (a) EXPRESSION
|
|
2034
|
|
Composition of pelacarsen
|
Tofersen and SOD-1
We believe tofersen is protected from generic competition in the U.S. and Europe until at least 2035. Additional patent applications
designed to protect tofersen in other foreign jurisdictions are being pursued. With Biogen’s license of tofersen, we assigned our interest in these patents to Biogen. The table below lists some key issued patents protecting tofersen in the U.S. and Europe:
|
Jurisdiction
|
|
Patent No.
|
|
Title
|
|
Expiration
|
|
Description of Claims
|
|
United States
|
|
10,385,341
|
|
COMPOSITIONS FOR MODULATING SOD-1 EXPRESSION
|
|
2035
|
|
Composition of tofersen
|
|
United States
|
|
10,669,546
|
|
COMPOSITIONS FOR MODULATING SOD-1 EXPRESSION
|
|
2035
|
|
Methods of treating a SOD-1 associated neurodegenerative disorder by administering tofersen
|
|
United States
|
|
10,968,453
|
|
COMPOSITIONS FOR MODULATING SOD-1 EXPRESSION
|
|
2035
|
|
Methods of treating a SOD-1 associated neurodegenerative disorder by administering a pharmaceutical composition of tofersen
|
|
Europe
|
|
3126499
|
|
COMPOSITIONS FOR MODULATING SOD-1 EXPRESSION
|
|
2035
|
|
Composition of tofersen
|
We seek patent protection in significant markets and/or countries for each medicine in development. We also seek to
maximize patent term. In some cases, the patent term can be extended to recapture a portion of the term lost during FDA regulatory review. The patent exclusivity period for a medicine will prevent generic medicines from entering the market. Patent
exclusivity depends on a number of factors including initial patent term and available patent term extensions based upon delays caused by the regulatory approval process.
Manufacturing Patents
We also own patents claiming methods of manufacturing and purifying oligonucleotides. These patents claim methods for
improving oligonucleotide drug manufacturing, including processes for large-scale oligonucleotide synthesis and purification. These methods allow us to manufacture oligonucleotides at lower cost by, for example, eliminating expensive manufacturing
steps.
We also rely on trade secrets, proprietary know-how and continuing technological innovation to develop and maintain a
competitive position in antisense therapeutics.
Government Regulation
Regulation by government authorities in the U.S. and other countries is a significant component in the development,
manufacture and commercialization of pharmaceutical products and services. In addition to regulations enforced by the FDA and relevant foreign regulatory authorities, we are also subject to regulation under the Occupational Safety and Health Act, the
Environmental Protection Act, the Toxic Substances Control Act, the Resource Conservation and Recovery Act and other present and potential future federal, state and local regulations.
Extensive regulation by the U.S. and foreign governmental authorities governs the development, manufacture and sale of our
medicines. In particular, our medicines are subject to a number of approval requirements by the FDA in the U.S. under the Federal Food, Drug and Cosmetic Act, or FDCA, and other laws and by comparable agencies in those foreign countries in which we
conduct business. The FDCA and other various federal, state and foreign statutes govern or influence the research, testing, manufacture, safety, labeling, storage, recordkeeping, approval, promotion, marketing, distribution, post-approval monitoring
and reporting, sampling, quality, and import and export of our medicines. State, local, and other authorities also regulate pharmaceutical manufacturing facilities and procedures.
Our manufacturing facility and our CMOs are subject to periodic inspection by the FDA and other foreign equivalents to
ensure that they are operating in compliance with cGMP requirements. In addition, marketing authorization for each new medicine may require a rigorous manufacturing pre-approval inspection by regulatory authorities. Post approval, there are strict
regulations regarding changes to the manufacturing process, and, depending on the significance of the change, changes may require prior FDA approval. FDA regulations also require investigation and correction of any deviations from cGMP and impose
reporting and documentation requirements upon us and any third-party manufacturers that we may decide to use.
The FDA must approve any new medicine before a manufacturer can market it in the U.S. In order to obtain approval, we and
our partners must complete clinical studies and prepare and submit an NDA to the FDA. If the FDA approves a medicine, it will issue an approval letter authorizing commercial marketing of the medicine and may require a risk evaluation and mitigation
strategy, or REMS, to help ensure the benefits of the medicine outweigh the potential risks. For example, TEGSEDI has a REMS program. The requirements for REMS can materially affect the potential market and profitability of our medicines. In foreign
jurisdictions, the drug approval process is similarly demanding.
For any approved medicine, domestic and foreign sales of the medicine depend, in part, on the availability and amount of
coverage and adequate reimbursement by third-party payers, including governments and private health plans. The process for determining whether a payer will provide coverage for a product may be separate from the process for setting the reimbursement
rate that the payer will pay for the product, or procedures which utilize such product. Private health plans may seek to manage cost and use of our medicines by implementing coverage and reimbursement limitations. For example, third-party payers may
limit coverage to specific products on an approved list, or formulary, which might not include all of U.S. FDA-approved products for a particular indication. In certain jurisdictions, governments may also regulate or influence coverage, reimbursement
and/or pricing of our medicines to control cost or affect use. Within the EU a variety of payers pay for medicines, with governments being the primary source of payment. Negotiating pricing with governmental authorities can delay commercialization.
Such pricing and reimbursement factors could impact our ability and that of our commercial partners to successfully commercialize approved medicines. Further, it is possible that additional governmental action is taken in response to the COVID-19
pandemic.
In the U.S. and foreign jurisdictions, the legislative landscape continues to evolve. There have been a number of
legislative and regulatory changes to the healthcare system that could affect our future results of operations. In particular, there have been and continue to be a number of initiatives at the U.S. federal and state levels and by foreign governments
that seek to reduce healthcare costs. There has also been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in efforts to bring more transparency to drug pricing, review
the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for medicines. Further, it is possible that additional governmental action is taken in response to the COVID-19 pandemic.
In addition, the distribution of prescription pharmaceutical products is subject to the Drug Supply Chain Security Act, or
DSCA, which regulates the distribution and tracing of prescription drugs and prescription drug samples at the federal level, and set minimum standards for the regulation of drug distributors by the states. The DSCA imposes requirements to ensure
accountability in distribution and to identify and remove counterfeit and other illegitimate products from the market.
Other healthcare laws that may affect our ability to operate include, for example, the following:
|
● |
The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, as amended by the Health Information Technology for Economic and
Clinical Health Act, which governs the conduct of certain electronic healthcare transactions and protects the security and privacy of protected health information;
|
|
● |
Foreign and state laws governing the privacy and security of health information, such as the General Data Protection Regulation, or GDPR, in the EU; and
the California Consumer Privacy Act, or CCPA, in California, some of which are more stringent than HIPAA and many of which differ from each other in significant ways and may not have the same effect; and
|
|
● |
The Physician Payments Sunshine Act, which requires manufacturers of medicines, devices, biologics, and medical supplies to report annually to the U.S.
Department of Health and Human Services information related to payments and other transfers of value to physicians (defined to include doctors, dentists, optometrists, podiatrists, and chiropractors), other healthcare providers (such as
physician assistants and nurse practitioners), and teaching hospitals, and ownership and investment interests held by physicians and their immediate family members.
|
Sales and Marketing
Numerous regulatory authorities in addition to the FDA, including, in the U.S., the Centers for Medicare and Medicaid
Services, other divisions of the U.S. Department of Health and Human Services, the U.S. Department of Justice, and similar foreign, state and local government authorities, regulate sales, promotion and other activities following drug approval. As
described above, the FDA regulates all advertising and promotion activities for drugs under its jurisdiction both prior to and after approval. Only those claims relating to safety and efficacy that the FDA has approved may be used in labeling.
Physicians may prescribe legally available drugs for uses that are not described in the drug’s labeling and that differ from those we tested and the FDA approved. Such off-label uses are common across medical specialties and often reflect a physician’s
belief that the off-label use is the best treatment for the patients. The FDA does not regulate the behavior of physicians in their choice of treatments, but FDA regulations do impose stringent restrictions on manufacturers’ communications regarding
off-label uses. If we do not comply with applicable FDA requirements, we may face adverse publicity, enforcement action by the FDA, corrective advertising, consent decrees and the full range of civil and criminal penalties available to the FDA.
Promotion of off-label uses of drugs can also implicate the false claims laws described below.
In the U.S. sales, marketing and scientific/educational programs must also comply with various federal and state laws
pertaining to healthcare “fraud and abuse,” including anti-kickback laws and false claims laws. Anti-kickback laws make it illegal for a prescription drug manufacturer to solicit, offer, receive, or pay any remuneration in exchange for, or to induce,
the referral of business, including the purchase or prescription of a particular drug. Due to the breadth of the statutory provisions, limited statutory exceptions and regulatory safe harbors, and the absence of guidance in the form of regulations and
very few court decisions addressing industry practices, it is possible that our practices might be challenged under anti-kickback or similar laws. Moreover, recent healthcare reform legislation has strengthened these laws. For example, the Patient
Protection and Affordable Act, as amended by the Health Care and Education Reconciliation Act of 2010, or Affordable Care Act, among other things, amends the intent requirement of the federal anti-kickback and criminal healthcare fraud statutes to
clarify that a person or entity does not need to have actual knowledge of this statute or specific intent to violate it. In addition, the Affordable Care Act clarifies that the government may assert that a claim that includes 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. False claims laws prohibit anyone from knowingly and willingly presenting, or causing to be presented for
payment, to third-party payers (including Medicare and Medicaid) claims for reimbursed drugs or services that are false or fraudulent, claims for items or services not provided as claimed, or claims for medically unnecessary items or services. Our
activities relating to the sale and marketing of our drugs may be subject to scrutiny under these laws. Violations of fraud and abuse laws may be punishable by criminal and civil sanctions, including fines and civil monetary penalties, the possibility
of exclusion from federal healthcare programs (including Medicare and Medicaid) and corporate integrity agreements, which impose, among other things, rigorous operational and monitoring requirements on companies. Similar sanctions and penalties also
can be imposed upon executive officers and employees, including criminal sanctions against executive officers under the so-called “responsible corporate officer” doctrine, even in situations where the executive officer did not intend to violate the law
and was unaware of any wrongdoing.
Given the significant penalties and fines that can be imposed on companies and individuals if convicted, allegations of
such violations often result in settlements even if the company or individual being investigated admits no wrongdoing. Settlements often include significant civil sanctions, including fines and civil monetary penalties, and corporate integrity
agreements. If the government were to allege or convict us or our executive officers of violating these laws, our business could be harmed. In addition, private individuals can bring similar actions. Our activities could be subject to challenge for the
reasons discussed above and due to the broad scope of these laws and the increasing attention being given to them by law enforcement authorities. Other healthcare laws that may affect our ability to operate include HIPAA, which prohibits, among other
things, executing or attempting to execute 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, also
governs the conduct of certain electronic healthcare transactions and protects the security and privacy of protected health information; analogous state laws governing the privacy and security of health information, some of which are more stringent
than HIPAA and many of which differ from each other in significant ways and may not have the same effect, and the Physician Payments Sunshine Act, which requires manufacturers of drugs, devices, biologics, and medical supplies to report annually to the
U.S. Department of Health and Human Services information related to payments and other transfers of value to physicians, other healthcare providers and teaching hospitals, and ownership and investment interests held by physicians and their immediate
family members. Further, there are an increasing number of state laws that require manufacturers to make reports to states on pricing and marketing information. Many of these laws contain ambiguities as to what is required to comply with the laws.
Given the lack of clarity in laws and their implementation, our reporting actions could be subject to the penalty provisions of the pertinent state authorities.
Similar rigid restrictions are imposed on the promotion and marketing of drugs in the E.U. and other countries. Even in
those countries where we may not be directly responsible for the promotion and marketing of our medicines, if our potential international distribution partners engage in inappropriate activity, it can have adverse implications for us.
The U.S. Foreign Corrupt Practices Act, or FCPA, prohibits certain individuals and entities, including us, from promising,
paying, offering to pay, or authorizing the payment of anything of value to any foreign government official, directly or indirectly, to obtain or retain business or an improper advantage. If we violate the FCPA, it could result in large civil and
criminal penalties as well as an adverse effect on our reputation, operations, and financial condition. We could also face collateral consequences such as debarment and the loss of export privileges.
