– In the pivotal phase 3 CELESTIAL trial,
CABOMETYX provided a statistically significant and clinically
meaningful improvement versus placebo in overall survival (OS)
–
Exelixis, Inc. (NASDAQ:EXEL) today announced it has completed
the submission of a supplemental New Drug Application (sNDA) to the
U.S. Food and Drug Administration (FDA) for CABOMETYX®
(cabozantinib) tablets as a treatment for patients with previously
treated advanced hepatocellular carcinoma (HCC). The sNDA
submission is based on results from the CELESTIAL randomized
pivotal phase 3 trial of CABOMETYX in patients with advanced HCC
who received prior sorafenib.
“We look forward to working closely with regulatory authorities
through the review process in anticipation of bringing CABOMETYX to
people diagnosed with advanced hepatocellular carcinoma, an
underserved patient community that urgently needs new treatment
options,” said Gisela Schwab, M.D., President, Product Development
and Medical Affairs and Chief Medical Officer, Exelixis. "We would
sincerely like to thank the study patients and clinicians who
participated in the CELESTIAL trial as well as our dedicated
clinical development, medical and regulatory teams for bringing us
another step closer to our goal of fully exploring the potential of
CABOMETYX and making it accessible to every patient who may benefit
from its use.”
On October 16, 2017, Exelixis announced that the independent
data monitoring committee for the study recommended that the
CELESTIAL trial be stopped for efficacy following review at the
second planned interim analysis, with cabozantinib providing a
statistically significant and clinically meaningful improvement in
OS compared with placebo in patients with previously treated
advanced HCC (pre-specified critical p-value ≤ 0.021). In March
2017, the FDA granted orphan drug designation to cabozantinib for
the treatment of advanced HCC.
An sNDA is an application to the FDA that, if approved, will
allow a drug sponsor to make changes to a previously approved
product label, including modifications to the indication.
About the CELESTIAL StudyCELESTIAL is a randomized,
double-blind, placebo-controlled study of cabozantinib in patients
with advanced HCC conducted at more than 100 sites globally in 19
countries. The trial was designed to enroll 760 patients with
advanced HCC who received prior sorafenib and may have received up
to two prior systemic cancer therapies for HCC and had adequate
liver function. Enrollment of the trial was completed in September
2017. Patients were randomized 2:1 to receive 60 mg of cabozantinib
once daily or placebo and were stratified based on etiology of the
disease (hepatitis C, hepatitis B or other), geographic region
(Asia versus other regions) and presence of extrahepatic spread
and/or macrovascular invasion (yes or no). No cross-over was
allowed between the study arms during the blinded treatment phase
of the trial. The primary endpoint for the trial is OS, and
secondary endpoints include objective response rate and
progression-free survival. Exploratory endpoints include
patient-reported outcomes, biomarkers and safety.
About HCCLiver cancer is the second-leading cause of
cancer death worldwide, accounting for more than 700,000 deaths and
nearly 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 nearly 42,000 new cases in the U.S. in 2018.2 HCC is the
fastest-rising cause of cancer-related death in U.S.3 Without
treatment, patients with advanced HCC usually survive less than 6
months.4
About CABOMETYX® (cabozantinib)CABOMETYX
tablets are approved in the United States for the treatment of
patients with advanced RCC. CABOMETYX tablets are also approved in
the European Union, Norway, Iceland, Australia, Switzerland and
South Korea for the treatment of advanced RCC in adults who have
received prior vascular endothelial growth factor (VEGF)-targeted
therapy. Ipsen also submitted to European Medicines Agency (EMA)
the regulatory dossier for cabozantinib as a treatment for
first-line advanced RCC in the European Union on August 28, 2017;
on September 8, 2017, Ipsen announced that the EMA validated the
application. 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, including
RCC.
CABOMETYX is not indicated for previously treated advanced
HCC.
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 have occurred with CABOMETYX. In two RCC studies, the
incidence of Grade ≥ 3 hemorrhagic events was 3% in
CABOMETYX-treated patients. Do not administer CABOMETYX to patients
that have or are at risk for severe hemorrhage.
