– Exelixis to submit a supplemental New Drug
Application to the U.S. Food and Drug Administration (FDA) in the
first quarter of 2018; cabozantinib previously granted orphan drug
designation by FDA –
– Data to be submitted for presentation at
an upcoming medical meeting –
Exelixis, Inc. (NASDAQ:EXEL) today announced that its global
phase 3 CELESTIAL trial met its primary endpoint of overall
survival (OS), with cabozantinib providing a statistically
significant and clinically meaningful improvement in median OS
compared to placebo in patients with advanced hepatocellular
carcinoma (HCC). The independent data monitoring committee for the
study recommended that the trial should be stopped for efficacy
following review of the second planned interim analysis. CELESTIAL
is a randomized, global phase 3 trial of cabozantinib versus
placebo in patients with advanced HCC who have been previously
treated with sorafenib. The safety data in the study were
consistent with the established profile of cabozantinib. Based on
these results, Exelixis plans to submit a supplemental New Drug
Application (sNDA) to the U.S. Food and Drug Administration (FDA)
in the first quarter of 2018. Detailed results from CELESTIAL will
be submitted for presentation at a future medical conference.
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the full release here:
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“We are excited that these positive results from the phase 3
CELESTIAL trial bring us one step closer to the potential of
offering previously treated patients with this aggressive form of
advanced liver cancer a much-needed new treatment option,” said
Gisela Schwab, M.D., President, Product Development and Medical
Affairs and Chief Medical Officer, Exelixis. “This is an important
milestone for the cabozantinib development program; we are
committed to studying cabozantinib in a range of tumor types as
part of our mission to deliver medicines that improve treatment
outcomes and give patients hope for the future.”
Exelixis will discuss the trial results with regulatory
authorities and determine next steps for the trial, including
offering patients currently receiving placebo the opportunity to
cross over to cabozantinib.
In March 2017, the FDA granted orphan drug designation to
cabozantinib for the treatment of advanced HCC. Orphan drug
designation is granted to treatments for diseases that affect fewer
than 200,000 people in the U.S. and provides certain incentives for
medications intended for the treatment, diagnosis or prevention of
rare diseases. At present, these incentives include seven years of
marketing exclusivity for the orphan indication, certain federal
grants, tax credits, and waiver of certain FDA fees.
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.
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.
Based on available clinical trial data from various published
trials conducted in the second-line setting of advanced HCC, the
CELESTIAL trial statistics for the primary endpoint of OS assumed a
median OS of 8.2 months for the placebo arm. A total of 621 events
provide the study with 90 percent power to detect a 32 percent
increase in median OS (HR = 0.76) at the final analysis. Two
interim analyses were planned and conducted at 50 percent and 75
percent of the planned 621 events.
About HCCLiver cancer is the third-leading cause of death
worldwide, and hepatocellular carcinoma (HCC) is the most common
form, making up about three-fourths of the nearly 41,000 cases that
will be diagnosed in 2017 in the U.S.1,2 Without treatment,
patients with advanced disease usually survive less than 6 months,
and it is estimated that 29,000 people will die due to liver cancer
in the U.S.2,3 Worldwide, nearly 800,000 new cases are diagnosed
annually, and the disease accounts for more than 700,000 deaths
each year.4
About CABOMETYX® (cabozantinib)CABOMETYX is the
tablet formulation of cabozantinib. Its targets include MET, AXL
and VEGFR-1, -2 and -3. In preclinical models, cabozantinib has
been shown to inhibit the activity of these receptors, which are
involved in normal cellular function and pathologic processes such
as tumor angiogenesis, invasiveness, metastasis and drug
resistance. CABOMETYX is available in 20 mg, 40 mg or 60 mg doses.
The recommended dose is 60 mg orally, once daily.
On April 25, 2016, the FDA approved CABOMETYX tablets for the
treatment of patients with advanced RCC who have received prior
anti-angiogenic therapy. In February of 2016, Exelixis and Ipsen
jointly announced an exclusive licensing agreement for the
commercialization and further development of cabozantinib
indications outside of the United States, Canada and Japan. This
agreement was amended in December of 2016 to include
commercialization rights for Ipsen in Canada. On September 9, 2016,
the European Commission approved CABOMETYX tablets for the
treatment of advanced RCC in adults who have received prior
vascular endothelial growth factor (VEGF)-targeted therapy in the
European Union, Norway and Iceland.
On January 30, 2017, Exelixis and Takeda Pharmaceutical Company
Limited announced an exclusive licensing agreement for the
commercialization and further clinical development of cabozantinib
for all future indications in Japan, including RCC.
CABOMETYX is not indicated for the treatment of 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 hemorrhage occurred with CABOMETYX.
The incidence of Grade ≥3 hemorrhagic events was 2.1% in
CABOMETYX-treated patients and 1.6% in everolimus-treated patients.
Fatal hemorrhages also occurred in the cabozantinib clinical
program. Do not administer CABOMETYX to patients that have or are
at risk for severe hemorrhage.
Gastrointestinal (GI) Perforations and Fistulas: Fistulas
were reported in 1.2% (including 0.6% anal fistula) of
CABOMETYX-treated patients and 0% of everolimus-treated patients.
GI perforations were reported in 0.9% of CABOMETYX-treated patients
and 0.6% of everolimus-treated patients. Fatal perforations
occurred in the cabozantinib clinical program. Monitor patients for
symptoms of fistulas and perforations. Discontinue CABOMETYX in
patients who experience a fistula that cannot be appropriately
managed or a GI perforation.
Thrombotic Events: CABOMETYX treatment results in an
increased incidence of thrombotic events. Venous thromboembolism
was reported in 7.3% of CABOMETYX-treated patients and 2.5% of
everolimus-treated patients. Pulmonary embolism occurred in 3.9% of
CABOMETYX-treated patients and 0.3% of everolimus-treated patients.