Both the federal and state governments in the U.S. and foreign governments continue to propose and pass new legislation and regulations
designed to contain or reduce the cost of healthcare. For example, in July 2021, the Biden administration released an executive order, “Promoting Competition in the American Economy,” with multiple provisions aimed at prescription drugs. In response to
Biden’s executive order, on September 9, 2021, the U.S. Department of Health and Human Services, or HHS, released a Comprehensive Plan for Addressing High Drug Prices that outlines principles for drug pricing reform and sets out a variety of potential
legislative policies that Congress could pursue as well as potential administrative actions HHS can take to advance these principles. No legislation or administrative actions have been finalized to implement these principles. Congress is also
considering additional health reform measures. Such legislation and regulations may result in decreased reimbursement, which may further exacerbate industry-wide pressure to reduce the prices charged for medical products.
Competition
Our Business in General
Some of our medicines may compete with existing therapies for market share and some of our medicines in development may
compete for patients in clinical trials. In addition, there are a number of companies pursuing the development of oligonucleotide-based technologies and the development of pharmaceuticals utilizing these technologies. These companies include
biopharmaceutical companies and large pharmaceutical companies acting either independently or together. Our medicines are differentiated from traditional small molecule medicines by their chemistry, how they move in the body, how they act in the body,
delivery technology, and formulations.
Our approved medicines and our medicines under development address numerous markets. The diseases our medicines target for which we have
or may receive marketing authorization will determine our competition. For some of our medicines, an important factor may be the timing of market introduction of competitive products. Accordingly, the relative speed with which we can develop medicines,
complete the clinical trials and marketing authorization processes and supply commercial quantities of the medicines to the market are important competitive factors. We expect to compete with products approved for sale based on a variety of factors,
including, among other things, product efficacy, safety, mechanism of action, dosing convenience, marketing and sales strategy and tactics, availability, price, and reimbursement.
Below we have included what we believe to be the competitive landscape for our marketed medicines and for the medicines we currently have
in Phase 3 trials. We have included medicines that we believe compete or may compete directly with our medicines. We included competitors, potential competitors that are past Phase 1 development or potential competitors that plan to start a pivotal
study this year. We do not believe that any medicines meet these criteria to compete with ION363.
SPINRAZA
We consider the following medicines as competitors to SPINRAZA for the indication of SMA:
|
Medicine
|
|
Company
|
|
Medicine Description (1)
|
|
Phase (1)
|
|
Route of Administration (1)
|
|
Zolgensma
(Onasemnogene abeparvovec)
|
|
Novartis
|
|
Gene therapy targeting the genetic root cause of SMA by replacing the missing or nonworking SMN1 gene
|
|
Approved for pediatric SMA patients less than 2 years of age
|
|
Intravenous infusion
|
|
Evrysdi
(Risdiplam)
|
|
Roche
|
|
A small molecule medicine that modulates splicing of the SMN2 gene
|
|
Approved for SMA patients of 2 months or older
|
|
Oral
|
| (1) |
Taken from public documents including respective company press releases, company presentations, and scientific presentations.
|
TEGSEDI and Eplontersen
We consider the following medicines as competitors and potential future competitors to TEGSEDI and eplontersen for the
indication of hATTR amyloidosis and/or ATTR cardiomyopathy:
|
Medicine
|
|
Company
|
|
Medicine Description (1)
|
|
Phase (1)
|
|
Route of Administration (1)
|
|
Onpattro
(Patisiran)
|
|
Alnylam
|
|
An RNAi medicine formulated with lipid nanoparticles to inhibit TTR mRNA
|
|
Approved hATTR/
Phase 3 ATTR-CM
|
|
Intravenous infusion
|
|
Vyndaqel/Vyndamax
(Tafamidis and tafamidis meglumine)
|
|
Pfizer
|
|
A small molecule medicine to stabilize TTR protein
|
|
Approved in U.S., EU, Japan and select other markets for hATTR-PN and/or ATTR-CM; indications vary by region
|
|
Oral
|
|
Vutrisiran
|
|
Alnylam
|
|
An RNAi medicine conjugated with GalNAC to inhibit TTR mRNA
|
|
Submitted US/EU for ATTR-PN, Phase 3 for ATTR-CM
|
|
Subcutaneous Injection
|
|
Acoramidis
|
|
Bridgebio
|
|
Small molecule that binds and stabilizes TTR in the blood
|
|
Phase 3 ATTR-CM
|
|
Oral
|
| (1) |
Taken from public documents including respective company press releases, company presentations, and scientific presentations.
|
WAYLIVRA and Olezarsen
We believe that the following medicines could compete with WAYLIVRA and olezarsen in FCS and SHTG:
|
Medicine
|
|
Company
|
|
Medicine Description (1)
|
|
Phase (1)
|
|
Route of Administration (1)
|
|
ARO-APOC3
|
|
Arrowhead Pharmaceuticals
|
|
Targets APOCIII by utilizing Targeted RNAi Molecule Platform
|
|
3 (FCS), 2 (SHTG)
|
|
Subcutaneous Injection
|
|
Lomitapide
|
|
Amryt Pharma
|
|
Microsomal triglyceride transfer protein (MTP) inhibitor
|
|
2 (FCS) (investigator led)
|
|
Oral
|
|
Evinacumab
|
|
Regenerion
|
|
ANGPTL3 mAb
|
|
2 (SHTG)
|
|
Intravenous Infusion
|
|
BIO89-100
|
|
Bio 89
|
|
FGF21 analog
|
|
2 (SHTG)
|
|
Subcutaneous Injection
|
| (1) |
Taken from public documents including respective company press releases, company presentations, and scientific presentations.
|
Donidalorsen
We believe that the following medicines could compete with donidalorsen as a prophylactic treatment for patients with HAE:
|
Medicine
|
|
Company
|
|
Medicine Description (1)
|
|
Phase (1)
|
|
Route of Administration (1)
|
|
Takhzyro
(lanadelumab-flyo)
|
|
Takeda
|
|
A monoclonal antibody that inhibits plasma kallikrein activity
|
|
Approved for HAE patients 12 years and older
|
|
Subcutaneous
Infusion
|
|
Cinryze
(C1-esterase inhibitor)
|
|
Takeda
|
|
A human plasma protein that mediates inflammation and coagulation
|
|
Approved for HAE patients 6 years and older
|
|
Intravenous
Infusion
|
|
Orladeyo
(berotralstat)
|
|
BioCryst
|
|
Oral plasma kallikrein inhibitor
|
|
Approved for HAE patients 12 years and older
|
|
Oral
|
|
Haegarda
(C1 esterase inhibitor)
|
|
CSL Behring
|
|
C1 esterase inhibitor
|
|
Approved for HAE patients 6 years and older
|
|
Subcutaneous
Infusion
|
|
garadacimab
|
|
CSL Behring
|
|
An anti-factor XIIa monoclonal antibody
|
|
3
|
|
Subcutaneous
Infusion
|
|
KVD824
|
|
KalVista
|
|
Oral plasma kallikrein inhibitor
|
|
2
|
|
Oral
|
|
NTLA-2002
|
|
Intellia
|
|
CRISPR therapeutic candidate designed to inactivate the kallikrein B1 gene
|
|
1/2
|
|
Intravenous
Infusion
|
| (1) |
Taken from public documents including respective company press releases, company presentations, and scientific presentations.
|
Pelacarsen
We believe that the following medicine could compete with pelacarsen in CVD in patients with elevated LP(a):
|
Medicine
|
|
Company
|
|
Medicine Description (1)
|
|
Phase (1)
|
|
Route of Administration (1)
|
|
AMG 890
|
|
Amgen/ Arrowhead Pharmaceuticals
|
|
RNAi therapeutic designed to lower Lp(a)
|
|
2
|
|
Subcutaneous Injection
|
| (1) |
Taken from public documents including respective company press releases, company presentations, and scientific presentations.
|
Tofersen
We believe that the following medicines could compete with tofersen in SOD1-ALS:
|
Medicine
|
|
Company
|
|
Medicine Description (1)
|
|
Phase (1)
|
|
Route of Administration (1)
|
|
Arimoclomol
|
|
Orphazyme
|
|
Provides cellular protection from abnormal proteins by activating molecular “chaperone” proteins that can repair or degrade the damaged proteins
|
|
3
|
|
Oral
|
|
NI-204
|
|
Neurimmune
|
|
A human derived antibody targeting misfolded SOD1
|
|
2
|
|
Intravenous
Infusion
|
| (1) |
Taken from public documents including respective company press releases, company presentations, and scientific presentations.
|
Environmental, Social and Governance Initiatives
We recognize the importance of Environmental, Social and Governance, or ESG, initiatives as it relates to our business
strategy and risk assessment. During 2020 and 2021, we took steps to formalize our corporate responsibility program. In December 2021, we issued our inaugural corporate responsibility report. As part of our ongoing work, we identified the following
corporate responsibility initiatives that we believe are most important to our business:
|
● |
Safety of patients in clinical trials;
|
|
● |
Drug safety and supply chain management;
|
|
● |
Access to medicines and tackling devastating diseases;
|
|
● |
Human resources management;
|
|
● |
Diversity, equity and inclusion;
|
|
● |
Employee health and safety; and
|
|
● |
Governance and business ethics
|
We have a relatively small environmental footprint, so our stewardship programs focus on improving eco-awareness,
identifying efficiencies and integrating more sustainable practices into our daily operations. Our priority assessment considered investor and other stakeholder interests and is aligned with the requirements of ESG ratings agencies and with leading ESG
frameworks, including the Sustainability Accounting Standards Board, or SASB.
We encourage you to view our 2021 Corporate Responsibility Report published on our website for more detailed information regarding our ESG initiatives. Nothing in the report or on our website shall be deemed incorporated by reference into this Annual Report on
Form 10-K.
Employees & Human Capital
As of February 16, 2022,
we employed 660 people, the vast majority of whom reside in the U.S. A significant number of our management and professional employees have had prior experience with pharmaceutical, biotechnology or medical product companies. Our average employee
turnover rate in 2021 was 16 percent, while the turnover for life sciences/ medical device companies over this period was 19 percent according to a survey published by Radford – an Aon Hewitt Company. Given the uniqueness and complexity of our
technology, it is critical to retain the knowledge and experience of outstanding long service employees. The experience and seniority of our employees is as critical to our future success as it has been to the success we have enjoyed to date.
Collective bargaining agreements do not cover any of our employees, and management
considers relations with our employees to be good. We believe that the future will be defined by outstanding people and we are committed to recruiting, developing, motivating, and rewarding them.
We encourage you to visit our website for more detailed information regarding our Human Capital programs and initiatives.
Nothing on our website shall be deemed incorporated by reference into this Annual Report on Form 10-K.
Benefits
Employees are rewarded individually on the basis of their responsibilities and accomplishments. We offer competitive compensation and
benefits to our employees. In addition to salary and bonus programs, we also offer:
|
● |
Comprehensive medical, dental and vision insurance;
|
|
● |
Stock options, RSUs and Employee Stock Purchase Plan, or ESPP;
|
|
● |
Vacation, holiday, sick time and paid time off for volunteering;
|
|
● |
Flexible spending accounts for health and dependent day care needs;
|
|
● |
Life, AD&D insurance and long-term disability insurance coverage options; and
|
|
● |
Employee Assistance Program, or EAP.
|
We recognize achievements with salary increases, stock awards, promotions, and bonus opportunities.
Pay Equity
We are committed to paying our employees fairly, regardless of their gender, race, or other personal characteristics. To
ensure we are achieving our commitment, we benchmark and evaluate pay based on market data and consider factors such as an employee’s role and experience, an employee’s performance and internal equity. We also regularly review our compensation
practices, both in terms of our overall workforce and individual employees, to ensure our pay is fair and equitable.
In 2021, we engaged an independent third-party expert to perform a pay equity analysis that reviewed pay equity by gender,
race and age. We plan to continue to engage a third-party expert to review pay equity every two to three years, as we determine necessary.
Diversity, Equity and Inclusion
At Ionis, we encourage diversity in our workforce. Prejudicial barriers to human potential and productivity are foreign
to our values. We recognize that for the full potential of our workforce to be realized, we must cultivate an inclusive culture where all employees feel empowered to contribute fully in an environment that values different perspectives, leading to
better ideas and increased innovation. We have several employee-led resource groups dedicated to different aspects of diversity and a diverse management team and board of directors.