- Gastrointestinal (GI) Perforations
and Fistulas: In RCC studies, fistulas were reported in 1% of
CABOMETYX-treated patients. Fatal perforations occurred in patients
treated with CABOMETYX. In RCC studies, gastrointestinal (GI)
perforations were reported in 1% of CABOMETYX-treated patients.
Monitor patients for symptoms of fistulas and perforations,
including abscess and sepsis. Discontinue CABOMETYX in patients who
experience a fistula which cannot be appropriately managed or a GI
perforation.
- Thrombotic Events: CABOMETYX
treatment results in an increased incidence of thrombotic events.
In RCC studies, venous thromboembolism occurred in 9% (including 5%
pulmonary embolism) and arterial thromboembolism occurred in 1% of
CABOMETYX-treated patients. Fatal thrombotic events occurred in the
cabozantinib clinical program. Discontinue CABOMETYX in patients
who develop an acute myocardial infarction or any other arterial
thromboembolic complication.
- Hypertension and Hypertensive
Crisis: CABOMETYX treatment results in an increased incidence
of treatment-emergent hypertension, including hypertensive crisis.
In RCC studies, hypertension was reported in 44% (18% Grade
≥ 3) of CABOMETYX-treated patients. Monitor blood pressure
prior to initiation and regularly during CABOMETYX treatment.
Withhold CABOMETYX for hypertension that is not adequately
controlled with medical management; when controlled, resume
CABOMETYX at a reduced dose. Discontinue CABOMETYX for severe
hypertension that cannot be controlled with anti-hypertensive
therapy. Discontinue CABOMETYX if there is evidence of hypertensive
crisis or severe hypertension despite optimal medical
management.
- Diarrhea: In RCC studies,
diarrhea occurred in 74% of patients treated with CABOMETYX.
Grade 3 diarrhea occurred in 11% of patients treated with
CABOMETYX. Withhold CABOMETYX in patients who develop intolerable
Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be managed with
standard antidiarrheal treatments until improvement to Grade 1;
resume CABOMETYX at a reduced dose.
- Palmar-Plantar Erythrodysesthesia
(PPE): In RCC studies, palmar-plantar erythrodysesthesia (PPE)
occurred in 42% of patients treated with CABOMETYX. Grade 3 PPE
occurred in 8% of patients treated with CABOMETYX. Withhold
CABOMETYX in patients who develop intolerable Grade 2 PPE or Grade
3 PPE until improvement to Grade 1; resume CABOMETYX at a reduced
dose.
- Reversible Posterior
Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical
vasogenic edema diagnosed by characteristic finding on MRI,
occurred in the cabozantinib clinical program. Perform an
evaluation for RPLS in any patient presenting with seizures,
headache, visual disturbances, confusion or altered mental
function. Discontinue CABOMETYX in patients who develop RPLS.
- Embryo-fetal Toxicity may be
associated with CABOMETYX. Advise pregnant women of the potential
risk to a fetus. Advise females of reproductive potential to use
effective contraception during CABOMETYX treatment and for 4 months
after the last dose.
- Adverse Reactions: The most
commonly reported (≥25%) adverse reactions are: diarrhea, fatigue,
nausea, decreased appetite, hypertension, PPE, weight decreased,
vomiting, dysgeusia, and stomatitis.
- Strong CYP3A4 Inhibitors: If
concomitant use with strong CYP3A4 inhibitors cannot be avoided,
reduce the CABOMETYX dosage.
- Strong CYP3A4 Inducers: If
concomitant use with strong CYP3A4 inducers cannot be avoided,
increase the CABOMETYX dosage.
- Lactation: Advise women not to
breastfeed while taking CABOMETYX and for 4 months after the final
dose.
