ZALTRAP® (ziv-aflibercept) Receives CHMP Positive Opinion in the European
Union for Previously Treated Metastatic Colorectal Cancer
PARIS and TARRYTOWN, N.Y., Nov. 16, 2012
PARIS and TARRYTOWN, N.Y., Nov. 16, 2012 /PRNewswire/ --Sanofi (EURONEXT: SAN
and NYSE: SNY) and Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today
announced that the Committee for Medicinal Products for Human Use (CHMP) of
the European Medicines Agency (EMA) adopted a positive opinion and recommended
the granting of marketing authorization for ZALTRAP^® (ziv-aflibercept)
Injection for Intravenous Infusion in combination with
irinotecan/5-fluorouracil/folinic acid (FOLFIRI) chemotherapy in adults with
metastatic colorectal cancer (mCRC) that is resistant to or has progressed
after an oxaliplatin-containing regimen.
The European Commission now needs to ratify the positive opinion from CHMP to
grant marketing authorization of ZALTRAP in all 27 European Union member
countries. A decision is expected from the European Commission in the first
quarter of 2013. The CHMP opinion was based on data from the pivotal VELOUR
"We are pleased that CHMP has supported our ZALTRAP application. This brings
us one step closer to bringing this novel treatment with a proven survival
benefit to colorectal cancer patients in Europe," said Debasish Roychowdhury,
M.D., Senior Vice President and Head, Sanofi Oncology.
"It is gratifying to see the years of effort that went into designing and
developing the angiogenesis inhibitor ZALTRAP translate into a clinical
benefit for patients with metastatic colorectal cancer that has progressed on
prior therapy," said George D. Yancopoulos, M.D., Ph.D., Chief Scientific
Officer of Regeneron and President of Regeneron Laboratories. "ZALTRAP is the
only agent that has demonstrated a statistically significant improvement in
overall survival in combination with FOLFIRI versus FOLFIRI alone in patients
who progressed on a prior oxaliplatin-containing regimen."
ZALTRAP received approval from the U.S. Food and Drug Administration (FDA) in
August 2012 after Priority Review and marketing authorization applications for
ZALTRAP are under review with other regulatory agencies worldwide. In the
U.S. ZALTRAP is approved with the U.S. proper name ziv-aflibercept for use in
combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI), in patients
with metastatic colorectal cancer (mCRC) that is resistant to or has
progressed following an oxaliplatin-containing regimen. The World Health
Organization (WHO) recommended international non-proprietary name for ZALTRAP
About the VELOUR Phase 3 Study
The VELOUR trial was a Phase 3 multinational, randomized, double-blind trial
comparing FOLFIRI in combination with either ZALTRAP or placebo in the
treatment of patients with mCRC. The study randomized 1,226 patients with
mCRC who previously had been treated with an oxaliplatin-containing regimen.
Twenty-eight percent of patients in the study received prior bevacizumab
therapy. The primary endpoint was overall survival. Secondary endpoints
included progression-free survival, overall response rate, and safety.
The VELOUR trial showed that in patients previously treated with an
oxaliplatin-containing regimen, adding ZALTRAP to FOLFIRI significantly
improved median survival from 12.06 months to 13.50 months (HR=0.817 [95% CI
0.714 to 0.935]; p=0.0032), an 18 percent relative risk reduction. A
significant improvement in progression-free survival from 4.67 months to 6.90
months (HR=0.758 [95% CI 0.661 to 0.869]; p=0.00007), a 24 percent relative
risk reduction, was also observed. The overall response rate in the ZALTRAP
plus FOLFIRI arm was 19.8% vs. 11.1% for FOLFIRI (p=0.0001).
The most common adverse reactions (all grades, greater than or equal to 20%
incidence) reported at a higher incidence (2% or greater between-arm
difference) in the ZALTRAP-FOLFIRI arm, in order of decreasing frequency, were
leucopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis,
fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased,
decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine
increased, and headache. The most common Grade 3-4 adverse reactions (greater
than or equal to 5%) reported at a higher incidence (2% or greater between-arm
difference) in the ZALTRAP-FOLFIRI arm, in order of decreasing frequency, were
neutropenia, diarrhea, hypertension, leucopenia, stomatitis, fatigue,
proteinuria, and asthenia.