Training and Development
We designed our training and development programs to help employees gain important Ionis knowledge and develop the skills
to be successful. All of our trainings from new hire through senior leader, are focused on the Ionis culture and core principles and learning what we mean when we say: “Working the Ionis Way.”
We empower our employees to build rewarding careers at Ionis, driven by a culture of yes that encourages personal and
professional employee growth. Ionis offers robust training opportunities with course offerings and events available to every employee regardless of level or function. In addition, employees also have access to Ionis’ learning and development library
that houses important information on career growth and planning. By supporting our employees, we know that each professional development milestone enables our continued success.
Information about our Executive Officers
The following sets forth certain information regarding our executive officers as of February 16, 2022:
|
Name
|
|
Age
|
|
Position
|
|
Brett P. Monia, Ph.D.
|
|
60
|
|
Chief Executive Officer
|
|
Joseph T. Baroldi
|
|
44
|
|
Executive Vice President, Chief Business Officer
|
|
C. Frank Bennett, Ph.D.
|
|
65
|
|
Executive Vice President, Chief Scientific Officer
|
|
Onaiza Cadoret-Manier
|
|
57
|
|
Executive Vice President, Chief Product Strategy and Operations Officer
|
|
Richard S. Geary, Ph.D.
|
|
64
|
|
Executive Vice President, Chief Development Officer
|
|
Elizabeth L. Hougen
|
|
60
|
|
Executive Vice President, Finance and Chief Financial Officer
|
|
Patrick R. O’Neil, Esq.
|
|
48
|
|
Chief Legal Officer, General Counsel and Corporate Secretary
|
|
Eugene Schneider, M.D.
|
|
49
|
|
Executive Vice President, Chief Clinical Development Officer
|
|
Eric E. Swayze, Ph.D.
|
|
56
|
|
Executive Vice President, Research
|
BRETT P. MONIA, Ph.D.
Chief Executive Officer
Dr. Monia was promoted to Chief Executive Officer in January 2020. From January 2018 to December 2019, Dr. Monia served
as Chief Operating Officer. From January 2012 to January 2018, Dr. Monia served as Senior Vice President. From February 2009 to January 2012, Dr. Monia served as our Vice President, Drug Discovery and Corporate Development and from October 2000 to
February 2009, he served as our Vice President, Preclinical Drug Discovery. From October 1989 to October 2000 he held various positions within our Molecular Pharmacology department.
JOSEPH T. BAROLDI
Executive Vice President, Chief Business Officer
Mr. Baroldi has served as Ionis’ Executive Vice President, Chief Business Officer since January 2022. Prior to Ionis, Mr.
Baroldi was the chief operating officer at Avidity Biosciences, a biotechnology company focused on oligonucleotide-based therapies. Prior to Avidity, Mr. Baroldi was vice president of Business Development and Alliance Management at Ionis from 2009 to
2020. Mr. Baroldi has also held positions in strategic planning and scientific research for Gen-Probe Inc. and Ionis.
C. FRANK BENNETT, Ph.D.
Executive Vice President, Chief Scientific Officer
Dr. Bennett has served as Ionis’ Executive Vice President, Chief Scientific Officer since April 2020. In January 2020, Dr.
Bennett was promoted to Chief Scientific Officer. From January 2006 to December 2019, Dr. Bennett served as Senior Vice President, Antisense Research. From June 1995 to January 2006, Dr. Bennett served as our Vice President, Research. From March 1993
to June 1995, he was Director, Molecular Pharmacology, and from May 1992 to March 1993, he was an Associate Director in our Molecular and Cellular Biology department. Prior to joining Ionis in 1989, Dr. Bennett was employed by SmithKline and French
Laboratories in various research positions. He is a member of the Board of Directors for Flamingo Therapeutics and an external member of the Hereditary Disease Foundation.
ONAIZA CADORET-MANIER
Executive Vice President, Chief Product Strategy and Operations Officer
Ms. Cadoret-Manier has served as Ionis’
Executive Vice President, Chief Product Strategy and Operations Officer since February 2022. From April 2020 to February 2022, Ms. Cadoret-Manier served as our Executive Vice President, Chief Corporate Development and Commercial Officer. Ms. Cadoret-Manier joined Ionis as Chief Corporate Development and Commercial Officer in January 2020. Prior to joining Ionis, from 2018 to 2019 Ms.
Cadoret-Manier was the chief commercial officer for Grail Biosciences, an early detection genomics company. Prior to Grail, Ms. Cadoret-Manier was vice president of the Respiratory Franchise at Genentech where she worked from 2011 to 2018. Ms.
Cadoret-Manier also has held multiple senior management positions overseeing corporate strategy, alliances, and marketing and sales for numerous disease areas for Genentech, Pfizer and Amylin Pharmaceuticals.
RICHARD S. GEARY, Ph.D.
Executive Vice President, Chief Development Officer
Dr. Geary has served as Ionis’ Executive Vice President, Chief Development Officer since January 2021. From April 2020 to
December 2020, Dr. Geary served as our Executive Vice President, Development and from August 2008 to March 2020, was our Senior Vice President, Development. From August 2003 to August 2008, Dr. Geary served as our Vice President, Preclinical
Development. From November 1995 to August 2003, he held various positions within the Preclinical Development department. Prior to joining Ionis in 1995, Dr. Geary was Senior Research Scientist and Group Leader for the bioanalytical and preclinical
pharmacokinetics group in the Applied Chemistry Department at Southwest Research Institute.
ELIZABETH L. HOUGEN
Executive Vice President, Finance and Chief Financial Officer
Ms. Hougen has served as Ionis’ Executive Vice President and Chief Financial Officer since April 2020. From January 2013
to March 2020, Ms. Hougen served as our Senior Vice President, Finance and Chief Financial Officer. From January 2007 to December 2012, Ms. Hougen served as our Vice President, Finance and Chief Accounting Officer and from May 2000 to January 2007, she
served as our Vice President, Finance. Prior to joining Ionis in 2000, Ms. Hougen was Executive Director, Finance and Chief Financial Officer for Molecular Biosystems, Inc., a public biotechnology company.
PATRICK R. O’NEIL, Esq.
Chief Legal Officer, General Counsel and Corporate Secretary
Mr. O’Neil has served as Ionis’ Chief Legal Officer and General Counsel since September 2021. Mr. O’Neil also serves as
our Corporate Secretary. From March 2020 to September 2021, Mr. O’Neil served as our Executive Vice President, Legal & General Counsel and Chief Compliance Officer. From January 2013 to March 2020, Mr. O’Neil served as our Senior Vice President,
Legal and General Counsel. From September 2010 to January 2013, Mr. O’Neil served as our Vice President, Legal and General Counsel and from January 2009 to September 2010, he served as our Vice President, Legal and Senior Transactions Counsel. From
October 2001 to January 2009 he held various positions within our Legal department. Prior to joining Ionis, Mr. O’Neil was an associate at Cooley LLP.
EUGENE SCHNEIDER, M.D.
Executive Vice President, Chief Clinical Development Officer
Dr. Schneider was promoted to Executive Vice President and Chief Clinical Development Officer of Ionis in January 2021.
From August 2018 to December 2020, Dr. Schneider served as our Senior Vice President, Head of Clinical Development. From April 2015 to July 2018, Dr. Schneider was our Vice President, Clinical Development, Severe and Rare Diseases. Dr. Schneider joined
Ionis in December 2013 as Executive Director, Clinical Development. Dr. Schneider has two decades of experience in clinical development primarily in the rare diseases space. Prior to joining Ionis, Dr. Schneider was senior medical director at both
Synageva BioPharma and Biovail Technologies Ltd.
ERIC E. SWAYZE, Ph.D.
Executive Vice President, Research
Dr. Swayze has served as Ionis’ Executive Vice President, Research since April 2020 and is responsible for leading
preclinical antisense drug discovery and antisense technology research. In January 2020, Dr. Swayze was promoted to Senior Vice President of Research. Previously, Dr. Swayze was Vice President of Chemistry and Neuroscience Drug Discovery at Ionis,
overseeing the advancement of multiple programs to clinical development. He joined Ionis in 1994 and has contributed to key technology advancements, including Ionis’ Generation 2.5 chemistry and LICA technology.
Item 1A. RISK FACTORS
Investing in our securities involves a high degree of risk. You should carefully consider the
following information about the risks described below, together with the other information contained in this report and in our other public filings in evaluating our business. If any of the following risks actually occur, our business could be
materially harmed, and our financial condition and results of operations could be materially and adversely affected. As a result, the trading price of our securities could decline, and you might lose all or part of your investment.
Risks Related to the COVID-19 Pandemic
Our business could be materially adversely affected by the effects of health epidemics. To date, we believe the impacts of the recent
COVID-19 pandemic on our business are limited and manageable.
Our business could be materially adversely affected by health epidemics in regions where we or our partners are commercializing our
medicines, have concentrations of clinical trial sites or other business operations, and could cause significant disruption in the operations of third-party manufacturers and contract research organizations upon whom we rely. For example, since
December 2019, a novel strain of coronavirus, SARS-CoV-2, causing a disease referred to as COVID-19, has spread worldwide. In March 2020, the World Health Organization declared the COVID-19 outbreak a pandemic, or the COVID-19 Pandemic, and the U.S.
government imposed restrictions on travel between the U.S., Europe and certain other countries. In addition, the Governor of the State of California and the Governor of the Commonwealth of Massachusetts, the states in which our offices are located,
each declared a state of emergency related to the spread of COVID-19 and issued executive orders that directed residents to stay at home.
In response to these public health directives and orders, in March 2020, we implemented work-from-home policies for most of our
employees globally and generally suspended business-related travel. In the U.S., as vaccinations have become more widely available, states have lifted restrictions implemented as part of the pandemic response and reopened their economies. In June
2021, the Governor of California terminated the vast majority of executive actions that were put in place beginning in March 2020, leaving only a subset of provisions that facilitate the ongoing recovery. In May 2021, the Commonwealth of Massachusetts
also lifted most of its pandemic restrictions. We continue to modify our policies for our employees in California, Massachusetts, and internationally to align with current local guidance. We believe the effects of these work-from-home and travel
policies have had a limited impact on our business.
These public health directives and orders have impacted our and our partners’ sales efforts. For example, some physician and hospital
policies that have been put in place as a result of the COVID-19 Pandemic restrict in-person access by third parties, which has in some cases impacted our commercialization efforts for TEGSEDI and WAYLIVRA. Additionally, Biogen has reported that it is
monitoring the demand for SPINRAZA, including the duration and degree to which it might see delays in starting new patients on SPINRAZA due to hospitals diverting resources necessary to administer SPINRAZA to care for COVID-19 patients. These and
similar, and perhaps more severe, disruptions in our or our partner’s commercial operations could materially impact our business, operating results and financial condition in the future.
Quarantines, shelter-in-place, executive and similar government orders, or the perception that such orders, shutdowns or other
restrictions on the conduct of business operations could occur, could impact personnel at third-party manufacturing facilities in the U.S. and other countries, or the availability or cost of materials, which would disrupt our supply chain. Recently
there have been major disruptions to the global supply chain due to the COVID-19 Pandemic. To date, we have not experienced any significant consequences to our business as a result of the current supply chain disruptions, but could in the future if
such disruptions persist or worsen.
We have experienced impacts to our clinical trial operations due to the COVID-19 Pandemic; however, we believe such impacts are limited
and manageable. Some examples of these impacts include:
|
● |
delays in clinical site initiation, site monitoring and patient enrollment due to restrictions imposed as a result of the COVID-19 Pandemic;
|
|
o |
For example, in March 2020, we instituted a temporary suspension of enrollment for new subjects in our Phase 3 studies of eplontersen based on advice from our trial
advisory committee; however, enrollment has resumed.
|
|
● |
some patients have not been able to meet protocol requirements, as quarantines have impeded patient movement and interrupted healthcare services;
|
|
● |
delays in site initiations due to principle investigators and site staff focusing on and prioritizing COVID-19 patient care; and
|
|
● |
delays in necessary interactions with regulators, ethics committees and other important agencies and contractors due to limitations in employee resources or forced
furlough of government or contractor personnel.
|
In addition, some of our partners have experienced impacts to their clinical trial operations as a result of the COVID-19 Pandemic. For
example, in December 2021, Novartis announced that enrollment for the Phase 3 HORIZON study had been delayed due to the COVID-19 Pandemic.
