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Exelixis Announces U.S. FDA Grants Priority Review for CABOMETYX® (Cabozantinib) as a Treatment for Previously Untreated Advanced Renal Cell Carcinoma

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– 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

  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 2017. Atlanta:
    American Cancer Society; 2017.
  4. Jonasch, E., Gao, J., Rathmell, W. Renal cell carcinoma. BMJ.
    2014; 349:g4797.
  5. 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.
  6. Decision Resources Report: Renal Cell Carcinoma. October 2014
    (internal data on file).
  7. Harshman, L., and Choueiri, T. Targeting the hepatocyte growth
    factor/c-Met signaling pathway in renal cell carcinoma. Cancer J.
    2013; 19:316-323.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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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