– Submission based on two clinical trials in
patients with advanced hepatocellular carcinoma who had received
prior systemic therapy –
Exelixis, Inc. (NASDAQ: EXEL) today announced that Takeda
Pharmaceutical Company Limited (Takeda), its partner responsible
for the clinical development and commercialization of CABOMETYX®
(cabozantinib) in Japan, has applied to the Japanese Ministry of
Health, Labor and Welfare (MHLW) for Manufacturing and Marketing
Approval of cabozantinib as a treatment for patients with
unresectable hepatocellular carcinoma (HCC) that had progressed
after prior systemic therapy.
Takeda’s application is based on the results of two clinical
trials in patients with advanced HCC who had received prior
systemic therapy: CELESTIAL (XL184-309), a global, randomized,
placebo-controlled, double-blind phase 3 clinical trial, and
Cabozantinib-2003, a phase 2 clinical trial conducted in Japan.
“We are excited about the progress our partner Takeda has made
on advancing cabozantinib toward regulatory approval in Japan for
patients with advanced liver cancer,” said Michael M. Morrissey,
Ph.D., President and Chief Executive Officer of Exelixis. “This
regulatory filing is an important milestone for patients in Japan
who currently have limited treatment options after they have
progressed following systemic therapy. We look forward to our
continued collaboration as Takeda works to bring cabozantinib to
patients in need of new therapies.”
Per the terms of Exelixis and Takeda’s collaboration and license
agreement, Exelixis is eligible to receive a $10 million milestone
payment from Takeda as a result of this latest submission for HCC,
which is anticipated to be received in the first quarter of 2020.
In April 2019, Takeda applied for approval to manufacture and sell
cabozantinib as a treatment for unresectable and metastatic renal
cell carcinoma (RCC) in Japan. Following the milestone associated
with this HCC regulatory filing, Exelixis will be eligible to
receive further development, regulatory and first-sale milestone
payments of up to $76 million from Takeda related both to
previously treated and previously untreated RCC and previously
treated HCC. Exelixis continues to be eligible to receive
additional development, regulatory and first-sale milestones for
potential future cabozantinib indications, and is also eligible for
sales revenue milestones and royalties on net sales of cabozantinib
in Japan.
Takeda fully funds cabozantinib development activities that are
exclusively for the benefit of Japan and is responsible for 20% of
the costs associated with global cabozantinib clinical trials,
providing the company opts into those trials.
About HCC
Liver cancer is a leading cause of cancer death worldwide,
accounting for more than 700,000 deaths and 800,000 new cases each
year.1 In the U.S., the incidence of liver cancer has more than
tripled since 1980.2 HCC is the most common form of liver cancer,
making up about three-fourths of the estimated 43,000 new cases in
the U.S. in 2020.2 HCC is the fastest-rising cause of
cancer-related death in the U.S.3 Without treatment, patients with
advanced HCC usually survive less than 6 months.4
About CABOMETYX® (cabozantinib)
In the U.S., CABOMETYX tablets are approved for the treatment of
patients with advanced RCC and for the treatment of patients with
HCC who have been previously treated with sorafenib. CABOMETYX
tablets have also received regulatory approvals in the European
Union and additional countries and regions worldwide. In 2016,
Exelixis granted Ipsen exclusive rights for the commercialization
and further clinical development of cabozantinib outside of the
United States and Japan. In 2017, Exelixis granted exclusive rights
to Takeda Pharmaceutical Company Limited for the commercialization
and further clinical development of cabozantinib for all future
indications in Japan.
Please see Important Safety Information below and full U.S.
prescribing information at
https://cabometyx.com/downloads/CABOMETYXUSPI.pdf.
U.S. Important Safety Information
- Hemorrhage: Severe and fatal hemorrhages occurred with
CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5%
in CABOMETYX patients. Discontinue CABOMETYX for Grade 3 or 4
hemorrhage. Do not administer CABOMETYX to patients who have a
recent history of hemorrhage, including hemoptysis, hematemesis, or
melena.
- Perforations and Fistulas: Gastrointestinal (GI)
perforations, including fatal cases, occurred in 1% of CABOMETYX
patients. Fistulas, including fatal cases, occurred in 1% of
CABOMETYX patients. Monitor patients for signs and symptoms of
perforations and fistulas, including abscess and sepsis.
Discontinue CABOMETYX in patients who experience a fistula that
cannot be appropriately managed or a GI perforation.
