– FDA assigns Prescription Drug User Fee Act
action date of February 15, 2018 –
Exelixis, Inc. (NASDAQ:EXEL) today announced that the U.S. Food
and Drug Administration (FDA) has determined the company’s
supplemental New Drug Application (sNDA) for CABOMETYX®
(cabozantinib) for patients with previously untreated advanced
renal cell carcinoma (RCC) to be sufficiently complete to permit a
substantive review. The FDA granted Priority Review of the filing
and assigned a Prescription Drug User Fee Act (PDUFA) action date
of February 15, 2018.
“The acceptance of the sNDA filing with a Priority Review is an
important regulatory milestone for CABOMETYX and for our mission to
improve treatment outcomes for patients with cancer,” said Gisela
Schwab, M.D., President, Product Development and Medical Affairs
and Chief Medical Officer, Exelixis. “We look forward to working
with the FDA as they review the application in our effort to offer
CABOMETYX to patients with previously untreated metastatic RCC who
are in need of new treatment options.”
The sNDA is based on data from CABOSUN, a randomized phase 2
trial conducted by The Alliance for Clinical Trials in Oncology as
part of Exelixis’ collaboration with the National Cancer
Institute’s Cancer Therapy Evaluation Program (NCI-CTEP).
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. CABOMETYX
was previously approved by the FDA on April 25, 2016 for the
treatment of patients with advanced RCC who have received prior
anti-angiogenic therapy. The approval was based on results from the
phase 3 METEOR trial, which demonstrated that CABOMETYX provided a
statistically significant and clinically meaningful improvement in
overall survival, progression-free survival (PFS), and objective
response rate as compared with everolimus in this patient
population.
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 CABOSUN 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. CABOSUN was conducted by The Alliance for
Clinical Trials in Oncology as part of Exelixis’ collaboration with
the NCI-CTEP. 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 and objective response rate. 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 2017 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.5 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.6
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.7,8 These proteins promote tumor
angiogenesis (blood vessel growth), growth, invasiveness and
metastasis.9-12 MET and AXL may provide escape pathways that drive
resistance to VEGF receptor inhibitors.7,8
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. Ipsen also submitted to
European Medicines Agency (EMA) the regulatory dossier for
cabozantinib as a treatment for first-line advanced RCC in the
European Union on August 28, 2017; on September 8, 2017, Ipsen
announced that the EMA validated the application.
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 previously
untreated advanced RCC.
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 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 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 Disclaimer
This press release contains forward-looking statements,
including, without limitation, statements related to: the impact of
the FDA’s grant of Priority Review for Exelixis’ sNDA for CABOMETYX
as a treatment for patients with previously untreated advanced
renal cell carcinoma on Exelixis’ ability to improve treatment
outcomes for patients with cancer; Exelixis’ plans to work with the
FDA during the regulatory review process; 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 “mission,” “look
forward,” “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: risks and
uncertainties related to regulatory review and approval processes
and Exelixis’ compliance with applicable legal and regulatory
requirements; risks related to the potential failure of
cabozantinib to demonstrate safety and efficacy in clinical
testing; Exelixis’ ability to conduct clinical trials of
cabozantinib sufficient to achieve a positive completion; 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
- 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.
- 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.
- American Cancer Society. Cancer Facts
& Figures 2017. Atlanta: American Cancer Society; 2017.
- Jonasch, E., Gao, J., Rathmell, W.
Renal cell carcinoma. BMJ. 2014; 349:g4797.
- Ko, J., Choueiri, T., et al. First-,
second- third-line therapy for mRCC: benchmarks for trial design
from the IMDC. Br J Cancer. 2014; 110:1917-1922.
- Decision Resources Report: Renal Cell
Carcinoma. October 2014 (internal data on file).
- Harshman, L., and Choueiri, T.
Targeting the hepatocyte growth factor/c-Met signaling pathway in
renal cell carcinoma. Cancer J. 2013; 19:316-323.
- Rankin, et al. Direct regulation of
GAS6/AXL signaling by HIF promotes renal metastasis through SRC and
MET. Proc Natl Acad Sci U S A. 2014; 111:13373-13378.
- 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.
- 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.
- 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.
- 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:Exelixis, Inc.Susan Hubbard, 650-837-8194EVP,
Public Affairs and Investor
Relationsshubbard@exelixis.comorMedia:Exelixis, Inc.Lindsay
Treadway, 650-837-7522Director, Public Affairs and Advocacy
Relationsltreadway@exelixis.com
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