Exelixis, Inc. (NASDAQ: EXEL) today announced that Takeda
Pharmaceutical Company Limited (Takeda), its partner responsible
for the clinical development and commercialization of CABOMETYX®
(cabozantinib) in Japan, received approval from the Japanese
Ministry of Health, Labor and Welfare to manufacture and market
CABOMETYX as a treatment for patients with curatively unresectable
or metastatic renal cell carcinoma (RCC).
The approval 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.
“Nearly 17,000 new cases of renal cell carcinoma are estimated
to be diagnosed in Japan annually, and since many cases are
diagnosed at an advanced stage, the prognosis remains poor for
these patients,” said Michael M. Morrissey, Ph.D., President and
Chief Executive Officer of Exelixis. “The approval of CABOMETYX is
an important milestone for people with kidney cancer in Japan, and
we are excited to continue our collaboration with Takeda as we work
to bring more options to patients who need novel therapies.”
Per the terms of Exelixis and Takeda’s collaboration and license
agreement, Exelixis is eligible to receive a $31 million milestone
payment from Takeda upon the first commercial sale of CABOMETYX for
unresectable or metastatic RCC. In January 2020, Takeda applied for
approval to manufacture and sell cabozantinib as a treatment for
patients with unresectable hepatocellular carcinoma (HCC) that had
progressed after prior systemic therapy in Japan, which triggered a
$10 million milestone payment. Exelixis will also be eligible to
receive further development, regulatory and first-sale milestone
payments of up to $45 million from Takeda related both to
previously treated and untreated RCC and previously treated HCC.
Exelixis continues to be eligible to receive additional
development, regulatory and first-sale milestones for potential
future cabozantinib indications and 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.
About RCC The American Cancer Society’s 2020 statistics
cite kidney cancer as among the top ten most commonly diagnosed
forms of cancer in the U.S. and estimate nearly 74,000 cases will
be diagnosed this year.1 The most common type of kidney cancer in
adults is RCC, which accounts for about 90% of cases.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%, with no identified cure.1
Approximately 32,000 patients in the U.S. and 71,000 worldwide will
require systemic treatment for advanced kidney cancer in 2020, with
an estimated 15,000 patients in the U.S. in need of a first-line
treatment.3
About 70% of RCC cases are known as “clear cell” carcinomas,
based on histology.2 The majority of clear cell RCC tumors have
below-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 Pharmaceutical
Company Limited for the commercialization and further clinical
development of cabozantinib for all future indications in
Japan.
Important Safety Information
Warnings and Precautions
Hemorrhage: Severe and fatal hemorrhages occurred with
CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5%
in CABOMETYX patients in RCC and HCC studies. 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: Gastrointestinal (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 Grade 4 fistula
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 3 weeks prior to scheduled dental
surgery or invasive dental procedures, if possible. Withhold
CABOMETYX for development of ONJ until complete resolution.
Impaired Wound Healing: Wound complications occurred with
CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to
elective surgery. Do not administer CABOMETYX for at least 2 weeks
after major surgery and until adequate wound healing is observed.
The safety of resumption of CABOMETYX after resolution of wound
healing complications has not been established.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS):
RPLS, a syndrome of subcortical vasogenic edema diagnosed by
characteristic findings 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.
Drug Interactions
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.
USE IN SPECIFIC POPULATIONS
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 system
genetics, 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 commercially available
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 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 Statements This press release contains
forward-looking statements, including, without limitation,
statements related to: the number of new cases of RCC estimated to
be diagnosed in Japan annually; the therapeutic potential of
CABOMETYX for patients with kidney cancer in Japan; the potential
for the collaboration between Exelixis and Takeda to bring more
options to patients who need novel therapies; Exelixis’ eligibility
to receive a $31 million milestone payment upon the first
commercial sale of CABOMETYX for unresectable or metastatic RCC;
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: the degree of market acceptance of CABOMETYX in
Japan, and Takeda’s ability to obtain or maintain coverage and
reimbursement for this product; Exelixis’ dependence on its
relationship with Takeda, including Takeda’s investment in the
resources necessary to successfully commercialize CABOMETYX in
Japan; Exelixis’ and Takeda’s continuing compliance with applicable
legal and regulatory requirements; Exelixis’ ability to protect its
intellectual property rights; Exelixis’ dependence on third-party
vendors for the manufacture and supply of cabozantinib; market
competition, including the potential for competitors to obtain
approval for generic versions of CABOMETYX; changes in economic and
business conditions; and other factors affecting the ability of
Exelixis and its commercial programs and partnerships discussed
under the caption “Risk Factors” in Exelixis’ Annual Report on Form
10-K filed with the Securities and Exchange Commission (SEC) on
February 25, 2020, 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, except as required
by law.
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 2020.
Available at:
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf.
Accessed March 2020. 2 American Cancer Society: What is Kidney
Cancer? Available at:
https://www.cancer.org/cancer/kidney-cancer/about/what-is-kidney-cancer.html.
Accessed March 2020. 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.
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Investors Contact: Susan Hubbard EVP, Public Affairs and
Investor Relations Exelixis, Inc. (650) 837-8194
shubbard@exelixis.com
Media Contact: Lindsay Treadway Senior Director, Public
Affairs and Advocacy Relations Exelixis, Inc. (650) 837-7522
ltreadway@exelixis.com
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