- Hepatic Impairment: In patients
with mild to 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 ExelixisFounded 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 genetic systems, 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. We discovered our lead compounds,
cabozantinib and cobimetinib, and advanced them into clinical
development before entering into partnerships with leading
biopharmaceutical companies in our efforts to bring these medicines
to patients globally. We are steadfast in our commitment to
prudently reinvest in our business to maximize the potential of our
pipeline. We intend to supplement 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 recently earned a spot on Deloitte’s Technology Fast 500
list, a yearly award program honoring the 500 fastest-growing
companies over the past four years. For more information about
Exelixis, please visit www.exelixis.com, follow @ExelixisInc on
Twitter or like Exelixis, Inc. on Facebook.
Exelixis Forward-Looking Statement DisclaimerThis press
release contains forward-looking statements, including, without
limitation, statements related to: the regulatory review process;
Exelixis’ goal of expanding the population of patients who might
benefit from CABOMETYX and the potential to bring CABOMETYX to
patients diagnosed with advanced HCC; the therapeutic potential of
CABOMETYX as a treatment for patients with advanced HCC; 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; and Exelixis’ mission to
deliver the next generation of Exelixis medicines and help patients
recover stronger and live longer. Words such as “look forward,”
“anticipation,” “goal,” “commitment,” “potential,” “intend,” or
other similar expressions identify forward-looking statements, but
the absence of these words does not necessarily mean that a
statement is not forward-looking. In addition, any statements that
refer to expectations, projections or other characterizations of
future events or circumstances are forward-looking statements.
These forward-looking statements 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 and Exelixis’ compliance with
applicable legal and regulatory requirements; risks related to the
potential failure of cabozantinib to demonstrate safety and
efficacy in clinical testing; Exelixis’ ability and the ability of
its collaborators to conduct clinical trials of cabozantinib, both
alone and in combination with other therapies, sufficient to
achieve a positive completion; Exelixis’ dependence on its
relationships with its collaboration partners, including, the level
of their investment in the resources necessary to successfully
commercialize cabozantinib and cobimetinib in the territories where
they are approved; market acceptance of CABOMETYX, COMETRIQ, and
COTELLIC and the availability of coverage and reimbursement for
these products; the risk that unanticipated developments could
adversely affect the commercialization of CABOMETYX, COMETRIQ, and
COTELLIC; the level of costs associated with Exelixis’
commercialization, research and development, in-licensing or
acquisition of product candidates, and other activities; Exelixis’
dependence on third-party vendors for the development, manufacture
and supply of its products; Exelixis’ ability to protect the
company’s intellectual property rights; market competition; changes
in economic and business conditions, and other factors discussed
under the caption “Risk Factors” in Exelixis’ annual report on Form
10-K filed with the Securities and Exchange Commission (SEC)
on February 26, 2018, and in Exelixis’ future filings with
the SEC. The forward-looking statements made in this press
release speak only as of the date of this press release. Exelixis
expressly disclaims any duty, obligation or undertaking to release
publicly any updates or revisions to any forward-looking statements
contained herein to reflect any change in Exelixis’ expectations
with regard thereto or any change in events, conditions or
circumstances on which any such statements are based.
Exelixis, the Exelixis logo, CABOMETYX,
COMETRIQ and COTELLIC are registered U.S. trademarks.
References:1 Cancer Incidence and Mortality Worldwide. Liver
Cancer. International Agency for Research on Cancer, GLOBOCAN 2012.
Available at:
http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed
March 2018.2 American Cancer Society: Cancer Facts and Figures
2018. Available at:
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf.
Accessed March 2018.3 Mittal S, El-Serag HB. Epidemiology of HCC:
Consider the Population. Journal of Clinical Gastroenterology.
2013. 47:S2-S6.4 Weledji E, Orock G, Ngowe M, NsaghaD. How grim is
hepatocellular carcinoma? Annals of Medicine and Surgery. 2014.
3:71-76.
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version on businesswire.com: http://www.businesswire.com/news/home/20180315005365/en/
Exelixis, Inc.Investors:Susan Hubbard,
650-837-8194EVP, Public Affairs and Investor
Relationsshubbard@exelixis.comorMedia:Lindsay Treadway,
650-837-7522Senior Director, Public Affairs and Advocacy
Relationsltreadway@exelixis.com
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