– Approval based on statistically
significant and clinically meaningful improvement in
progression-free survival for CABOMETYX versus sunitinib in CABOSUN
trial –
– Triggers $50 million milestone payment to
Exelixis under licensing agreement with Ipsen –
Exelixis, Inc. (Nasdaq:EXEL) today announced that its partner
Ipsen received approval from the European Commission (EC) for
CABOMETYX® (cabozantinib) 20 mg, 40 mg and 60 mg for the first-line
treatment of adults with intermediate- or poor-risk advanced renal
cell carcinoma (RCC) in the European Union.
“The expanded marketing authorization of CABOMETYX to include
previously untreated patients in Europe with intermediate- or
poor-risk advanced kidney cancer is an exciting milestone for a
patient population in need of more treatment options,” said Michael
M. Morrissey, Ph.D., President and Chief Executive Officer of
Exelixis. “We look forward to our continued collaboration with our
partners Ipsen and Takeda to bring new options to more patients
with difficult-to-treat cancers in Europe and around the
world.”
Under the terms of the Collaboration and License Agreement with
Ipsen, Exelixis will receive a milestone payment of $50 million for
the EC approval, of which approximately $46 million was recognized
as collaboration revenue in the first quarter of 2018. The payment
will be made by Ipsen within the next 70 days.
CABOMETYX was approved in the European Union in September 2016
for the treatment of advanced RCC in adults following prior
vascular endothelial growth factor (VEGF)-targeted therapy. The
expanded EC approval to include first-line treatment is based on
results of the CABOSUN trial, which met its primary endpoint of
improved progression-free survival (PFS) compared with sunitinib in
patients with previously untreated advanced RCC determined to be
intermediate- or poor-risk by the International Metastatic RCC
Database Consortium (IMDC) criteria. In December 2017, the U.S.
Food and Drug Administration (FDA) approved CABOMETYX for the
expanded indication of patients with advanced RCC based on the
results from the CABOSUN trial.
Please see Important Safety Information below and full U.S.
prescribing information at
https://cabometyx.com/downloads/CABOMETYXUSPI.pdf.
About the CABOSUN Study
On May 23, 2016, Exelixis announced that the phase 2 CABOSUN
study met its primary endpoint, demonstrating a statistically
significant and clinically meaningful improvement in PFS compared
with sunitinib in patients with advanced intermediate- or poor-risk
RCC as determined by investigator assessment. The CABOSUN study was
conducted by The Alliance for Clinical Trials in Oncology and was
sponsored by the National Cancer Institute-Cancer Therapy
Evaluation Program (NCI-CTEP) under the Cooperative Research and
Development Agreement with Exelixis for the development of
cabozantinib. These results were first presented by Dr. Toni
Choueiri at the European Society for Medical Oncology (ESMO) 2016
Congress, and published in the Journal of Clinical Oncology
(Choueiri, JCO, 2016).1 In June 2017, a blinded independent
radiology review committee (IRC) confirmed that cabozantinib
provided a clinically meaningful and statistically significant
improvement in the primary efficacy endpoint of
investigator-assessed PFS. Results from the IRC review were
presented by Dr. Toni Choueiri at the ESMO 2017 Congress.
CABOSUN was a randomized, open-label, active-controlled phase 2
trial that enrolled 157 patients with advanced RCC determined to be
intermediate- or poor-risk by the IMDC criteria. Patients were
randomized 1:1 to receive cabozantinib (60 mg once daily) or
sunitinib (50 mg once daily, 4 weeks on followed by 2 weeks off).
The primary endpoint was PFS. Secondary endpoints included overall
survival, objective response rate and safety. Eligible patients
were required to have locally advanced or metastatic clear-cell
RCC, ECOG performance status 0-2 and had to be intermediate- or
poor-risk per the IMDC criteria (Heng, JCO, 2009).2 Prior systemic
treatment for RCC was not permitted.
About Advanced Renal Cell Carcinoma
The American Cancer Society’s 2018 statistics cite kidney cancer
as among the top ten most commonly diagnosed forms of cancer among
both men and women in the U.S.3 Clear cell RCC is the most common
type of kidney cancer in adults.4 If detected in its early stages,
the five-year survival rate for RCC is high; for patients with
advanced or late-stage metastatic RCC, however, the five-year
survival rate is only 12 percent, with no identified cure for the
disease.3 Approximately 30,000 patients in the U.S. and 68,000
globally require treatment, and an estimated 14,000 patients in the
U.S. each year are in need of a first-line treatment for advanced
kidney cancer.5
The majority of clear cell RCC tumors have lower than normal
levels of a protein called von Hippel-Lindau, which leads to higher
levels of MET, AXL and VEGF.6,7 These proteins promote tumor
angiogenesis (blood vessel growth), growth, invasiveness and
metastasis.8,9,10,11 MET and AXL may provide escape pathways that
drive resistance to VEGF receptor inhibitors.7,8
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, and in the
European Union for previously untreated intermediate- or poor-risk
advanced RCC. Regulatory applications were recently submitted for
CABOMETYX for additional advanced hepatocellular carcinoma (HCC)
indications: on March 15, 2018, Exelixis announced the completed
submission of a supplemental New Drug Application to the U.S. FDA
for CABOMETYX for previously treated patients with 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 hepatocellular
carcinoma in the European Union.
