Sanofi and Regeneron Announce New ZALTRAP (ziv-aflibercept) Analyses in Previously Treated Metastatic Colorectal Cancer To Be Presented at Upcoming ASCO GI Symposium
Bridgewater, NJ and Tarrytown, NY – January 22, 2013 – Sanofi US and Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced the presentation of three ZALTRAP® (ziv-aflibercept) Injection for Intravenous Infusion abstracts on January 26, 2013 during the 2013 American Society of Clinical Oncology Gastrointestinal Cancers Symposium in San Francisco, CA.
Key abstracts to be presented during General Poster Session C from 7:00-7:55 AM and Noon – 2:00 PM, Moscone West Building, 800 Howard Street, are:
• Abstract #451: Analysis of overall survival and safety during the course of the phase III VELOUR trial comparing FOLFIRI and ziv-aflibercept or placebo in patients with mCRC that progressed on prior oxaliplatin treatment ( C7 ) Paul Ruff - University of Witwatersrand Faculty of Health Sciences, City, Country
• Abstract # 465: North American subgroup results from VELOUR: ziv-aflibercept versus placebo plus FOLFIRI in mCRC that is resistant to or has progressed after an oxaliplatin-containing regimen (C21) Edith P. Mitchell - Kimmel Cancer Center of Thomas Jefferson University, Philadelphia, PA, USA
• Abstract #469: On-treatment progression-free survival analysis of ziv-aflibercept –FOLFIRI treatment within 28 days of progression in mCRC: Updated efficacy result from the VELOUR study ( C25 )
Presenter: David Raymond Ferry, New Cross Hospital, Wolverhampton, UK
About ZALTRAP® (ziv-aflibercept) Injection for Intravenous
ZALTRAP is indicated for use in combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen. ZALTRAP was approved by the U.S. Food and Drug Administration on August 3, 2012. ZALTRAP received a CHMP positive opinion for marketing authorization in the European Union in November 2012, and marketing authorization applications for ZALTRAP are under review by the European Medicines Agency and other regulatory agencies worldwide.
ZALTRAP is a recombinant fusion protein, which acts as a soluble receptor that binds to Vascular Endothelial Growth Factor-A (VEGF-A), VEGF-B and placental growth factor (PIGF). Inhibition of these factors can result in decreased neovascularization and decreased vascular permeability. ZALTRAP is formulated as a hyperosomotic solution and must be diluted prior to intravenous administration. ZALTRAP is intended for intravenous infusion only and is not to be administered by other routes. 2/6
ZALTRAP was discovered by Regeneron Pharmaceuticals and co-developed with Sanofi. Sanofi and Regeneron co-commercialize ZALTRAP in the United States. In the US, ZALTRAP is a registered trademark of Regeneron Pharmaceuticals, Inc.
Important Safety Information for ZALTRAP®
WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, COMPROMISED
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
WARNINGS AND PRECAUTIONS
• Patients treated with ZALTRAP have an increased risk of
hemorrhage, including severe and sometimes fatal hemorrhagic
events. o Bleeding/hemorrhage (all grades) occurred in 38% of
ZALTRAP/FOLFIRI patients vs. 19% of placebo/FOLFIRI patients. Grade
3-4 hemorrhagic events, including GI hemorrhage, hematuria, and
post-procedural hemorrhage, occurred in 3% of ZALTRAP/FOLFIRI
patients vs. 1% of placebo/FOLFIRI patients. Severe intracranial
hemorrhage and pulmonary hemorrhage/hemoptysis including fatal
events have occurred in patients receiving ZALTRAP.
o Monitor patients for signs and symptoms of bleeding. Do not initiate ZALTRAP in patients with severe hemorrhage. Discontinue ZALTRAP in patients who develop severe hemorrhage.
• GI perforation including fatal GI perforation can occur
in patients receiving ZALTRAP. o Across three clinical trials
(colorectal, pancreatic, and lung cancer), GI perforation (all
grades/Grade 3-4) occurred in 0.8% /0.8% of Zaltrap patients and
0.3% /0.2% for placebo patients.
o Monitor patients for signs and symptoms of GI perforation. Discontinue ZALTRAP in patients who experience GI perforation.
• ZALTRAP impairs wound healing in animal models. Grade 3
compromised wound healing occurred in 2 patients (0.3%) treated
with ZALTRAP/FOLFIRI and none of the patients treated with
placebo/FOLFIRI. o Discontinue ZALTRAP in patients with compromised
o Suspend ZALTRAP for at least 4 weeks prior to elective surgery and do not initiate/resume ZALTRAP until at least 4 weeks after major surgery and surgical wound is fully healed.
o For minor surgery such as central venous access port placement, biopsy, and tooth extraction, ZALTRAP may be initiated/resumed once the surgical wound is fully healed.