The spread of COVID-19 has caused a broad impact globally. While the potential economic impact brought by, and the duration of, the
COVID-19 Pandemic may be difficult to assess or predict, it could result in significant disruption of global financial markets, reducing our ability to access capital, which could in the future negatively affect our liquidity. In addition, a recession
or market correction resulting from the spread of COVID-19 could materially affect our business and has and could continue to affect the value of our securities.
The global COVID-19 Pandemic continues to rapidly evolve. While we have not yet experienced material adverse effects to our business as a
result of the COVID-19 Pandemic, the ultimate impact of the COVID-19 Pandemic or a similar health epidemic is highly uncertain and subject to change. As such, we do not yet know the full extent of delays or impacts on our business, our clinical trials,
healthcare systems or the global economy as a whole. However, these effects could have a material impact on our operations, and we will continue to monitor the COVID-19 Pandemic closely.
Risks Related to the Commercialization of our Medicines
We have limited experience as a company in commercializing medicines and we will have to invest significant resources to develop these
capabilities. If we are unable to establish effective marketing, sales, market access, distribution, and related functions, or enter into agreements with third parties to commercialize our medicines, we may not be able to generate revenue from our
medicines.
We have limited experience as a company in commercializing medicines and we will have to invest significant financial
and management resources to develop the infrastructure required to successfully commercialize our medicines. There are significant risks involved in building and managing a sales organization, including our ability to hire, retain and incentivize
qualified individuals, generate sufficient sales leads, provide adequate training to sales and marketing personnel, and effectively manage a geographically dispersed sales and marketing team. We will also need to scale-up existing internal support
functions to aid our commercialization efforts, in particular, regulatory affairs and medical affairs. Any failure to effectively build or maintain the infrastructure required to successfully commercialize our medicines, including our sales,
marketing, market access, distribution, and related capabilities, or scale-up our existing support functions, could adversely impact the revenue we generate from our medicines. In addition, if we choose to rely on third parties to assist us in
commercializing our medicines, we may not be able to enter into collaborations or hire consultants or external service providers on acceptable financial terms, or at all. If we do engage third parties to assist us in the commercialization of our
medicines, our product revenues and profitability may be lower than if we commercialized such medicines ourselves.
If the market does not accept our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, and our medicines in development,
we are not likely to generate substantial revenues or become consistently profitable.
Even if our medicines are authorized for marketing, our success will depend upon the medical community, patients and
third-party payers accepting our medicines as medically useful, cost-effective, safe and convenient. Even when the FDA or foreign regulatory authorities authorize our or our partners’ medicines for commercialization, doctors may not prescribe our
medicines to treat patients. Furthermore, we and our partners may not successfully commercialize additional medicines.
Additionally, in many of the markets where we
or our partners may sell our medicines in the future, if we or our partners cannot agree with the government or other third-party payers regarding the price we can charge for our medicines, then we may not be able to sell our medicines in that
market. Similarly, cost control initiatives by governments or third-party payers could decrease the price received for our medicines or increase patient coinsurance to a level that makes our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, and
our medicines in development, economically unviable. If the pricing of any of our medicines decreases for any reason, it will reduce our revenue for such medicine. For example, Biogen has disclosed that SPINRAZA revenue has decreased in part
due to lower pricing in the U.S. and certain rest of world markets.
The degree of market acceptance for our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, and our medicines in
development, depends upon a number of factors, including the:
|
● |
receipt and scope of marketing authorizations;
|
|
● |
establishment and demonstration in the medical and patient community of the efficacy and safety of our medicines and their potential advantages over
competing products;
|
|
● |
cost and effectiveness of our medicines compared to other available therapies;
|
|
● |
patient convenience of the dosing regimen for our medicines; and
|
|
● |
reimbursement policies of government and third-party payers.
|
Based on the profile of our medicines, physicians, patients, patient advocates, payers or the medical community in general
may not accept or use any medicines that we may develop.
For example, TEGSEDI requires periodic blood and urine monitoring, is available in the U.S. only through a REMS program,
and the product label in the U.S. has a boxed warning for thrombocytopenia and glomerulonephritis. Our main competition in the U.S. market for TEGSEDI is patisiran, marketed by Alnylam Pharmaceuticals, Inc. Although patisiran requires intravenous
administration and pre-treatment with steroids, it does not have a boxed warning nor is it available only through a REMS program. Additionally, the product label for WAYLIVRA in the EU requires regular blood monitoring. In each case, these label
requirements have negatively affected our ability to attract and retain patients for these medicines. If we or our partner cannot effectively maintain patients on TEGSEDI or WAYLIVRA, including due to limitations or restrictions on the ability to
conduct periodic blood and urine monitoring of our patients as a result of the current COVID-19 Pandemic, we may not be able to generate substantial revenue from TEGSEDI or WAYLIVRA sales.
If we or our partners fail to compete effectively, our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, and our
medicines in development, will not generate significant revenues.
Our competitors engage in drug discovery throughout the world, are numerous, and include, among others, major
pharmaceutical companies and specialized biopharmaceutical firms. Other companies are engaged in developing antisense technology. Our competitors may succeed in developing medicines that are:
|
● |
priced lower than our medicines;
|
|
● |
reimbursed more favorably by government and other third-party payers than our medicines;
|
|
● |
safer than our medicines;
|
|
● |
more effective than our medicines; or
|
|
● |
more convenient to use than our medicines.
|
These competitive developments could make our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, and our medicines in
development, obsolete or non-competitive.
Certain of our partners are pursuing other technologies or developing other medicines either on their own or in
collaboration with others, including our competitors, to treat the same diseases our own collaborative programs target. Competition may negatively impact a partner’s focus on and commitment to our medicines and, as a result, could delay or otherwise
negatively affect the commercialization of our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA.
Many of our competitors have substantially greater financial, technical and human resources than we do. In addition, many
of these competitors have significantly greater experience than we do in conducting preclinical testing and human clinical studies of new pharmaceutical products, in obtaining FDA and other regulatory authorizations of such products and in
commercializing such products. Accordingly, our competitors may succeed in obtaining regulatory authorization for products earlier than we do.
There are several pharmaceutical and biotechnology companies engaged in the development or commercialization in certain
geographic markets of products against targets that are also targets of products in our development pipeline. For example:
|
● |
Onasemnogene abeparvovec and risdiplam compete with SPINRAZA;
|
|
● |
Patisiran, tafamidis, and tafamidis meglumine compete with TEGSEDI and could compete with eplontersen;
|
|
● |
Vutrisiran and acoramidis could compete with TEGSEDI and eplontersen;
|
|
● |
ARO-APOC3, lomitapide, evinacumab, BIO89-100, and gemcabene could compete with WAYLIVRA and olezarsen;
|
|
● |
AMG890 could compete with pelacarsen;
|
|
● |
Arimoclomol, ultomiris, mastinib and trehalose could compete with tofersen; and
|
|
● |
Lanadelumab-flyo, C1 esterase inhibitor, berotralstat, C1 esterase inhibitor
subcutaneous, garadacimab, KVD824, and NTLA-2002 could compete with donidalorsen.
|
SPINRAZA injection for intrathecal use is an antisense medicine indicated for the treatment of SMA patients of all ages approved in over
50 countries. Specifically, SPINRAZA faces competition from onasemnogene abeparvovec, a gene therapy product that was approved in the U.S. in May 2019 and in the EU in May 2020 for the treatment of SMA, as well as risdiplam, an oral product for the
treatment of SMA that was approved in the U.S. in August 2020 and in the EU in March 2021. Biogen has disclosed that SPINRAZA revenue has decreased primarily due to a reduction in demand as a result of increased competition and that future sales of
SPINRAZA may be adversely affected by competing products.
Additionally, companies that are developing medicines that target the same patient populations as our medicines in development may compete
with us to enroll participants in the clinical trials for such medicines, which could make it more difficult for us to complete enrollment for these clinical trials.
Our medicines could be subject to regulatory limitations following approval.
Following approval of a medicine, we and our partners must comply with comprehensive government regulations regarding the
manufacture, marketing and distribution of medicines. Promotional communications regarding prescription medicines must be consistent with the information in the product’s approved labeling. We or our partners may not obtain the labeling claims
necessary or desirable to successfully commercialize our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, and our medicines in development.
The FDA and foreign regulatory bodies have the authority to impose significant restrictions on an approved medicine
through the product label and on advertising, promotional and distribution activities. For example:
|
● |
in the U.S., TEGSEDI’s label contains a boxed warning for thrombocytopenia and glomerulonephritis;
|
|
● |
TEGSEDI requires periodic blood and urine monitoring; and
|
|
● |
in the U.S., TEGSEDI is available only through a REMS program.
|
Prescription medicines may be promoted only for the approved indications in accordance with the approved label. 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.
In addition, when approved, the FDA or a foreign regulatory authority may condition approval on the performance of
post-approval clinical studies or patient monitoring, which could be time consuming and expensive. For example, in connection with the conditional marketing approval for WAYLIVRA in the EU, we are required to conduct a post-authorization safety study
to evaluate the safety of WAYLIVRA on thrombocytopenia and bleeding in FCS patients taking WAYLIVRA. If the results of such post-marketing studies are not satisfactory, the FDA, EC or other foreign regulatory authority may withdraw marketing
authorization or may condition continued marketing on commitments from us or our partners that may be expensive and time consuming to fulfill.
If we or others identify side effects after any of our medicines are on the market, or if manufacturing problems occur
subsequent to regulatory approval, or if we, our manufacturers or our partners fail to comply with regulatory requirements, we or our partners may, among other things, lose regulatory approval and be forced to withdraw products from the market, need to
conduct additional clinical studies, incur restrictions on the marketing, distribution or manufacturing of the product, and/or change the labeling of our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA.
We depend on our collaboration with Biogen for the development and commercialization of SPINRAZA.
We have entered into a collaborative arrangement with Biogen to develop and commercialize SPINRAZA. We entered into this
collaboration primarily to:
|
● |
fund our development activities for SPINRAZA;
|
|
● |
seek and obtain regulatory approvals for SPINRAZA; and
|
|
● |
successfully commercialize SPINRAZA.
|
We are relying on Biogen to obtain additional regulatory approvals for SPINRAZA, generate additional clinical data for
SPINRAZA, manufacture and successfully commercialize SPINRAZA. In general, we cannot control the amount and timing of resources that Biogen devotes to our collaboration. If Biogen fails to further develop SPINRAZA, obtain additional regulatory
approvals for SPINRAZA, manufacture or commercialize SPINRAZA, or if Biogen’s efforts are not effective, our business may be negatively affected.
Our collaboration with Biogen may not continue for various reasons. Biogen can terminate our collaboration at any time. If
Biogen stops developing or commercializing SPINRAZA, we would have to seek or spend additional funding, and SPINRAZA’s commercialization may be harmed or delayed.
Our collaboration with Biogen may not result in the continued successful commercialization of SPINRAZA. If Biogen does not
continue to successfully commercialize SPINRAZA, we will receive limited revenues for SPINRAZA.
We depend on our collaboration with AstraZeneca for the joint development and commercialization of eplontersen.
We have entered into a collaborative arrangement with AstraZeneca to develop and commercialize eplontersen. Under the
terms of the collaboration agreement, Ionis and AstraZeneca will co-develop and co-commercialize eplontersen in the U.S. and AstraZeneca will have the sole right to commercialize eplontersen in all other countries. Prior to co-commercializing
eplontersen in the U.S., we will need to negotiate a co-commercialization agreement with AstraZeneca to govern the parties’ performance of co-commercialization, which agreement will include a commercial plan and budget. As a company we do not have
experience with co-commercialization arrangements. We also do not have control over the amount and timing of resources that AstraZeneca devotes to our collaboration, particularly outside of the U.S. If the co-commercialization arrangement for
eplontersen is not successful for any reason, eplontersen may not meet our commercial objectives and our revenues for eplontersen may be limited.
In addition, a Joint Steering Committee, or JSC, having equal membership from us and AstraZeneca, and various
subcommittees oversee and coordinate the development, manufacturing, commercialization and other exploitation activities for eplontersen in the U.S. by mutual agreement. If any subcommittee cannot reach unanimous agreement on any matter within its
respective scope of authority, such matter may be referred to the JSC for resolution. If the JSC cannot come to a mutual agreement on any particular matter, this could delay our ability to develop or commercialize eplontersen.