About ZALTRAP^® (ziv-aflibercept) Injection for Intravenous Infusion
ZALTRAP is recombinant fusion protein that binds the angiogenic proteins
Vascular Endothelial Growth Factor-A (VEGF-A), VEGF-B and placental growth
factor (PIGF). VEGF-A is one of the mediators contributing to angiogenesis.
VEGF-B and PlGF, related growth factors in the VEGF family, may contribute to
tumor angiogenesis as well. In the U.S., ZALTRAP is a registered trademark of
Regeneron Pharmaceuticals, Inc.
Important Safety Information for ZALTRAP from the U.S. Prescribing Information
WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, COMPROMISED WOUND HEALING
Severe and sometimes fatal hemorrhage, including gastrointestinal (GI)
hemorrhage, has been reported in the patients who have received ZALTRAP in
combination with FOLFIRI. Monitor patients for signs and symptoms of GI
bleeding and other severe bleeding. Do not administer ZALTRAP to patients
with severe hemorrhage.
GI perforation including fatal GI perforation can occur in patients receiving
ZALTRAP. Discontinue ZALTRAP therapy in patients who experience GI
Severe compromised wound healing can occur in patients receiving
ZALTRAP/FOLFIRI. Discontinue ZALTRAP in patients with compromised wound
healing. Suspend ZALTRAP for at least 4 weeks prior to elective surgery, and
do not resume ZALTRAP for at least 4 weeks following major surgery and until
the surgical wound is fully healed.
WARNINGS AND PRECAUTIONS
oPatients treated with ZALTRAP^® have an increased risk of hemorrhage,
including severe and sometimes fatal hemorrhagic events.
oMonitor patients for signs and symptoms of bleeding.
oDo not initiate ZALTRAP to patients with severe hemorrhage.
oDiscontinue ZALTRAP in patients who develop severe hemorrhage.
oGI perforation including fatal GI perforation can occur in patients
oMonitor patients for signs and symptoms of GI perforation.
oDiscontinue ZALTRAP in patients who experience GI perforation.
oDiscontinue ZALTRAP in patients with compromised wound healing.
oSuspend ZALTRAP for at least 4 weeks prior to elective surgery
oDo not initiate/resume ZALTRAP until at least 4 weeks after surgery
and surgical wound is fully healed.
oFistula formation involving GI and non-GI sites occurs at a higher
incidence in patients treated with ZALTRAP. Discontinue ZALTRAP therapy
in patients who develop fistula.
oAn increased risk of Grade 3-4 hypertension has been observed in patients
oMonitor blood pressure every two weeks or more frequently and treat
with appropriate anti-hypertensive therapy during treatment with
oTemporarily suspend ZALTRAP until hypertension is controlled, and
reduce ZALTRAP dose to 2 mg/kg for subsequent cycles.
oDiscontinue ZALTRAP in patients with hypertensive crisis.
oArterial thromboembolic events (ATE), including transient ischemic attack,
cerebrovascular accident, and angina pectoris, occurred more frequently in
patients who have received ZALTRAP. Discontinue ZALTRAP in patients who
experience an ATE.
oSevere proteinuria, nephrotic syndrome, and thrombotic microangiopathy
(TMA) occurred more frequently in patients treated with ZALTRAP.
oSuspend ZALTRAP when proteinuria greater than or equal to 2 grams/24
hours and resume ZALTRAP when proteinuria <2 grams/24 hours.
oIf recurrent, suspend until proteinuria <2 grams/24hours and then
reduce ZALTRAP dose to 2 mg/kg.
oDiscontinue ZALTRAP if nephrotic syndrome or TMA develops.
oA higher incidence of neutropenic complications (febrile neutropenia and
neutropenic infection) occurred in patients receiving ZALTRAP.
oDelay administration of ZALTRAP/FOLFIRI until neutrophil count is
greater than or equal to1.5 x 10^9/L.
oIncidence of severe diarrhea and dehydration is increased in patients
treated with ZALTRAP/FOLFIRI.
oThe incidence of diarrhea is increased in patients greater than or
equal to 65 years of age. Monitor closely.