Events of arterial thromboembolism were reported in 0.9% of
CABOMETYX-treated patients and 0.3% of everolimus-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. Hypertension was reported in 37% (15% Grade ≥3) of
CABOMETYX-treated patients and 7.1% (3.1% Grade ≥3) of
everolimus-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: Diarrhea occurred in 74% of patients treated
with CABOMETYX and in 28% of patients treated with everolimus.
Grade 3 diarrhea occurred in 11% of CABOMETYX-treated patients and
in 2% of everolimus-treated patients. 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. Dose modification due to diarrhea occurred in 26% of
patients.
Palmar-Plantar Erythrodysesthesia Syndrome (PPES):
Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 42%
of patients treated with CABOMETYX and in 6% of patients treated
with everolimus. Grade 3 PPES occurred in 8.2% of CABOMETYX-treated
patients and in <1% of everolimus-treated patients. Withhold
CABOMETYX in patients who develop intolerable Grade 2 PPES or Grade
3 PPES until improvement to Grade 1; resume CABOMETYX at a reduced
dose. Dose modification due to PPES occurred in 16% of
patients.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS):
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: CABOMETYX can cause fetal harm
when administered to a pregnant woman. Advise pregnant women of the
potential risk to a fetus. Advise females of reproductive potential
to use effective contraception during treatment with CABOMETYX and
for 4 months after the last dose.
Adverse Reactions: The most commonly reported (≥25%)
adverse reactions are: diarrhea, fatigue, nausea, decreased
appetite, PPES, hypertension, vomiting, weight decreased, and
constipation.
Drug Interactions: Strong CYP3A4 inhibitors and inducers:
Reduce the dosage of CABOMETYX if concomitant use with strong
CYP3A4 inhibitors cannot be avoided. Increase the dosage of
CABOMETYX if concomitant use with strong CYP3A4 inducers cannot be
avoided.
Lactation: Advise a lactating woman not to breastfeed
during treatment with CABOMETYX and for 4 months after the final
dose.
Reproductive Potential: Contraception―Advise females of
reproductive potential to use effective contraception during
treatment with CABOMETYX and for 4 months after the final dose.
Infertility ―CABOMETYX may impair fertility in females and
males of reproductive potential.
Hepatic Impairment: Reduce the CABOMETYX dose in patients
with mild (Child-Pugh score [C-P] A) or moderate (C-P B) hepatic
impairment. CABOMETYX is not recommended for use in patients with
severe hepatic impairment.
Please see full Prescribing Information at
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 them to
patients globally. With growing revenues from the three resulting
commercialized products – CABOMETYX®, COMETRIQ®, and COTELLIC® – we
are reinvesting in our business to maximize the potential of our
pipeline, which we intend to supplement 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. For more information about Exelixis,
please visit www.exelixis.com or follow @ExelixisInc on
Twitter.
Forward-Looking Statement DisclaimerThis press release
contains forward-looking statements, including, without limitation,
statements related to: Exelixis’ plans to submit an sNDA to the FDA
in the first quarter of 2018 for the treatment of patients with
advanced HCC; Exelixis’ plan to submit the detailed results from
CELESTIAL for presentation at a future medical conference; the
therapeutic potential of cabozantinib as a treatment for patients
with advanced liver cancer; Exelixis’ commitment to studying
cabozantinib in a range of tumor types as part of the company’s
mission to deliver medicines that improve treatment outcomes and
give patients hope for the future; Exelixis’ plan to discuss the
trial results with regulatory authorities and determine next steps
for the trial, including offering patients currently receiving
placebo the opportunity to cross over to the cabozantinib arm;
growing revenues from CABOMETYX, COMETRIQ, and COTELLIC 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; and
Exelixis’ mission to deliver the next generation of Exelixis
medicines and help patients recover stronger and live longer. Words
such as “plans,” “will,” “potential,” “committed,” “mission,” “next
steps,” 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; the availability of data at the referenced time;
Exelixis’ ability to conduct clinical trials of cabozantinib
sufficient to achieve a positive completion; risks related to the
potential failure of cabozantinib to demonstrate safety and
efficacy in clinical testing; Exelixis’ dependence on its
relationships with its cabozantinib collaboration partners,
including, the level of their investment in the resources necessary
to successfully commercialize cabozantinib in the territories where
it is 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 and other activities;
Exelixis’ dependence on its relationship with Genentech/Roche with
respect to cobimetinib and Exelixis’ ability to maintain its rights
under the collaboration; Exelixis’ dependence on third-party
vendors; 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’ quarterly report on Form 10-Q filed
with the Securities and Exchange Commission (SEC) on August 2,
2017, 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. Hepatocellular Carcinoma – United States, 2001-2006.
Morbidity and Mortality Weekly Report. Centers for Disease Control
and Prevention. Available at
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5917a3.htm. Accessed
October 2017.2. American Cancer Society: Cancer Facts and Figures
2017. Available at:
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2017/cancer-facts-and-figures-2017.pdf.
Accessed October 2017.3. Weledji E, Orock G, Ngowe M, NsaghaD. How
grim is hepatocellular carcinoma? Annals of Medicine and Surgery.
2014. (3):71-76.4. Estimated cancer incidence, mortality and
prevalence worldwide. International Agency for Research on Cancer,
GLOBOCAN 2012. Available at:
http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed
October 2017.
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Exelixis, Inc.Investors:Susan Hubbard, 650-837-8194EVP,
Public Affairs and Investor
Relationsshubbard@exelixis.comorMedia:Lindsay Treadway,
650-837-7522Director, Public Affairs and Advocacy
Relationsltreadway@exelixis.com
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