We are relying on third parties to market, sell and distribute TEGSEDI and WAYLIVRA.
We have entered into agreements with third parties to commercialize TEGSEDI and WAYLIVRA as follows:
|
● |
In April 2021, we entered into a distribution agreement with Sobi to commercialize TEGSEDI in the U.S. and Canada;
|
|
● |
In December 2020, we entered into a distribution agreement with Sobi to commercialize TEGSEDI and WAYLIVRA in Europe; and
|
|
● |
In August 2018, we granted PTC the exclusive right to commercialize TEGSEDI and WAYLIVRA in Latin America and
certain Caribbean countries.
|
We are relying on Sobi and PTC to effectively market, sell and distribute TEGSEDI and WAYLIVRA and have less control over sales efforts
and may receive less revenue than if we commercialized TEGSEDI or WAYLIVRA by ourselves. If Sobi or PTC does not successfully commercialize TEGSEDI or WAYLIVRA, including as a result of delays or disruption caused by the current COVID-19 Pandemic, we
may receive limited revenue for TEGSEDI or WAYLIVRA in the U.S., Canada, Europe, Latin America or certain Caribbean countries, which could have a material adverse effect on our business, prospects, financial condition and results of operations.
Our operations are subject to additional healthcare laws.
Our operations are subject to additional healthcare laws, including federal and state anti-kickback laws, false claims laws, transparency
laws, such as the federal Sunshine Act, and health information privacy and security laws, which are subject to change at any time. For example, in November
2020, the U.S. Department of Health and Human Services issued a final rule modifying the anti-kickback law safe harbors for Medicare Part D plans, pharmacies, and pharmaceutical benefit managers. Efforts to ensure that our operations comply
with current applicable healthcare laws and regulations involve substantial costs. 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. Penalties for violations of applicable healthcare laws and regulations may include significant civil, criminal and administrative penalties, damages, disgorgement, fines,
imprisonment, exclusion of products from government funded healthcare programs, such as Medicare and Medicaid, and additional reporting requirements and oversight if we enter into a corporate integrity agreement or similar agreement to resolve
allegations of non-compliance with these laws. In addition, violations may also result in reputational harm, diminished profits and future earnings.
If government or other third-party payers fail to provide adequate coverage and payment rates for our medicines, including
SPINRAZA, TEGSEDI and WAYLIVRA, and our medicines in development, our revenue will be limited.
In both domestic and foreign markets, sales of our current and future products will depend in part upon the availability of coverage and
reimbursement from third-party payers. The majority of patients in the U.S. who would fit within our target patient populations for our medicines have their healthcare supported by a combination of Medicare coverage, other government health programs
such as Medicaid, managed care providers, private health insurers and other organizations. Coverage decisions may depend upon clinical and economic standards that disfavor new medicines when more established or lower cost therapeutic alternatives are
already available or subsequently become available. Assuming coverage is approved, the resulting reimbursement payment rates might not be enough to make our medicines affordable. Even if favorable coverage status and adequate reimbursement rates are
attained, less favorable coverage policies and reimbursement rates may be implemented in the future. Accordingly, SPINRAZA, TEGSEDI and WAYLIVRA, and our medicines in development, will face competition from other therapies and medicines for limited
financial resources. We or our partners may need to conduct post-marketing studies to demonstrate the cost-effectiveness of any future products to satisfy third-party payers. These studies might require us to commit a significant amount of management
time and financial and other resources. Third-party payers may never consider our future products as cost-effective. Adequate third-party coverage and reimbursement might not be available to enable us to maintain price levels sufficient to realize an
appropriate return on investment in product development.
Third-party payers, whether foreign or domestic, or governmental or commercial, are developing increasingly sophisticated
methods of controlling healthcare costs. In addition, in the U.S., no uniform policy of coverage and reimbursement for medicines exists among third-party payers. Therefore, coverage and reimbursement for medicines can differ significantly from payer to
payer. For example, the Affordable Care Act was passed in March 2010, and substantially changed the way healthcare is financed by both governmental and private insurers, and continues to significantly impact the U.S. pharmaceutical industry. There have
been judicial and Congressional challenges to certain aspects of the Affordable Care Act, as well as efforts to repeal or replace certain aspects of the Affordable Care Act. It is unclear how future litigation and healthcare reform measures will impact
the Affordable Care Act and our business.
Further, we believe that future coverage,
reimbursement and pricing will likely be subject to increased restrictions both in the U.S. and in international markets. In the U.S., recent health reform measures have resulted in reductions in Medicare and other healthcare funding, and there have
been several recent U.S. Congressional inquiries, legislation and executive orders designed to, among other things, reduce drug prices (e.g., by supporting drug price negotiation in Medicare Parts B and D, with those negotiated prices also available
to commercial plans, and progressing legislation to slow price increases over time on existing drugs), increase competition (e.g., by supporting legislation to speed the entry of biosimilar and generic drugs, including shortening the period of
exclusivity, policies in Medicare Part B to increase the prescribing of biosimilars by physicians, and a prohibition on “pay-for-delay” agreements and anti-competitive practices by drug manufacturers), lower out-of-pocket drug costs for patients
(e.g., by capping Medicare Part D beneficiary out-of-pocket pharmacy expenses), and foster scientific innovation to promote better health care and improved health (e.g., by investing in public and private research and incentivizing the market to promote discovery of valuable and accessible new treatments). At the state level, legislatures have increasingly passed legislation and implemented
regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in
some cases, designed to encourage importation from other countries and bulk purchasing. Third-party coverage and reimbursement for medicines may not be available or adequate in either the U.S. or international markets, and third-party payers, whether
foreign or domestic, or governmental or commercial, may allocate their resources to address the current COVID-19 Pandemic or experience delays or disruptions in their ability to devote resources to coverage and reimbursement matters related to our
products or medicines as a result of the COVID-19 Pandemic, which would negatively affect the potential commercial success of our products, our revenue and our profits.
If we cannot manufacture our medicines or contract with a third party to manufacture our medicines at costs that allow us
to charge competitive prices to buyers, we cannot market our products profitably.
To successfully commercialize any of our medicines, we would need to optimize and manage large-scale commercial
manufacturing capabilities either on a standalone basis or through a third-party manufacturer. We rely on third-party manufacturers to supply the drug substance and drug product for TEGSEDI and drug product for WAYLIVRA. Any delays or disruption to our
own or third-party commercial manufacturing capabilities, including any interruption to our supply chain as a result of the current COVID-19 Pandemic, could limit the commercial success of our medicines. In addition, as our drug development and
commercial pipeline increases and matures, we will have a greater need for clinical trial and commercial manufacturing capacity. For example, we have plans to expand our manufacturing infrastructure to support our wholly owned pipeline. If we are not
successful in executing this expansion, it could limit our ability to meet our manufacturing requirements and commercial objectives in the future.
Additionally, we have limited experience manufacturing pharmaceutical products of the chemical class represented by our
medicines, called oligonucleotides, on a commercial scale for the systemic administration of a medicine. There are a small number of suppliers for certain capital equipment and raw materials that we use to manufacture our medicines, and some of these
suppliers will need to increase their scale of production to meet our projected needs for commercial manufacturing. Further, we must continue to improve our manufacturing processes to allow us to reduce our drug costs. We or our partners may not be
able to manufacture our medicines at a cost or in quantities necessary to make commercially successful products.
Also, manufacturers, including us, must adhere to the FDA’s cGMP regulations and similar regulations in foreign countries,
which the applicable regulatory authorities enforce through facilities inspection programs. We, our partners and our contract manufacturers may not comply or maintain compliance with cGMP, or similar foreign regulations. Non-compliance could
significantly delay or prevent receipt of marketing authorizations for our medicines, including authorizations for SPINRAZA, TEGSEDI and WAYLIVRA, and our medicines in development, or result in enforcement action after authorization that could limit
the commercial success of our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, and our medicines in development.
Risks Related to the Development and Regulatory Approval of our Medicines
If we or our partners fail to obtain regulatory approval for our medicines and additional approvals for SPINRAZA, TEGSEDI
and WAYLIVRA, we or our partners cannot sell them in the applicable markets.
We cannot guarantee that any of our medicines will be considered safe and effective or will be approved for
commercialization. In addition, it is possible that SPINRAZA, TEGSEDI and WAYLIVRA may not be approved in additional markets or for additional indications. We and our partners must conduct time-consuming, extensive and costly clinical studies to
demonstrate the safety and efficacy of each of our medicines before they can be approved or receive additional approvals for sale. We and our partners must conduct these studies in compliance with FDA regulations and with comparable regulations in
other countries.
We and our partners may not obtain necessary regulatory approvals on a timely basis, if at all, for our medicines. It is
possible that regulatory agencies will not approve our medicines for marketing or SPINRAZA, TEGSEDI or WAYLIVRA in additional markets or for additional indications. If the FDA or another regulatory agency believes that we or our partners have not
sufficiently demonstrated the safety or efficacy of any of our medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, or our medicines in development, the agency will not approve the specific medicine or will require additional studies, which can be time
consuming and expensive and will delay or harm commercialization of the medicine. For example, in August 2018 we received a complete response letter from the FDA regarding the new drug application for WAYLIVRA in which the FDA determined that the
safety concerns identified with WAYLIVRA in our clinical development program outweighed the expected benefits of triglyceride lowering in patients with FCS. We also received a Non-W from Health Canada for WAYLIVRA in November 2018.
The FDA or other comparable foreign regulatory authorities can delay, limit or deny approval of a medicine for many
reasons, including:
|
● |
such authorities may disagree with the design or implementation of our clinical studies;
|
|
● |
we or our partners may be unable to demonstrate to the satisfaction of the FDA or other regulatory authorities that a medicine is safe and effective for
any indication;
|
|
● |
such authorities may not accept clinical data from studies conducted at clinical facilities that have deficient clinical practices or that are in
countries where the standard of care is potentially different from that in the U.S.;
|
|
● |
we or our partners may be unable to demonstrate that our medicine’s clinical and other benefits outweigh its safety risks to support approval;
|
|
● |
such authorities may disagree with the interpretation of data from preclinical or clinical studies;
|
|
● |
such authorities may find deficiencies in the manufacturing processes or facilities of third-party manufacturers who manufacture clinical and commercial
supplies for our medicines, or may delay the inspection of such facilities due to restrictions related to the COVID-19 Pandemic; and
|
|
● |
the approval policies or regulations of such authorities or their prior guidance to us or our partners during clinical development may significantly
change in a manner rendering our clinical data insufficient for approval.
|
Failure to receive marketing authorization for our medicines, or failure to receive additional marketing authorizations
for SPINRAZA, TEGSEDI or WAYLIVRA, or delays in these authorizations, could prevent or delay commercial introduction of the medicine, and, as a result, could negatively impact our ability to generate revenue from product sales.
We may not be able to benefit from orphan drug designation for our medicines.
In the U.S., under the Orphan Drug Act, the FDA may designate a medicine as an orphan drug if it is intended to treat a
rare disease or condition affecting fewer than 200,000 individuals in the U.S. Orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process, but it can provide financial incentives,
such as tax advantages and user-fee waivers, as well as longer regulatory exclusivity periods. The FDA has granted orphan drug designation to eplontersen for the treatment of patients with transthyretin-mediated amyloidosis. The FDA and EMA have
granted orphan drug designation to TEGSEDI for the treatment of patients with polyneuropathy due to hATTR amyloidosis, to WAYLIVRA for the treatment of patients with FCS, and to tominersen for the treatment of patients with HD. In addition, the EMA has
granted orphan drug designation to WAYLIVRA for the treatment of patients with FPL. Even if approval is obtained on a medicine that has been designated as an orphan drug, we may lose orphan drug exclusivity if the FDA or EMA determines that the request
for designation was materially defective or if we cannot assure sufficient quantity of the applicable medicine to meet the needs of patients with the rare disease or condition, or if a competitor is able to gain approval for the same medicine in a
safer or more effective form or that makes a major contribution to patient care. If we lose orphan drug exclusivity on any of our medicines, we may face increased
competition and lose market share for such medicine.