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.
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 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 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 Disclaimer
This press release contains forward-looking statements,
including, without limitation, statements related to: the
therapeutic potential of CABOMETYX as a treatment for patients in
Europe with intermediate- or poor-risk advanced RCC; Exelixis’ plan
to work with Ipsen and Takeda to bring new treatment options to
more patients with difficult-to-treat cancers in Europe and around
the world; the timing for receipt and related revenue recognition
requirements of the $50 million milestone payment from Ipsen to
Exelixis for the approval of the first-line treatment of RCC;
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 “continued,” “will,” “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: the degree of market acceptance of CABOMETYX,
COMETRIQ, and COTELLIC and the availability of sufficient coverage
and adequate reimbursement for these products; Exelixis’ dependence
on its relationships with its collaboration partners, including the
level of their investment in the resources necessary to
successfully commercialize partnered compounds in the territories
where they are approved; risks and uncertainties related to
regulatory review and approval processes and Exelixis’ compliance
with applicable regulatory and legal requirements; risks related to
the potential failure of cabozantinib and cobimetinib, both alone
and in combination with other therapies, to demonstrate safety and
efficacy in clinical testing; the availability of data at the
referenced times; Exelixis’ ability and the ability of its
collaborators to conduct clinical trials of cabozantinib and
cobimetinib, both alone and in combination with other therapies,
sufficient to achieve a positive completion; 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 its intellectual property rights; market
competition, including the potential for competitors to obtain
approval for generic versions of Exelixis’ marketed products;
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 May 2, 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 and CABOMETYX are
registered U.S. trademarks.
____________________
References
1 Choueiri, T.K., et al. Cabozantinib versus Sunitinib as
Initial Targeted Therapy for Patients with Metastatic Renal Cell
Carcinoma of Poor or Intermediate Risk: The Alliance A031203
CABOSUN Trial. Am J Clin Oncol. 2016; 35:591-597.
2 Heng D.Y., Xie W., Regan M.M., et al. Prognostic factors for
overall survival in patients with metastatic renal cell carcinoma
treated with vascular endothelial growth factor-targeted agents:
Results from a large, multicenter study. Am J Clin Oncol. 2009;
27:5794-5799.
3 American Cancer Society. Cancer Facts & Figures 2018.
Atlanta: American Cancer Society; 2018.
4 Jonasch, E., Gao, J., Rathmell, W. Renal cell carcinoma. BMJ.
2014; 349:g4797.
5 Decision Resources Report: Renal Cell Carcinoma. October 2014
(internal data on file).
6 Harshman, L., and Choueiri, T. Targeting the hepatocyte growth
factor/c-Met signaling pathway in renal cell carcinoma. Cancer J.
2013; 19:316-323.
7 Rankin, et al. Direct regulation of GAS6/AXL signaling by HIF
promotes renal metastasis through SRC and MET. Proc Natl Acad Sci
USA. 2014; 111:13373-13378.
8 Zhou, L., Liu, X-D., Sun, M., et al. Targeting MET and AXL
overcomes resistance to sunitinib therapy in renal cell carcinoma.
Oncogene. 2016; 35:2687-2697.
9 Koochekpour, et al. The von Hippel-Lindau tumor suppressor
gene inhibits hepatocyte growth factor/scatter factor-induced
invasion and branching morphogenesis in renal carcinoma cells. Mol
Cell Biol. 1999; 19:5902–5912.
10 Takahashi, A., Sasaki, H., Kim, S., et al. Markedly increased
amounts of messenger RNAs for vascular endothelial growth factor
and placenta growth factor in renal cell carcinoma associated with
angiogenesis. Cancer Res. 1994; 54:4233-4237.
11 Nakagawa, M., Emoto, A., Hanada, T., Nasu, N., Nomura, Y.
Tubulogenesis by microvascular endothelial cells is mediated by
vascular endothelial growth factor (VEGF) in renal cell carcinoma.
Br J Urol. 1997; 79:681-687.
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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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