oDiscontinue ZALTRAP in patients who develop reversible posterior
oThe most common adverse reactions (all grades, greater than or equal to
20% incidence) reported at a higher incidence (2% or greater between-arm
difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency,
were leukopenia, diarrhea, neutropenia, proteinuria, AST increased,
stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight
decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum
creatinine increased, and headache.
oThe most common Grade 3-4 adverse reactions (greater than or equal to 5%)
reported at a higher incidence (2% or greater between-arm difference) in
the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were
neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue,
proteinuria, and asthenia.
oInfections occurred at a higher frequency in patients receiving
ZALTRAP/FOLFIRI (46%, all grades; 12%, Grade 3-4) than in patients
receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3-4), including
urinary tract infection, nasopharyngitis, upper respiratory tract
infection, pneumonia, catheter site infection, and tooth infection.
oIn patients with mCRC, venous thromboembolic events (VTE), consisting
primarily of deep venous thrombosis and pulmonary embolism, occurred in 9%
of patients treated with ZALTRAP/FOLFIRI and 7% of patients treated with
Please click here for full U.S. Prescribing Information for ZALTRAP
(ziv-aflibercept) Injection for Intravenous Infusion, including Boxed WARNING,
and visit: www.ZALTRAP.com
About Colorectal Cancer
Worldwide, colorectal cancer is the third most commonly diagnosed cancer in
males and the second most in females, with more than 1.2 million new cases
diagnosed in 2008. One of the deadliest cancers, colorectal cancer was
responsible for more than 600,000 deaths globally in 2008 alone. According to
the American Cancer Society, approximately 60 percent of colorectal cancer
cases are diagnosed at the locally advanced or metastatic stage. Although
survival for early stage disease is relatively high, once colorectal cancer
metastasizes to distant organs, five-year survival is estimated to be 12
About Sanofi Oncology
Based in Cambridge, Massachusetts, USA and Vitry, France, Sanofi Oncology is
dedicated to translating science into effective therapeutics that address
unmet medical needs for cancer and organ transplant patients. Starting with a
deep understanding of the disease and the patient, Sanofi Oncology employs
innovative approaches to drug discovery and clinical development, with the
ultimate goal of bringing the right medicines to the right patients to help
them live healthier and longer lives. We believe in the value of partnerships
that combine our internal scientific expertise with that of industry and
academic experts. Our portfolio includes 11 marketed products and more than
15 investigational compounds in clinical development, including small
molecules and biological agents.
Sanofi, a global and diversified healthcare leader, discovers, develops and
distributes therapeutic solutions focused on patients' needs. Sanofi has core
strengths in the field of healthcare with seven growth platforms: diabetes
solutions, human vaccines, innovative drugs, consumer healthcare, emerging
markets, animal health and the new Genzyme. Sanofi is listed in Paris
(EURONEXT: SAN) and in New York (NYSE: SNY).
About Regeneron Pharmaceuticals, Inc.
Regeneron is a fully integrated biopharmaceutical company that discovers,
invents, develops, manufactures, and commercializes medicines for the
treatment of serious medical conditions. Regeneron markets three products in
the United States, EYLEA^® (aflibercept) Injection, ZALTRAP^®
(ziv-aflibercept) Injection for Intravenous Infusion, and ARCALYST^®
(rilonacept) Injection for Subcutaneous Use; ZALTRAP is co-commercialized with
Sanofi. Phase 3 studies are in progress with EYLEA in two additional
indications and with product candidates sarilumab and REGN727. Regeneron has
active research and development programs in many disease areas, including
ophthalmology, inflammation, cancer, and hypercholesterolemia. Additional
information and recent news releases are available on the Regeneron web site
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and therapeutic applications of Regeneron's products, product candidates and
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whether as a result of new information, future events, or otherwise, unless
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Media Relations Investor Relations
Marisol Peron Sebastien Martel
Tel. : + (33) 1 53 77 45 02 Tel. : + (33) 1 53 77 45 45
Oncology Division Communications
Tel: 1 (617) 768-1993; Mobile 1(781) 572-1147
Media Relations Investor Relations
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SOURCE Regeneron Pharmaceuticals, Inc.
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