POSITIVE CHMP OPINION FOR XTANDI (ENZALUTAMIDE) IN ADVANCED PROSTATE CANCER
Enzalutamide recommended for approval in the European Union (EU) for the
treatment of adult men with metastatic castration-resistant prostate cancer
whose disease has progressed on or after docetaxel therapy
CHERTSEY, England & SAN FRANCISCO, CA -- April 26, 2013
Today, Astellas Pharma Europe Ltd., the European Headquarters of Tokyo-based
Astellas Pharma Inc. (TSE:4503), and Medivation, Inc. (Nasdaq: MDVN) have
received a positive opinion from the European Medicines Agency’s (EMA)
Committee for Medicinal Products for Human Use (CHMP), recommending European
Commission (EC) approval for XTANDI^® (enzalutamide) capsules for the
treatment of adult men with metastatic castration-resistant prostate cancer
whose disease has progressed on or after docetaxel therapy.
Enzalutamide is a novel, once-daily, oral androgen receptor inhibitor. It
inhibits multiple steps in the androgen receptor (AR) signaling pathway, which
has been shown preclinically to decrease cancer cell growth and can induce
cancer cell death (apoptosis). ^ The positive CHMP opinion is based on results
from the phase III AFFIRM study which confirmed that enzalutamide demonstrated
a statistically significant improvement (p<0.0001) in overall survival
compared to placebo, with a median survival of 18.4 months in the enzalutamide
group versus 13.6 months in the placebo group, an advantage of 4.8 months
[hazard ratio (HR) = 0.631]. The study also concluded that enzalutamide was
generally well tolerated by patients and met all secondary endpoints. The most
common adverse reaction leading to treatment discontinuation was seizure,
which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of
the placebo-treated patients.
The CHMP's positive recommendation will be reviewed by the European Commission
(EC), which has authority to approve medicines for the European Union.
Astellas anticipates a final decision from the EC shortly, as this usually
occurs approximately 60 days after a CHMP recommendation.
Professor Johann de Bono, Professor of Experimental Cancer Medicine, Head of
Drug Development Unit, and of the Prostate Cancer Targeted Therapy Group, The
Institute of Cancer Research and Royal Marsden NHS Foundation Trust, comments:
“This is an important development in prostate cancer therapeutics that will
provide a critically important new treatment option for patients with advanced
prostate cancer. Enzalutamide has a major impact on patient survival from this
common disease, and will hopefullybecome a key component of prostate cancer
treatment initially in late stage disease following chemotherapy.”
Important US Label Safety Information for XTANDI
Contraindications- XTANDI can cause fetal harm when administered to a pregnant
woman based on its mechanism of action. XTANDI is not indicated for use in
women. XTANDI is contraindicated in women who are or may become pregnant.
Warnings and Precautions- In the randomized clinical trial, seizure occurred
in 0.9% of patients on XTANDI. No patients on the placebo arm experienced
seizure. Patients experiencing a seizure were permanently discontinued from
therapy. All seizures resolved.
Patients with a history of seizure, taking medications known to decrease the
seizure threshold, or with other risk factors for seizure were excluded from
the clinical trial. Because of the risk of seizure associated with XTANDI use,
patients should be advised of the risk of engaging in any activity where
sudden loss of consciousness could cause serious harm to themselves or others.
Adverse Reactions- The most common adverse drug reactions (≥ 5%) reported in
patients receiving XTANDI in the randomized clinical trial were
asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral
edema, musculoskeletal pain, headache, upper respiratory infection, muscular
weakness, dizziness, insomnia, lower respiratory infection, spinal cord
compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and
hypertension. Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1%
Grade 3-4) and in 6% on placebo (no Grade 3-4). Grade 1-4 elevations in
bilirubin occurred in 3% of XTANDI patients and 2% on placebo. One percent of
XTANDI patients compared to 0.3% on placebo died from infections or sepsis.
Falls or injuries related to falls occurred in 4.6% of XTANDI patients vs 1.3%
on placebo. Falls were not associated with loss of consciousness or seizure.
Fall-related injuries were more severe in XTANDI patients and included
non-pathologic fractures, joint injuries, and hematomas. Grade 1 or 2
hallucinations occurred in 1.6% of XTANDI patients and 0.3% on placebo, with
the majority on opioid-containing medications at the time of the event.
Drug Interactions- Effect of Other Drugs on XTANDI: Administration of strong
CYP2C8 inhibitors can increase the plasma exposure to XTANDI.
Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if
possible. If co-administration of XTANDI cannot be avoided, reduce the dose of
XTANDI. Co-administration of XTANDI with strong or moderate CYP3A4 and CYP2C8
inducers can alter the plasma exposure of XTANDI and should be avoided if
Effect of XTANDI on Other Drugs: XTANDI is a strong CYP3A4 inducer and a
moderate CYP2C9 and CYP2C19 inducer in humans. Avoid CYP3A4, CYP2C9 and
CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the
plasma exposures of these drugs. If XTANDI is co-administered with warfarin
(CYP2C9 substrate), conduct additional INR monitoring.