If the results of clinical testing indicate that any of our medicines are not suitable for commercial use, we may need to
abandon one or more of our drug development programs.
Drug discovery and development has inherent risks and the historical failure rate for drugs is high. Antisense medicines
are a relatively new approach to therapeutics. If we cannot demonstrate that our medicines are safe and effective for human use in the intended indication, we may need to abandon one or more of our drug development programs.
Even if our medicines are successful in preclinical and human clinical studies, the medicines may not be successful in
late-stage clinical studies.
Successful results in preclinical or initial
human clinical studies, including the Phase 2 results for some of our medicines in development, may not predict the results of subsequent clinical studies. If any of our medicines in Phase 3 clinical studies, including the studies of eplontersen, olezarsen, donidalorsen, ION363, pelacarsen and tofersen, do not show sufficient efficacy in patients with the targeted indication, or if such studies are
discontinued for any other reason, it could negatively impact our development and commercialization goals for these medicines and our stock price could decline.
In the past, we have invested in clinical
studies of medicines that have not met the primary clinical endpoints in their Phase 3 studies or have been discontinued for other reasons. For example, in October 2021, Biogen reported that tofersen did not meet the primary clinical endpoint in the Phase 3 VALOR study; however, trends favoring tofersen were seen across multiple secondary and exploratory
measures of disease activity and clinical function. In addition, in March 2021, Roche decided to discontinue dosing in the Phase 3 GENERATION HD1 study of tominersen in patients with manifest Huntington’s disease based on the results of a pre-planned
review of data from the Phase 3 study conducted by an unblinded Independent Data Monitoring Committee. Similar results could occur in clinical studies for our other medicines, including the studies of eplontersen
, olezarsen, donidalorsen, ION363 and pelacarsen.
There are a number of factors that could cause a clinical study to fail or be delayed, including:
|
● |
the clinical study may produce negative or inconclusive results;
|
|
● |
regulators may require that we hold, suspend or terminate clinical research for noncompliance with regulatory requirements;
|
|
● |
we, our partners, the FDA or foreign regulatory authorities could suspend or terminate a clinical study due to adverse side effects of a medicine on
subjects or lack of efficacy in the trial;
|
|
● |
we, or our partners, may decide, or regulators may require us, to conduct additional preclinical testing or clinical studies;
|
|
● |
enrollment in our clinical studies may be slower than we anticipate;
|
|
● |
we or our partners, including our independent clinical investigators, contract research organizations and other third-party service providers on which we
rely, may not identify, recruit and train suitable clinical investigators at a sufficient number of study sites or timely enroll a sufficient number of study subjects in the clinical study;
|
|
● |
the institutional review board for a prospective site might withhold or delay its approval for the study;
|
|
● |
people who enroll in the clinical study may later drop out due to adverse events, a perception they are not benefiting from participating in the study, fatigue with the
clinical study process or personal issues;
|
|
● |
a clinical study site may deviate from the protocol for the study;
|
|
● |
the cost of our clinical studies may be greater than we anticipate;
|
|
● |
our partners may decide not to exercise any existing options to license and conduct additional clinical studies for our medicines; and
|
|
● |
the supply or quality of our medicines or other materials necessary to conduct our clinical studies may be insufficient, inadequate or delayed.
|
The current COVID-19 Pandemic could make some of these factors more likely to occur.
In addition, our current medicines, including SPINRAZA, TEGSEDI and WAYLIVRA, are chemically similar to each other. As a
result, a safety observation we encounter with one of our medicines could have, or be perceived by a regulatory authority to have, an impact on a different medicine we are developing. This could cause the FDA or other regulators to ask questions or
take actions that could harm or delay our ability to develop and commercialize our medicines or increase our costs. For example, the FDA or other regulatory agencies could request, among other things, any of the following regarding one of our
medicines: additional information or commitments before we can start or continue a clinical study, protocol amendments, increased safety monitoring, additional product labeling information, and post-approval commitments. This happened in connection
with the conditional marketing approval for WAYLIVRA in the EU, as the EC is requiring us to conduct a post-authorization safety study to evaluate the safety of WAYLIVRA on thrombocytopenia and bleeding in FCS patients taking WAYLIVRA. We have ongoing
post-marketing studies for WAYLIVRA and TEGSEDI and an EAP for WAYLIVRA. Adverse events or results from these studies or the EAPs could negatively impact our pending or future marketing approval applications for WAYLIVRA and TEGSEDI in patients with
FCS or hATTR amyloidosis or the commercial opportunity for WAYLIVRA or TEGSEDI.
Any failure or delay in our clinical studies,
including the studies of tofersen, pelacarsen, eplontersen, olezarsen, donidalorsen, and ION363, could reduce the commercial potential or viability
of our medicines.
We depend on third parties to conduct our clinical studies for our medicines and any failure of those parties to fulfill
their obligations could adversely affect our development and commercialization plans.
We depend on independent clinical
investigators, contract research organizations and other third-party service providers to conduct our clinical studies for our medicines and expect to continue to do so in the future. For example, we use clinical research organizations, such as Icon
Clinical Research Limited, Syneos Health, Inc., PPD and Medpace for the clinical studies for our medicines, including eplontersen, olezarsen,
donidalorsen, ION363, pelacarsen and tofersen. We rely heavily on these parties for successful execution of our clinical studies, but do not control many aspects of their activities. For example, the investigators are not our employees. However, we
are responsible for ensuring that these third parties conduct each of our clinical studies in accordance with the general investigational plan and approved protocols for the study. Third parties may not complete activities on schedule or may not
conduct our clinical studies in accordance with regulatory requirements or our stated protocols. The failure of these third parties to carry out their obligations, including as a result of delays or disruption caused by the current COVID-19 Pandemic
that may affect the third party’s ability to conduct the clinical studies for our medicines, or a termination of our relationship with these third parties, could delay or prevent the development, marketing authorization and commercialization of our
medicines or additional marketing authorizations for TEGSEDI and WAYLIVRA.
Since corporate partnering is a significant part of our strategy to fund the advancement and commercialization of our
development programs, if any of our collaborative partners fail to fund our collaborative programs, or if we cannot obtain additional partners, we may have to delay or stop progress on our drug development programs.
To date, corporate partnering has played a significant role in our strategy to fund our development programs and to add
key development resources. We plan to continue to rely on additional collaborative arrangements to develop and commercialize many of our unpartnered medicines. However, we may not be able to negotiate favorable collaborative arrangements for these drug
programs. If we cannot continue to secure additional collaborative partners, our revenues could decrease and the development of our medicines could suffer.
Our corporate partners are developing and/or funding many of the medicines in our development pipeline. For example, we
are relying on:
|
● |
AstraZeneca for the joint development and funding of eplontersen;
|
|
● |
Novartis for development and funding of pelacarsen;
|
|
● |
Biogen for development and funding of tofersen; and
|
|
● |
Roche for development and funding of tominersen.
|
If any of these pharmaceutical companies stops developing and/or funding these medicines, our business could suffer and we
may not have, or be willing to dedicate, the resources available to develop these medicines on our own. Our collaborators can terminate their relationships with us under certain circumstances, many of which are outside of our control. For example,
after a review of data from the global Phase 2b study of vupanorsen, Pfizer decided to discontinue the clinical development program for vupanorsen.
Even with funding from corporate partners, if our partners do not effectively perform their obligations under our
agreements with them, it would delay or stop the progress of our drug development and commercial programs.
In addition to receiving funding, we enter into collaborative arrangements with third parties to:
|
● |
conduct clinical studies;
|
|
● |
seek and obtain marketing authorizations; and
|
|
● |
manufacture, market and sell our medicines.
|
Once we have secured a collaborative arrangement to further develop and commercialize one of our drug development
programs, such as our collaborations with AstraZeneca, Bayer, Biogen, GSK, Janssen, Novartis, and Roche, these collaborations may not continue or result in commercialized medicines, or may not progress as quickly as we first anticipated.
For example, a collaborator such as AstraZeneca, Bayer, Biogen, GSK, Janssen, Novartis, or Roche, could determine that it
is in its financial interest to:
|
● |
pursue alternative technologies or develop alternative products that may be competitive with the medicine that is part of the collaboration with us;
|
|
● |
pursue higher-priority programs or change the focus of its own development programs; or
|
|
● |
choose to devote fewer resources to our medicines than it does for its own medicines.
|
If any of these occur, it could affect our partner’s commitment to the collaboration with us and could delay or otherwise
negatively affect the commercialization of our medicines, including SPINRAZA, pelacarsen, tofersen, and eplontersen.
If we do not progress in our programs as anticipated, the price of our securities could decrease.
For planning purposes, we estimate and may
disclose the timing of a variety of clinical, regulatory and other milestones, such as when we anticipate a certain medicine will enter clinical trials, when we anticipate completing a clinical study, or when we anticipate filing an application for,
or obtaining, marketing authorization, or when we or our partners plan to commercially launch a medicine. We base our estimates on present facts and a variety of assumptions, many of which are outside of our control, including the current COVID-19
Pandemic. If we do not achieve milestones in accordance with our or our investors’ or securities analysts’ expectations, including milestones related to SPINRAZA, TEGSEDI, WAYLIVRA, eplontersen, olezarsen, donidalorsen, ION363, pelacarsen and tofersen, the price of our securities could decrease.
Risks Associated with our Businesses as a Whole
Risks related to our financial condition
We have incurred losses, and our business will suffer if we fail to consistently achieve profitability in the future.
Because drug discovery and development requires substantial lead-time and money prior to commercialization, our expenses
have generally exceeded our revenue since we were founded in January 1989. As of December 31, 2021, we had an accumulated deficit of
approximately $1.2 billion and stockholders’ equity of approximately $0.8 billion. Most of our historical losses resulted from costs incurred in connection with our research and development programs and from selling, general and administrative costs associated
with our operations. Most of our income has come from collaborative arrangements, including commercial revenue from royalties and R&D revenue, with additional income from research grants and the sale or licensing of our patents, as well as interest
income. If we do not continue to earn substantial revenue, we may incur additional operating losses in the future. We may not successfully develop any additional medicines or achieve or sustain future profitability.
If we fail to obtain timely funding, we may need to curtail or abandon some of our programs.
Many of our medicines are undergoing clinical studies or are in the early stages of research and development. Most of our
drug programs will require significant additional research, development, manufacturing, preclinical and clinical testing, marketing authorizations, preclinical activities and commitment of significant additional resources prior to their successful
commercialization. These activities will require significant cash. As of December 31, 2021, we had cash, cash equivalents and short-term
investments equal to $2.1 billion. If we or our partners do not meet our goals to successfully commercialize our medicines, including SPINRAZA,
TEGSEDI and WAYLIVRA, or to license certain medicines and proprietary technologies, we will need additional funding in the future. Our future capital requirements will depend on many factors, such as the following:
|
● |
successful commercialization of SPINRAZA, TEGSEDI and WAYLIVRA;
|
|
● |
additional marketing approvals for WAYLIVRA and TEGSEDI;
|
|
● |
the profile and launch timing of our medicines, including eplontersen, olezarsen, donidalorsen, ION363, pelacarsen and tofersen;
|
|
● |
changes in existing collaborative relationships and our ability to establish and maintain additional collaborative arrangements;
|
|
● |
continued scientific progress in our research, drug discovery and development programs;
|
|
● |
the size of our programs and progress with preclinical and clinical studies;
|
|
● |
the time and costs involved in obtaining marketing authorizations;
|
|
● |
competing technological and market developments, including the introduction by others of new therapies that address our markets; and
|
|
● |
our manufacturing requirements and capacity to fulfill such requirements.
|
If we need additional funds, we may need to raise them through public or private financing. Additional financing may not
be available at all or on acceptable terms. If we raise additional funds by issuing equity securities, the shares of existing stockholders will be diluted and the price, as well as the price of our other securities, may decline. If adequate funds are
not available or not available on acceptable terms, we may have to cut back on one or more of our research, drug discovery or development programs. Alternatively, we may obtain funds through arrangements with collaborative partners or others, which
could require us to give up rights to certain of our technologies or medicines.
Risks related to our intellectual property
If we cannot protect our patent rights or our other proprietary rights, others may compete more effectively against us.