- Thrombotic Events: CABOMETYX increased the risk of
thrombotic events. Venous thromboembolism occurred in 7% (including
4% pulmonary embolism) and arterial thromboembolism in 2% of
CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX
patients. Discontinue CABOMETYX in patients who develop an acute
myocardial infarction or serious arterial or venous thromboembolic
event requiring medical intervention.
- Hypertension and Hypertensive Crisis: CABOMETYX can
cause hypertension, including hypertensive crisis. Hypertension
occurred in 36% (17% Grade 3 and <1% Grade 4) of CABOMETYX
patients. Do not initiate CABOMETYX in patients with uncontrolled
hypertension. Monitor blood pressure regularly during CABOMETYX
treatment. Withhold CABOMETYX for hypertension that is not
adequately controlled with medical management; when controlled,
resume at a reduced dose. Discontinue CABOMETYX for severe
hypertension that cannot be controlled with anti-hypertensive
therapy or for hypertensive crisis.
- Diarrhea: Diarrhea occurred in 63% of CABOMETYX
patients. Grade 3 diarrhea occurred in 11% of CABOMETYX patients.
Withhold CABOMETYX until improvement to Grade 1 and resume at a
reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea
that cannot be managed with standard antidiarrheal treatments, or
Grade 4 diarrhea.
- Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in
44% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX
patients. Withhold CABOMETYX until improvement to Grade 1 and
resume at a reduced dose for intolerable Grade 2 PPE or Grade 3
PPE.
- Proteinuria: Proteinuria occurred in 7% of CABOMETYX
patients. Monitor urine protein regularly during CABOMETYX
treatment. Discontinue CABOMETYX in patients who develop nephrotic
syndrome.
- Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1%
of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis,
osteitis, bone erosion, tooth or periodontal infection, toothache,
gingival ulceration or erosion, persistent jaw pain, or slow
healing of the mouth or jaw after dental surgery. Perform an oral
examination prior to CABOMETYX initiation and periodically during
treatment. Advise patients regarding good oral hygiene practices.
Withhold CABOMETYX for at least 28 days prior to scheduled dental
surgery or invasive dental procedures. Withhold CABOMETYX for
development of ONJ until complete resolution.
- Wound Complications: Wound complications were reported
with CABOMETYX. Stop CABOMETYX at least 28 days prior to scheduled
surgery. Resume CABOMETYX after surgery based on clinical judgment
of adequate wound healing. Withhold CABOMETYX in patients with
dehiscence or wound healing complications requiring medical
intervention.
- Reversible Posterior Leukoencephalopathy Syndrome
(RPLS): RPLS, a syndrome of subcortical vasogenic edema
diagnosed by characteristic finding on MRI, can occur with
CABOMETYX. Evaluate for RPLS in patients presenting with seizures,
headache, visual disturbances, confusion, or altered mental
function. Discontinue CABOMETYX in patients who develop RPLS.
- Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm.
Advise pregnant women and females of reproductive potential of the
potential risk to a fetus. Verify the pregnancy status of females
of reproductive potential prior to initiating CABOMETYX and advise
them to use effective contraception during treatment and for 4
months after the last dose.
- Adverse Reactions: The most commonly reported (≥25%)
adverse reactions are: diarrhea, fatigue, decreased appetite, PPE,
nausea, hypertension, and vomiting.
- Strong CYP3A4 Inhibitors: If coadministration with
strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX
dosage. Avoid grapefruit or grapefruit juice.
- Strong CYP3A4 Inducers: If coadministration with strong
CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage.
Avoid St. John’s wort.
- Lactation: Advise women not to breastfeed during
CABOMETYX treatment and for 4 months after the final dose.
- Hepatic Impairment: In patients with moderate hepatic
impairment, reduce the CABOMETYX dosage. CABOMETYX is not
recommended for use in patients with severe hepatic
impairment.
Please see accompanying full Prescribing Information
https://cabometyx.com/downloads/CABOMETYXUSPI.pdf.
About Exelixis
Founded in 1994, Exelixis, Inc. (NASDAQ: EXEL) is a commercially
successful, oncology-focused biotechnology company that strives to
accelerate the discovery, development and commercialization of new
medicines for difficult-to-treat cancers. Following early work in
model system genetics, we established a broad drug discovery and
development platform that has served as the foundation for our
continued efforts to bring new cancer therapies to patients in
need. Our discovery efforts have resulted in four commercially
available products, CABOMETYX® (cabozantinib), COMETRIQ®
(cabozantinib), COTELLIC® (cobimetinib) and MINNEBRO®
(esaxerenone), and we have entered into partnerships with leading
pharmaceutical companies to bring these important medicines to
patients worldwide. Supported by revenues from our marketed
products and collaborations, we are committed to prudently
reinvesting in our business to maximize the potential of our
pipeline. We are supplementing our existing therapeutic assets with
targeted business development activities and internal drug
discovery — all to deliver the next generation of Exelixis
medicines and help patients recover stronger and live longer.