For Full Prescribing Information, please visit www.XtandiHCP.com.
About Prostate Cancer
Prostate cancer is the most frequently diagnosed cancer among European men and
it is becoming more common. Advanced prostate cancer is defined as cancer that
has spread outside of the prostate to other areas of the body (metastasized).
^ A high number of men with advanced prostate cancer eventually develop a
resistance to first-line treatment, which is called castration-resistant
prostate cancer (CRPC).
Patients with metastatic CRPC currently have few treatment options. There is
an unmet need in this area for new compounds that target the cancer
differently and which may provide alternative therapeutic options for patients
at this late stage of their disease.
XTANDI Mechanism of Action
XTANDI (enzalutamide) is an androgen receptor inhibitor that acts on different
steps in the androgen receptor signaling pathway. XTANDI has been shown to
competitively inhibit androgen binding to androgen receptors and inhibit
androgen receptor nuclear translocation and interaction with DNA. A major
metabolite, N-desmethyl enzalutamide, exhibited similar in vitro activity to
XTANDI. XTANDI decreased proliferation and induced cell death of prostate
cancer cells in vitro, and decreased tumor volume in a mouse prostate cancer
XTANDI^® (enzalutamide) was approved by the U.S. Food and Drug Administration
on August 31, 2012 for the treatment of patients with metastatic
castration-resistant prostate cancer (mCRPC) who have previously received
The phase III AFFIRM trial is a randomized, double-blind, placebo-controlled,
multinational trial evaluating enzalutamide (160 mg/day) versus placebo in
1,199 men with progressive metastatic castration-resistant prostate cancer who
were previously treated with docetaxel-based chemotherapy. Enrollment was
completed in November 2010 and the interim analysis was triggered at 520
events. The median age of study participants was 69 years at baseline.
The AFFIRM study was conducted at sites in the United States, Canada, Europe,
Australia, South America and South Africa.
The primary endpoint of the AFFIRM trial was overall survival. Key secondary
endpoints included time to prostate-specific antigen (PSA) progression,
radiographic progression free survival (rPFS) and time to first
skeletal-related event (SRE).
In the phase III AFFIRM trial, enzalutamide was generally well tolerated. The
most common adverse reactions were hot flushes and headache. Seizure was
reported in 0.9% of enzalutamide-treated patients. Serious adverse events,
adverse events causing patients to stop treatment, and adverse events causing
death were all lower in the enzalutamide group than in the placebo group.
About Astellas Pharma Europe
Astellas Pharma Europe Ltd., located in the UK, is the European Headquarters
of Tokyo-based Astellas Pharma Inc. Astellas is a pharmaceutical company
dedicated to improving the health of people around the world through the
provision of innovative and reliable pharmaceuticals. As a global company,
Astellas is committed to combining outstanding research and development (R&D)
and marketing capabilities to continue to grow in the world pharmaceutical
market. Astellas Pharma Europe Ltd. manages 21 affiliate offices located
across Europe, the Middle East and Africa. In addition, the Company has an R&D
site and three manufacturing plants in Europe. The company employs
approximately 4,300 staff across these regions. For more information about
Astellas Pharma Europe, please visit http://www.astellas.eu
Medivation, Inc. is a biopharmaceutical company focused on the rapid
development of novel therapies to treat serious diseases for which there are
limited treatment options. Medivation aims to transform the treatment of these
diseases and offer hope to critically ill patients and their families. For
more information, please visit us at www.medivation.com.
This press release includes forward-looking statements made pursuant to the
safe harbor provisions of the U.S. federal securities laws, including
statements regarding the potential timing of further regulatory action.
Forward-looking statements involve risks and uncertainties that could cause
actual results to differ significantly from those projected, including risks
detailed in Medivation's filings with the Securities and Exchange Commission,
or SEC, including its annual report on Form 10-K for the year ended December
31, 2012, filed with the SEC on February 28, 2013. You are cautioned not to
place undue reliance on the forward-looking statements, which speak only as of
the date of this release. Medivation disclaims any obligation or undertaking
to update, supplement or revise any forward-looking statements contained in
this press release.
About the Medivation/Astellas Collaboration
In October 2009, Medivation and Astellas entered into a global agreement to
jointly develop and commercialize enzalutamide (formerly MDV3100).The
companies are collaborating on a comprehensive development program that
includes studies to develop enzalutamide across the full spectrum of advanced
prostate cancer. The companies are jointly commercializing enzalutamide in the
United States and Astellas will have responsibility for commercializing
enzalutamide outside the U.S, pending further regulatory approval.
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