– In the phase 3 pivotal CELESTIAL trial,
CABOMETYX demonstrated a statistically significant and clinically
meaningful overall survival benefit –
Exelixis, Inc. (NASDAQ:EXEL) today announced that its partner
Ipsen received a positive opinion from the Committee for Medicinal
Products for Human Use (CHMP), the scientific committee of the
European Medicines Agency (EMA), for CABOMETYX® (cabozantinib)
tablets as a monotherapy for the treatment of hepatocellular
carcinoma (HCC) in adults who have been previously treated with
sorafenib. The positive CHMP opinion will now be reviewed by the
European Commission, which has the authority to approve medicines
for the European Union.
“This positive CHMP opinion represents significant progress for
patients in Europe with this aggressive form of liver cancer who
progress on prior systemic therapy, a large underserved patient
population that currently only has one approved second-line
treatment option,” said Michael M. Morrissey, Ph.D., President and
Chief Executive Officer of Exelixis. “We are excited about the
potential therapeutic benefits CABOMETYX may offer the liver cancer
community and look forward to the European Commission’s
decision.”
Under the terms of the Collaboration Agreement with Ipsen,
Exelixis is eligible to receive a milestone payment of $40 million
for the approval of the second-line treatment of HCC. This
milestone would be paid by Ipsen within 70 days of the approval
decision by the European Commission.
CABOMETYX is currently approved in the European Union for the
treatment of advanced renal cell carcinoma (RCC) in adults who have
received prior VEGF-targeted therapy and for previously untreated
intermediate- or poor-risk advanced RCC. The CHMP recommendation to
expand the indication is based on results from the CELESTIAL trial
of CABOMETYX in patients with advanced HCC who received prior
sorafenib. In this phase 3 pivotal trial, CABOMETYX demonstrated a
statistically significant and clinically meaningful improvement in
overall survival (OS) versus placebo.
On May 29, 2018, Exelixis announced that the U.S. Food and Drug
Administration (FDA) accepted for filing the supplemental New Drug
Application (sNDA) for CABOMETYX for previously treated advanced
HCC and assigned a Prescription Drug User Fee Act (PDUFA) action
date of January 14, 2019. 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.
Please see Important Safety Information below and full U.S.
prescribing information at
https://cabometyx.com/downloads/CABOMETYXUSPI.pdf.
About the CELESTIAL Study
CELESTIAL 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 PFS. Exploratory
endpoints include patient-reported outcomes, biomarkers and
safety.
In October 2017, Exelixis announced that the independent data
monitoring committee for the CELESTIAL study recommended that the
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. The data, originally presented at the 2018 American
Society of Clinical Oncology’s Gastrointestinal Cancers Symposium
(ASCO-GI) in January 2018, were published in The New England
Journal of Medicine in July 2018.1
About HCC
Liver cancer is the second-leading cause of cancer death
worldwide, accounting for more than 700,000 deaths and 800,000 new
cases each year.2 In the U.S., the incidence of liver cancer has
more than tripled since 1980.3 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 2018.4 HCC is the fastest-rising
cause of cancer-related death in U.S.1 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 VEGF-targeted therapy; in the
European Union for previously untreated intermediate- or poor-risk
advanced RCC; and in Canada for adult patients with advanced RCC
who have received prior VEGF targeted therapy. In March 2017, the
FDA granted orphan drug designation to cabozantinib for the
treatment of advanced HCC. On March 28, 2018, Ipsen announced that
the European Medicines Agency validated its application for a new
indication for cabozantinib as a treatment for previously treated
advanced HCC in the European Union; on September 20, 2018 the CHMP
provided a positive opinion for CABOMETYX as a monotherapy for the
treatment of HCC in adults who have been previously treated with
sorafenib. 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.
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 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 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 three commercially available products,
CABOMETYX® (cabozantinib), COMETRIQ® (cabozantinib) and COTELLIC®
(cobimetinib), and 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. In
July 2018, Exelixis was added to 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 Statement Disclaimer
This press release contains forward-looking statements,
including, without limitation, statements related to: the
regulatory review process in the European Union; the therapeutic
potential of CABOMETYX as a treatment option for adult patients in
the European Union with advanced HCC who have been previously
treated with sorafenib; Exelixis’ eligibility to receive a $40
million milestone payment from Ipsen for the approval of CABOMETYX
as a treatment for previously treated advanced HCC in the European
Union, and the timing for receipt of such payment; 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 European Commission may not approve cabozantinib
as a treatment for previously treated advanced HCC; 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 and their
adherence to their obligations under relevant collaboration
agreements; 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’
Quarterly Report on Form 10-Q filed with the Securities and
Exchange Commission (SEC) on August 1, 2018, 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.
1 Abou-Alfa, G, Meyer T, Cheng AL, et al. Cabozantinib in
patients with advanced and progressing hepatocellular
carcinoma. N Engl J Med. 2018. 379:54-63.
2 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 September 2018.
3 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 September 2018.
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/20180920006004/en/
Investors:Exelixis, Inc.Susan Hubbard, 650-837-8194EVP,
Public Affairs andInvestor
Relationsshubbard@exelixis.comorMedia:Exelixis, Inc.Lindsay
Treadway, 650-837-7522Senior Director, Public Affairs andAdvocacy
Relationsltreadway@exelixis.com
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