Our success depends to a significant degree upon whether we can continue to develop, secure and maintain intellectual
property rights to proprietary products and services. However, we may not receive issued patents on any of our pending patent applications in the U.S. or in other countries and we may not be able to obtain, maintain or enforce our patents and other
intellectual property rights which could impact our ability to compete effectively. In addition, the scope of any of our issued patents may not be sufficiently broad to provide us with a competitive advantage. Furthermore, other parties may
successfully challenge, invalidate or circumvent our issued patents or patents licensed to us so that our patent rights do not create an effective competitive barrier or revenue source.
We cannot be certain that the U.S. Patent and Trademark Office, or U.S. PTO, and courts in the U.S. or the patent offices and courts in
foreign countries will consider the claims in our patents and applications covering SPINRAZA, TEGSEDI, WAYLIVRA, or any of our medicines in development as patentable. Method-of-use patents protect the use of a product for the specified method. This
type of patent does not prevent a competitor from making and marketing a product that is identical to our product for an indication that is outside the scope of the patented method. Moreover, even if competitors do not actively promote their product
for our targeted indications, physicians may prescribe these products off-label. Although off-label prescriptions may infringe or contribute to the infringement of method-of-use patents, the practice is common and such infringement is difficult to
prevent, even through legal action.
If we or any licensor partner loses or cannot obtain patent protection for SPINRAZA, TEGSEDI, WAYLIVRA, or any of our other medicines in
development, it could have a material adverse impact on our business.
Intellectual property litigation could be expensive and prevent us from pursuing our programs.
From time to time we have to defend our intellectual property rights. If we are involved in an intellectual property
dispute, we may need to litigate to defend our rights or assert them against others. Disputes can involve arbitration, litigation or proceedings declared by the U.S. PTO or the International Trade Commission or foreign patent authorities. 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 price
of our common stock.
If a third party claims that our medicines or technology infringe its patents or other intellectual property rights, we
may have to discontinue an important product or product line, alter our products and processes, pay license fees or cease certain activities. We may not be able to obtain a license to needed intellectual property on favorable terms, if at all. There
are many patents issued or applied for in the biotechnology industry, and we may not be aware of patents or patent applications held by others that relate to our business. This is especially true since patent applications in the U.S. are filed
confidentially for the first 18 months. Moreover, the validity and breadth of biotechnology patents involve complex legal and factual questions for which important legal issues remain.
Risks related to our personnel
If our management transition is not successful our business could suffer.
In January 2020, Dr. Crooke, our founder and Chief Executive Officer, transitioned from Chief Executive Officer to Executive Chairman of
our Board of Directors, and Dr. Monia, who was our Chief Operating Officer and a member of our team since our founding over 30 years ago, began serving as our Chief Executive Officer. Following the 2021 Annual Meeting of Stockholders, Dr. Crooke
stepped down from the Board and now serves as a Strategic Advisor to the Company, providing strategic advice and continuing to participate in the Company’s scientific activities. In June 2021, Dr. Loscalzo, a member of our Board since February 2014, was appointed Chairman of the Board. If this transition is not successful, our business could suffer.
The loss of key personnel, or the inability to attract and retain highly skilled personnel, could make it more difficult
to run our business and reduce our likelihood of success.
We are dependent on the principal members of
our management and scientific staff. We do not have employment agreements with any of our executive officers that would prevent them from leaving us. The loss of our management and key scientific employees might slow the achievement of important
research and development goals. It is also critical to our success that we recruit and retain qualified scientific personnel to perform research and development work. We may not be able to attract and retain skilled and experienced scientific
personnel on acceptable terms because of intense competition for experienced scientists among many pharmaceutical and health care companies, universities and non-profit research institutions. In addition, failure to succeed in clinical studies may
make it more challenging to recruit and retain qualified scientific personnel.
Risks related to taxes
Our ability to use our net operating loss carryovers and certain other tax attributes may be limited.
Under the Internal Revenue Code of 1986, as amended, or the Code, a corporation is generally allowed a deduction for net operating losses,
or NOLs, carried over from a prior taxable year. Under the Code, we can carryforward our NOLs to offset our future taxable income, if any, until such NOLs are used or expire. The same is true of other unused tax attributes, such as tax credits.
Under the current U.S. federal income tax law, U.S. federal NOLs generated in taxable years beginning after December 31, 2017 may be
carried forward indefinitely, but the deductibility of such U.S. federal NOLs in taxable years beginning after December 31, 2020 is limited to 80 percent of taxable income. It is uncertain if and to what extent various states will conform to current
U.S. federal income tax law, and there may be periods during which states suspend or otherwise limit the use of NOLs for state income tax purposes.
In addition, under Sections 382 and 383 of the Code, and corresponding provisions of state law, if a corporation undergoes an “ownership
change,” which is generally defined as a greater than 50 percentage-point cumulative change, by value, in its equity ownership over a three-year period, the corporation’s ability to use its pre-change NOL carryforwards and other pre-change tax
attributes to offset its post-change income or taxes may be limited. We may experience ownership changes in the future as a result of subsequent shifts in our stock ownership, some of which may be outside of our control. If an ownership change occurs
and our ability to use our NOL carryforwards or other tax attributes is materially limited, it would harm our future operating results by effectively increasing our future tax obligations. As a result of the Akcea Merger, we are subject to the separate
return limitation year, or SRLY, rules. Under the SRLY rules, our utilization of Akcea’s pre-merger NOL and tax credit carryforwards is limited to the amount of income that Akcea contributes to our consolidated taxable income. The Akcea pre-merger tax
attributes cannot be used to offset any of the income that Ionis contributes to our consolidated taxable income. In addition, at the state level, there may be periods during which the use of net operating losses is suspended or otherwise limited, which
could accelerate or permanently increase state taxes owed.
Our future taxable income could be impacted by changes in tax laws, regulations and treaties.
A change in tax laws, treaties or regulations, or their interpretation, of any country in which we operate could
materially affect us.
We could be subject to additional tax liabilities.
We are subject to U.S. federal, state, local and foreign income taxes, sales taxes in the U.S., withholding taxes and transaction taxes in
foreign jurisdictions. Significant judgment is required in evaluating our tax positions and our worldwide provision for taxes. During the ordinary course of business, there are many activities and transactions for which the ultimate tax determination
is uncertain. In addition, our tax obligations and effective tax rates could be adversely affected by changes in the relevant tax, accounting and other laws, regulations, principles and interpretations, including those relating to income tax nexus, by
recognizing tax losses or lower than anticipated earnings in jurisdictions where we have lower statutory rates and higher than anticipated earnings in jurisdictions where we have higher statutory rates, by changes in foreign currency exchange rates, or
by changes in the valuation of our deferred tax assets and liabilities. We may be audited in various jurisdictions, and such jurisdictions may assess additional taxes, sales taxes and value-added taxes against us. Although we believe our tax estimates
are reasonable, the final determination of any tax audits or litigation could be materially different from our historical tax provisions and accruals, which could have a material adverse effect on our operating results or cash flows in the period for
which a determination is made.
General risk factors
If the price of our securities continues to be highly volatile, this could make it harder to liquidate your investment and
could increase your risk of suffering a loss.
The market price of our common stock, like that of the securities of many other biopharmaceutical companies, has been and
is likely to continue to be highly volatile. These fluctuations in our common stock price may significantly affect the trading price of our securities. During the 12 months preceding December 31, 2021, the market price of our common stock ranged from $64.37 to $25.04 per share. Many factors can affect the market price of our securities, including, for example, fluctuations in our operating results, announcements
of collaborations, clinical study results, technological innovations or new products being developed by us or our competitors, the commercial success of our approved medicines, governmental regulation, marketing authorizations, changes in payers’
reimbursement policies, developments in patent or other proprietary rights and public concern regarding the safety of our medicines.
The current COVID-19 Pandemic has caused a significant
disruption of global financial markets and has resulted in increased volatility in the trading price of our common stock. Additionally, broad market and
industry factors may materially harm the market price of our common stock irrespective of our operating performance. The stock market in general, and NASDAQ and the market for biotechnology companies in particular, have experienced extreme price and
volume fluctuations that have often been unrelated or disproportionate to the operating performance of the particular companies affected. The trading prices and valuations of these stocks, and of ours, may not be predictable. A loss of investor
confidence in the market for biotechnology or pharmaceutical stocks or the stocks of other companies which investors perceive to be similar to us, the opportunities in the biotechnology and pharmaceutical market or the stock market in general, could
depress our stock price regardless of our business, prospects, financial conditions or results of operations.
Provisions in our certificate of incorporation, convertible notes documents, call spread hedge transaction documents and
Delaware law may prevent stockholders from receiving a premium for their shares.
Our certificate of incorporation provides for classified terms for the members of our board of directors. Our certificate
also includes a provision that requires at least 66 2/3 percent of our voting stockholders to approve a merger or certain other business transactions with, or proposed by, any holder of 15 percent or more of our voting stock, except in cases where
certain directors approve the transaction or certain minimum price criteria and other procedural requirements are met.
Our certificate of incorporation also requires that any action required or permitted to be taken by our stockholders must
be taken at a duly called annual or special meeting of stockholders and may not be taken by written consent. In addition, only our board of directors, chairman of the board or chief executive officer can call special meetings of our stockholders. We
have in the past, and may in the future, implement a stockholders’ rights plan, also called a poison pill, which could make it uneconomical for a third party to acquire our company on a hostile basis. In addition, our board of directors has the
authority to fix the rights and preferences of, and issue shares of preferred stock, which may have the effect of delaying or preventing a change in control of our company without action by our stockholders.
The provisions of our convertible senior notes could make it more difficult or more expensive for a third party to acquire
us. Upon the occurrence of certain transactions constituting a fundamental change, holders of the notes will have the right, at their option, to require us to repurchase all of their notes or a portion of their notes, which may discourage certain types
of transactions in which our stockholders might otherwise receive a premium for their shares over the then current market prices.
In April 2021, we completed a $632.5 million
offering of 0% Notes and used a portion of the net proceeds from the issuance of the 0% Notes to repurchase $247.9 million of our 1% Notes for $257.0 million. In
December 2019, we entered into privately negotiated exchange and/or subscription agreements with certain new investors and certain holders of our existing 1% Notes to exchange $375.6 million of our 1% Notes for $439.3 million of our 0.125% Notes, and
to issue $109.5 million of our 0.125% Notes. Additionally, in connection with the pricing of our 0% Notes and 0.125% Notes, we entered into call spread transactions in which we purchased note hedges and sold warrants. Terminating or unwinding the call spread transactions could require us to make substantial payments to the counterparties under those agreements or may increase our stock price. The
costs or any increase in stock price that may arise from terminating or unwinding such agreements could make an acquisition of our company significantly more expensive to the purchaser.
These provisions, as well as Delaware law, including Section 203 of the Delaware General Corporation Law, and other of our
agreements, may discourage certain types of transactions in which our stockholders might otherwise receive a premium for their shares over then current market prices, and may limit the ability of our stockholders to approve transactions that they think
may be in their best interests.
Future sales of our common stock in the public market could adversely affect the trading price of our securities.
Future sales of substantial amounts of our common stock in the public market, or the perception that such sales could
occur, could adversely affect trading prices of our securities. For example, we may issue approximately 17.5 million shares of our common stock upon conversion of our 0% Notes and 0.125% Notes, up to 10.9 million shares in connection with the warrant
transactions we entered into in connection with the issuance of our 0% Notes, and up to 6.6 million shares in connection with the warrant transactions we entered into in connection with the issuance of our 0.125% Notes, in each case subject to
customary anti-dilution adjustments. The addition of any of these shares into the public market may have an adverse effect on the price of our securities.
In addition, pursuant to the call spread transactions we entered into in connection with the pricing of our 0% Notes and
0.125% Notes, the counterparties are likely to modify their hedge positions from time to time at or prior to the conversion or maturity of the notes by purchasing and selling shares of our common stock, other of our securities, or other instruments,
including over-the-counter derivative instruments, that they may wish to use in connection with such hedging, which may have a negative effect on the conversion value of those notes and an adverse impact on the trading price of our common stock. The
call spread transactions are expected generally to reduce potential dilution to holders of our common stock upon any conversion of our 0% Notes or 0.125% Notes or offset any cash payments we are required to make in excess of the principal amount of the
converted 0% Notes or 0.125% Notes, as the case may be. However, the warrant transactions could separately have a dilutive effect to the extent that the market value per share of our common stock exceeds the applicable strike price of the warrants.
