Exelixis’ Partner Takeda Announces Filing of New Drug Application in Japan for CABOMETYX® (Cabozantinib) for Advanced Renal Cell Carcinoma
April 25, 2019
— Regulatory submission triggers $10 million milestone payment to
Exelixis under collaboration and license agreement with Takeda —
— Submission based on METEOR and CABOSUN trials as well as Takeda
bridging study —
ALAMEDA, Calif.–(BUSINESS WIRE)–Exelixis,
Inc. (Nasdaq: EXEL) today announced that Takeda Pharmaceutical
Company Limited (Takeda), its partner responsible for the clinical
development and commercialization of cabozantinib in Japan, has applied
to the Japanese Ministry of Health, Labor and Welfare (MHLW) for
approval to manufacture and sell CABOMETYX® (cabozantinib) as a
treatment for unresectable and metastatic renal cell carcinoma (RCC) in
the country. As a result of the submission, Exelixis will receive a $10
million milestone payment from Takeda, anticipated to be received in the
second quarter of 2019.
Takeda’s application is based on the results of three clinical trials:
METEOR, the Exelixis-sponsored phase 3 pivotal trial of cabozantinib
versus everolimus in patients with advanced RCC that experienced disease
progression following treatment with at least one prior VEGF receptor
tyrosine kinase inhibitor (VEGFR-TKI); CABOSUN, the Alliance for
Clinical Trials in Oncology-sponsored phase 2 trial comparing
cabozantinib with sunitinib in patients with previously untreated
advanced RCC with intermediate- or poor-risk disease; and
Cabozantinib-2001, a Takeda-sponsored phase 2 trial in 35 Japanese
patients with advanced RCC who had progressed after prior VEGFR-TKI
therapy. Takeda’s phase 2 trial was the subject of a late-breaking
abstract at the 107th Annual Meeting of the Japanese
Urological Society on April 18, 2019.
“Takeda has proven to be a very effective partner in cabozantinib’s
development program in Japan since the signing of our collaboration and
licensing agreement in early 2017,” said Michael M. Morrissey, Ph.D.,
President and Chief Executive Officer of Exelixis. “This Japanese
regulatory filing is an important milestone on the path toward offering
CABOMETYX as a new therapeutic option for patients with unresectable,
metastatic renal cell carcinoma in Japan. We congratulate our Takeda
colleagues on the filing and look forward to further progress.”
Per the terms of Exelixis and Takeda’s collaboration and license
agreement, Exelixis received a $50 million upfront payment at the time
of signing. Following the milestone associated with this regulatory
filing, Exelixis will be eligible to receive from Takeda further
development, regulatory and first-sale milestone payments of up to $80
million related both to previously treated and previously untreated RCC
and previously treated hepatocellular carcinoma (HCC), as well as
additional development, regulatory and first-sale milestones for
potential future cabozantinib indications. Exelixis 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. As of today, Takeda has opted into and
is co-funding CheckMate 9ER, the ongoing phase 3 pivotal trial of
cabozantinib plus nivolumab versus sunitinib in previously untreated
advanced RCC.
About RCC
The American Cancer Society’s 2019 statistics cite kidney cancer as
among the top ten most commonly diagnosed forms of cancer among both men
and women in the U.S.1 Clear cell RCC is the most common type
of kidney cancer in adults.2 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.1
Approximately 32,000 patients in the U.S. and 70,000 globally require
treatment, and an estimated 15,000 patients in the U.S. each year are in
need of a first-line treatment for advanced kidney cancer.3
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.4,5 These proteins promote tumor angiogenesis
(blood vessel growth), growth, invasiveness and metastasis.6,7,8,9
MET and AXL may provide escape pathways that drive resistance to VEGF
receptor inhibitors.5,6
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 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 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: GastrointestinaI (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
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. Our discovery efforts
have resulted in four approved 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
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: Exelixis’ timing for receipt
of a $10 million milestone payment from Takeda for Takeda’s submission
of an application to the Japanese MHLW for approval to manufacture and
sell CABOMETYX as a treatment for unresectable and metastatic RCC in
Japan; the potential for CABOMETYX as a new therapeutic option for
patients with unresectable and metastatic RCC in Japan; 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 unresectable and metastatic RCC; 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-K filed with the Securities and
Exchange Commission (SEC) on February 22, 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 American Cancer Society: Cancer Facts & Figures 2019.
Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2019/cancer-facts-and-figures-2019.pdf.
Accessed April 2019.
2 Jonasch, E., Gao, J., Rathmell, W., Renal cell carcinoma. BMJ.
2014; 349:g4797.
3 Decision Resources Report: Renal Cell Carcinoma. October
2014 (internal data on file).
4 Harshman, L., and Choueiri, T. Targeting the hepatocyte
growth factor/c-Met signaling pathway in renal cell carcinoma. Cancer
J. 2013; 19:316-323.
5 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.
6 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.
7 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.
8 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.
9 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.
Contacts
Investor Contact:
Susan Hubbard
EVP, Public
Affairs and
Investor Relations
Exelixis, Inc.
(650)
837-8194
[email protected]
Media Contact:
Claire McConnaughey
Senior
Manager, Public Affairs
Exelixis, Inc.
(650)
837-7052
[email protected]