Exelixis is a member of the Standard & Poor’s (S&P) MidCap
400 index, which measures the performance of profitable mid-sized
companies. For more information about Exelixis, please visit
www.exelixis.com, follow @ExelixisInc on Twitter or like Exelixis,
Inc. on Facebook.
Forward-Looking Statements
This press release contains forward-looking statements,
including, without limitation, statements related to: the potential
for Takeda, as part of its continuing collaboration with Exelixis,
to bring CABOMETYX to patients in need of new therapies; the
anticipated timing for receipt of a $10 million milestone payment
from Takeda for Takeda’s submission of an application to the
Japanese MHLW for Manufacturing and Marketing Approval of CABOMETYX
as a treatment for patients in Japan with unresectable HCC who
progressed after prior systemic therapy; Exelixis’ eligibility for
future development, regulatory and first-sale milestone payments,
plus sales revenue milestones and royalties on net sales under its
collaboration with Takeda; and Exelixis’ plans to reinvest in its
business to maximize the potential of the company’s pipeline,
including through targeted business development activities and
internal drug discovery. Any statements that refer to expectations,
projections or other characterizations of future events or
circumstances are forward-looking statements and are based upon
Exelixis’ current plans, assumptions, beliefs, expectations,
estimates and projections. Forward-looking statements involve risks
and uncertainties. Actual results and the timing of events could
differ materially from those anticipated in the forward-looking
statements as a result of these risks and uncertainties, which
include, without limitation: risks and uncertainties related to
regulatory review and approval processes, including that the
Japanese MHLW may not approve CABOMETYX as a treatment for patients
with unresectable HCC who progressed after prior systemic therapy;
unexpected concerns that may arise as a result of the occurrence of
adverse safety events or additional data analyses of clinical
trials evaluating cabozantinib; Exelixis’ dependence on its
relationships with its collaboration partners, including their
pursuit of regulatory approvals for cabozantinib in new
indications; Exelixis’ ability to protect its intellectual property
rights; market competition; changes in economic and business
conditions; and other factors affecting the ability of Exelixis and
its partners to obtain regulatory approval for cabozantinib in new
indications discussed under the caption “Risk Factors” in Exelixis’
Annual Report on Form 10-Q filed with the Securities and Exchange
Commission (SEC) on October 30, 2019, and in Exelixis’ future
filings with the SEC. All forward-looking statements in this press
release are based on information available to Exelixis as of the
date of this press release, and Exelixis undertakes no obligation
to update or revise any forward-looking statements contained
herein.
Exelixis, the Exelixis logo, CABOMETYX,
COMETRIQ and COTELLIC are registered U.S. trademarks. MINNEBRO is a
Japanese trademark.
_____________________ 1 International Agency
for Research on Cancer. GLOBOCAN 2018. Liver Fact Sheet. Available
at:
http://gco.iarc.fr/today/data/factsheets/cancers/11-Liver-fact-sheet.pdf.
Accessed January 2020. 2 American Cancer Society: Cancer Facts
& Figures 2020. Available at:
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf.
Accessed January 2020. 3 Siegel R, Miller K, Jemal A: Cancer
Statistics, 2020. CA: A Cancer Journal for Clinicians. Volume 70,
Issue 1: 7-30. Available at:
https://acsjournals.onlinelibrary.wiley.com/doi/full/10.3322/caac.21590.
Accessed January 2020. 4 Weledji E, Orock G, Ngowe M, NsaghaD. How
grim is hepatocellular carcinoma? Ann Med Surg. 2014. 3:71-76.
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version on businesswire.com: https://www.businesswire.com/news/home/20200128005841/en/
Investors: Susan Hubbard EVP, Public Affairs and Investor
Relations Exelixis, Inc. (650) 837-8194 shubbard@exelixis.com
Media: Lindsay Treadway Senior Director, Public Affairs
and Advocacy Relations Exelixis, Inc. (650) 837-7522
ltreadway@exelixis.com
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