We are exposed to potential product liability claims, and insurance against these claims may not be available to us at a
reasonable rate in the future or at all.
Our business exposes us to potential product liability risks that are inherent in the testing, manufacturing, marketing
and sale of therapeutic products, including potential product liability claims related to SPINRAZA, TEGSEDI and WAYLIVRA, and our medicines in development. We have clinical study insurance coverage and commercial product liability insurance coverage.
However, this insurance coverage may not be adequate to cover claims against us, or be available to us at an acceptable cost, if at all. Regardless of their merit or eventual outcome, product liability claims may result in decreased demand for our
medicines, injury to our reputation, withdrawal of clinical study volunteers and loss of revenues. Thus, whether or not we are insured, a product liability claim or product recall may result in losses that could be material.
We are dependent on information technology systems, infrastructure and data, which exposes us to data security risks.
We are dependent upon our own and third-party information technology systems, infrastructure and data, including mobile technologies, to
operate our business. The multitude and complexity of our computer systems may make them vulnerable to service interruption or destruction, disruption of data integrity, malicious intrusion, or random attacks. Likewise, data privacy or security
incidents or breaches by employees or others may pose a risk that sensitive data, including our intellectual property, trade secrets or personal information of our employees, patients, customers or other business partners may be exposed to unauthorized
persons or to the public. Cyber-attacks are increasing in their frequency, sophistication and intensity, with third-party phishing and social engineering attacks in particular increasing during the COVID-19 Pandemic. Cyber-attacks could include the
deployment of harmful malware, denial-of-service, social engineering and other means to affect service reliability and threaten data confidentiality, integrity and availability. Our business partners face similar risks and any security breach of their
systems could adversely affect our security posture. A security breach or privacy violation that leads to disclosure or modification of or prevents access to patient information, including personally identifiable information or protected health
information, could harm our reputation, compel us to comply with federal and state breach notification laws and foreign law equivalents, subject us to financial penalties and mandatory and costly corrective action, require us to verify the correctness
of database contents and otherwise subject us to litigation or other liability under laws and regulations that protect personal data, any of which could disrupt our business and result in increased costs or loss of revenue. Moreover, the prevalent use
of mobile devices that access confidential information increases the risk of data security breaches, which could lead to the loss of confidential information, trade secrets or other intellectual property. While we have invested, and continue to invest,
in the protection of our data and information technology infrastructure, our efforts may not prevent service interruptions or identify breaches in our systems that could adversely affect our business and operations and result in the loss of critical or
sensitive information, which could result in financial, legal, business or reputational harm to us. In addition, our liability insurance may not be sufficient in type or amount to cover us against claims related to security breaches, cyber-attacks and
other related breaches.
Because we use biological materials, hazardous materials, chemicals and radioactive compounds, if we do not comply with
laws regulating the protection of the environment and health and human safety, our business could be adversely affected.
Our research, development and manufacturing activities involve the use of potentially harmful biological materials as well
as materials, chemicals and various radioactive compounds that could be hazardous to human health and safety or the environment. We store most of these materials and various wastes resulting from their use at our facilities in Carlsbad, California
pending ultimate use and disposal. We cannot completely eliminate the risk of contamination, which could cause:
|
● |
interruption of our research, development and manufacturing efforts;
|
|
● |
injury to our employees and others;
|
|
● |
environmental damage resulting in costly clean up; and
|
|
● |
liabilities under federal, state and local laws and regulations governing health and human safety, as well as the use, storage, handling and disposal of
these materials and resultant waste products.
|
In such an event, we may be held liable for any resulting damages, and any liability could exceed our resources. Although
we carry insurance in amounts and types that we consider commercially reasonable, we do not have insurance coverage for losses relating to an interruption of our research, development or manufacturing efforts caused by contamination, and the coverage
or coverage limits of our insurance policies may not be adequate. If our losses exceed our insurance coverage, our financial condition would be adversely affected.
Our business may be adversely affected by climate change, extreme weather events, earthquakes, pandemics, civil or
political unrest, terrorism or other catastrophic events.
In recent years, extreme weather events and changing weather patterns have become more common. As a result, we are
potentially exposed to varying natural disaster or extreme weather risks such as hurricanes, tornadoes, fires, droughts, floods, or other events that may result from the impact of climate change on the environment. The potential impacts of climate
change may also include increased operating costs associated with additional regulatory requirements and investments in reducing energy, water use and greenhouse gas emissions. In addition, we manufacture most of our research and clinical supplies in a
manufacturing facility located in Carlsbad, California. We manufacture the finished drug product for TEGSEDI and WAYLIVRA at third-party contract manufacturers. Biogen manufactures the finished drug product for SPINRAZA. The facilities and the
equipment we, our partners and our contract manufacturers use to research, develop and manufacture our medicines would be costly to replace and could require substantial lead time to repair or replace. Our facilities or those of our partners or
contract manufacturers may be harmed by natural disasters or other events outside our control, such as earthquakes, pandemics, war, civil or political unrest, deliberate acts of sabotage, terrorism or industrial accidents such as fire and explosion,
whether due to human or equipment error, and if such facilities are affected by a disaster or other event, our development and commercialization efforts would be delayed. Although we possess property damage and business interruption insurance coverage,
this insurance may not be sufficient to cover all of our potential losses and may not continue to be available to us on acceptable terms, or at all. In addition, our development and commercialization activities could be harmed or delayed by a shutdown
of the U.S. government, including the FDA.
Our business is subject to changing regulations for corporate governance and public disclosure that has increased both our
costs and the risk of noncompliance.
Each year we are required to evaluate our internal control systems in order to allow management to report on and our
Independent Registered Public Accounting Firm to attest to, our internal controls as required by Section 404 of the Sarbanes-Oxley Act. As a result, we continue to incur additional expenses and divert our management’s time to comply with these
regulations. In addition, if we cannot continue to comply with the requirements of Section 404 in a timely manner, we might be subject to sanctions or investigation by regulatory authorities, such as the SEC, the Public Company Accounting Oversight
Board, or PCAOB, or The Nasdaq Global Select Market. Any such action could adversely affect our financial results and the market price of our common stock.
The SEC and other regulators have continued to adopt new rules and regulations and make additional changes to existing
regulations that require our compliance. On July 21, 2010, the Dodd-Frank Wall Street Reform and Protection Act, or the Dodd-Frank Act, was enacted. There are significant corporate governance and executive compensation-related provisions in the
Dodd-Frank Act that require the SEC to adopt, or where the SEC has adopted, additional rules and regulations in these areas such as “say on pay” and proxy access. Stockholder activism, the current political environment and the current high level of
government intervention and regulatory reform may lead to substantial new regulations and disclosure obligations, which may lead to additional compliance costs and impact the manner in which we operate our business.
Negative conditions in the global credit markets and financial services and other industries may adversely affect our
business.
The global credit markets, the financial services industry, the U.S. capital markets, and the U.S. economy as a whole are
currently experiencing substantial turmoil and uncertainty characterized by unprecedented intervention by the U.S. federal government in response to the COVID-19 Pandemic. In the past, the failure, bankruptcy, or sale of various financial and other
institutions created similar turmoil and uncertainty in such markets and industries. It is possible that a crisis in the global credit markets, the U.S. capital markets, the financial services industry or the U.S. economy may adversely affect our
business, vendors and prospects, as well as our liquidity and financial condition. More specifically, our insurance carriers and insurance policies covering all aspects of our business may become financially unstable or may not be sufficient to cover
any or all of our losses and may not continue to be available to us on acceptable terms, or at all. In addition, due to the rapidly rising inflation rate, we may experience increased costs of goods and services for our business.
A variety of risks associated with operating our business and marketing our medicines internationally could adversely affect our business.
In addition to our U.S. operations, we are commercializing TEGSEDI in the EU, Canada, Latin America and certain Caribbean countries, and WAYLIVRA in the EU, Latin America and certain Caribbean countries. We face risks associated with our international
operations, including possible unfavorable regulatory, pricing and reimbursement, political, tax and labor conditions, which could harm our business. Because we have international operations, we are subject to numerous risks associated with
international business activities, including:
|
● |
compliance with differing or unexpected regulatory requirements for our medicines and foreign employees;
|
|
● |
complexities associated with managing multiple payer reimbursement regimes, government payers or patient self-pay systems;
|
|
● |
difficulties in staffing and managing foreign operations;
|
|
● |
in certain circumstances, increased dependence on the commercialization efforts and regulatory compliance of third-party distributors or strategic
partners;
|
|
● |
foreign government taxes, regulations and permit requirements;
|
|
● |
U.S. and foreign government tariffs, trade restrictions, price and exchange controls and other regulatory requirements;
|
|
● |
anti-corruption laws, including the Foreign Corrupt Practices Act, or the FCPA, and its equivalent in foreign jurisdictions;
|
|
● |
economic weakness, including inflation, natural disasters, war, events of terrorism, political instability or public health issues or pandemics, such as
the current COVID-19 Pandemic, in particular foreign countries or globally;
|
|
● |
fluctuations in currency exchange rates, which could result in increased operating expenses and reduced revenue, and other obligations related to doing
business in another country;
|
|
● |
compliance with tax, employment, privacy, immigration and labor laws, regulations and restrictions for employees living or traveling abroad;
|
|
● |
workforce uncertainty in countries where labor unrest is more common than in the U.S.; and
|
|
● |
changes in diplomatic and trade relationships.
|
The United Kingdom’s exit from the E.U. could increase these risks.
Our business activities outside of the U.S. are subject to the FCPA and similar anti-bribery or anti-corruption laws, regulations or rules
of other countries in which we operate, including the United Kingdom’s Bribery Act 2010. In many other countries, the healthcare providers who prescribe pharmaceuticals are employed by their government, and the purchasers of pharmaceuticals are
government entities; therefore, any dealings with these prescribers and purchasers may be subject to regulation under the FCPA. There is no certainty that all employees and third-party business partners (including our distributors, wholesalers, agents,
contractors and other partners) will comply with anti-bribery laws. In particular, we do not control the actions of manufacturers and other third-party agents, although we may be liable for their actions. Violation of these laws may result in civil or
criminal sanctions, which could include monetary fines, criminal penalties, and disgorgement of past profits, which could have an adverse impact on our business and financial condition
.
The impact on us of the vote by the United Kingdom to leave the European Union cannot be predicted.
The withdrawal of the UK from the EU, commonly referred to as “Brexit,” may adversely impact our ability to obtain regulatory approvals of
our medicines in the EU, result in restrictions or imposition of taxes and duties for importing our medicines into the EU, and may require us to incur additional expenses in order to develop, manufacture and commercialize our medicines in the EU.
Following the result of a referendum in 2016, the UK left the EU on January 31, 2020. Pursuant to the formal withdrawal arrangements
agreed between the UK and the EU, the UK was subject to a transition period that ended December 31, 2020, or the Transition Period, during which EU rules continued to apply. A trade and cooperation agreement, or the Trade and Cooperation Agreement,
that outlines the future trading relationship between the UK and the EU was signed in December 2020.
Since a significant proportion of the regulatory framework in the UK applicable to our business and our medicines is derived from EU
directives and regulations, Brexit has had, and may continue to have, a material impact upon the regulatory regime with respect to the development, manufacture, importation, approval and commercialization of our medicines in the UK or the EU. For
example, Great Britain is no longer covered by the centralized procedures for obtaining EU-wide marketing authorization from the EMA, and a separate marketing authorization will be required to market our medicines in Great Britain. It is currently
unclear whether the Medicines & Healthcare products Regulatory Agency in the UK is sufficiently prepared to handle the increased volume of marketing authorization applications that it is likely to receive. Any delay in obtaining, or an inability to
obtain, any marketing approvals, as a result of Brexit or otherwise, would delay or prevent us from commercializing our medicines in the UK or the EU.
While the Trade and Cooperation Agreement provides for the tariff-free trade of medicinal products between the UK and the EU, there may be
additional non-tariff costs to such trade which did not exist prior to the end of the Transition Period. Further, should the UK diverge from the EU from a regulatory perspective in relation to medicinal products, tariffs could be put into place in the
future. We could therefore, both now and in the future, face significant additional expenses (when compared to the position prior to the end of the Transition Period) to operate our business.