ZALTRAP® (Ziv-aflibercept) Receives CHMP Positive Opinion in the European Union for Previously Treated Metastatic Colorectal Cancer

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Monday, November 19, 2012

Sanofi and Regeneron Pharmaceuticals, Inc. 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 trial.

"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 is aflibercept.

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 perforation.

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

  • Patients treated with ZALTRAP® have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events.
  • Monitor patients for signs and symptoms of bleeding.
  • Do not initiate ZALTRAP to patients with severe hemorrhage.
  • Discontinue ZALTRAP in patients who develop severe hemorrhage.
  • GI perforation including fatal GI perforation can occur in patients receiving ZALTRAP.
  • Monitor patients for signs and symptoms of GI perforation.
  • Discontinue ZALTRAP in patients who experience GI perforation.
  • Discontinue ZALTRAP in patients with compromised wound healing.
  • Suspend ZALTRAP for at least 4 weeks prior to elective surgery
  • Do not initiate/resume ZALTRAP until at least 4 weeks after surgery and surgical wound is fully healed.
  • Fistula 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.
  • An increased risk of Grade 3-4 hypertension has been observed in patients receiving ZALTRAP.
  • Monitor blood pressure every two weeks or more frequently and treat with appropriate anti-hypertensive therapy during treatment with ZALTRAP.
  • Temporarily suspend ZALTRAP until hypertension is controlled, and reduce ZALTRAP dose to 2 mg/kg for subsequent cycles.
  • Discontinue ZALTRAP in patients with hypertensive crisis.
  • Arterial 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.
  • Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) occurred more frequently in patients treated with ZALTRAP.
  • Suspend ZALTRAP when proteinuria greater than or equal to 2 grams/24 hours and resume ZALTRAP when proteinuria <2 grams/24 hours.
  • If recurrent, suspend until proteinuria <2 grams/24hours and then reduce ZALTRAP dose to 2 mg/kg.
  • Discontinue ZALTRAP if nephrotic syndrome or TMA develops.
  • A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) occurred in patients receiving ZALTRAP.
  • Delay administration of ZALTRAP/FOLFIRI until neutrophil count is greater than or equal to1.5 x 109/L.
  • Incidence of severe diarrhea and dehydration is increased in patients treated with ZALTRAP/FOLFIRI.
  • The incidence of diarrhea is increased in patients greater than or equal to 65 years of age. Monitor closely.
  • Discontinue ZALTRAP in patients who develop reversible posterior leukoencephalopathy syndrome.

ADVERSE REACTIONS

  • 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 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.
  • 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, leukopenia, stomatitis, fatigue, proteinuria, and asthenia.
  • Infections 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.
  • In 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 placebo/FOLFIRI.

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 percent.

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.

About Sanofi

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 and in New York.

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 at www.regeneron.com.

Contact
Sanofi
Marisol Peron
+ (33) 1 53 77 45 02
marisol.peron@sanofi.com
Regeneron
Peter Dworkin
1 (914) 847-7640
peter.dworkin@regeneron.com

Source: Regeneron Pharmaceuticals, Inc.

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