• Fistula formation involving GI and non-GI sites occurs at a higher incidence in patients treated with ZALTRAP. Fistulas (anal, enterovesical, enterocutaneous, colovaginal, intestinal sites) were reported in 1.5% (9/611) of ZALTRAP/FOLFIRI treated patients and 0.5% (3/605) of placebo/FOLFIRI patients. Grade 3 GI fistula formation occurred in 2 patients treated with Zaltrap (0.3%) and 1 placebo-treated patient (0.2%). Discontinue ZALTRAP therapy in patients who develop fistula.
• An increased risk of Grade 3-4 hypertension has been
observed in patients receiving ZALTRAP. o There is no clinical
trial experience administering ZALTRAP to patients with NYHA class
III or IV heart failure. In patients with mCRC, Grade 3
hypertension (defined as requiring adjustment in existing
anti-hypertensive therapy or treatment with more than one drug) was
reported in 1.5% of patients treated with placebo/FOLFIRI and 19%
treated with ZALTRAP/FOLFIRI. Grade 4 hypertension (hypertensive
crisis) was reported in 1 patient (0.2%) treated with
ZALTRAP/FOLFIRI. Of patients treated with ZALTRAP/FOLFIRI who
developed Grade 3-4 hypertension, 54% had onset during the first
two cycles of treatment.
o Monitor blood pressure at least every two weeks, treat with appropriate anti-hypertensive therapy, and continue monitoring blood pressure regularly during ZALTRAP treatment. 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 or hypertensive encephalopathy.
• Arterial thromboembolic events (ATE), including transient ischemic attack, cerebrovascular accident, and angina pectoris, occurred more frequently in patients who have received ZALTRAP. ATE occurred in 2.6% of ZALTRAP/FOLFIRI patients and 1.7% of placebo/FOLFIRI patients. Grade 3-4 events occurred in 11 patients (1.8%) treated with ZALTRAP/FOLFIRI and 4 patients (0.7%) treated with placebo/FOLFIRI. Discontinue ZALTRAP in patients who experience an ATE.
• Severe proteinuria, nephrotic syndrome, and thrombotic
microangiopathy (TMA) occurred more frequently in patients treated
with ZALTRAP. o Proteinuria was reported in 62% of ZALTRAP/FOLFIRI
patients compared to 41% of placebo/FOLFIRI patients. Grade 3-4
proteinuria occurred in 8% of ZALTRAP/FOLFIRI patients compared to
1% of placebo/FOLFIRI patients. Nephrotic syndrome occurred in 2
patients (0.5%) treated with ZALTRAP/FOLFIRI compared to none of
the patients treated with placebo/FOLFIRI. TMA was reported in 3 of
2258 patients with cancer enrolled across completed studies.
o Monitor proteinuria by urine dipstick analysis and urinary protein creatinine ratio (UPCR) for the development or worsening of proteinuria. Obtain a 24-hour urine collection in patients with a UPCR ?1.
o Suspend ZALTRAP when proteinuria ≥2 grams/24 hours and resume ZALTRAP when proteinuria <2 grams/24 hours.
o If recurrent, suspend until proteinuria <2 grams/24hours and then reduce ZALTRAP dose to 2 mg/kg.
o Discontinue ZALTRAP if nephrotic syndrome or TMA develops.
• A higher incidence of neutropenic complications (febrile
neutropenia and neutropenic infection) occurred in patients
receiving ZALTRAP. o Grade 3-4 neutropenia occurred in 37% of
ZALTRAP/FOLFIRI patients compared to 30% of placebo/FOLFIRI
patients. Grade 3-4 febrile neutropenia occurred in 4% of
ZALTRAP/FOLFIRI patients compared to 2% of placebo/FOLFIRI
patients. Grade 3-4 neutropenic infection/sepsis occurred in 1.5%
of ZALTRAP/FOLFIRI patients compared to 1.2% of placebo/FOLFIRI
o Monitor CBC with differential count at baseline and prior to initiation of each cycle of ZALTRAP. Delay administration of ZALTRAP/FOLFIRI until neutrophil count is ≥1.5 x 109/L.
• Incidence of severe diarrhea and dehydration is increased
in patients treated with ZALTRAP/FOLFIRI. o Grade 3-4 diarrhea was
reported in 19% of ZALTRAP/FOLFIRI patients compared to 8% of
placebo/FOLFIRI patients. Grade 3-4 dehydration was reported in 4%
of ZALTRAP/FOLFIRI patients compared to 1% of placebo/FOLFIRI
o The incidence of diarrhea is increased in patients ≥65 years of age compared to patients ?65 years of age. Monitor closely.
• RPLS (also known as posterior reversible encephalopathy syndrome) was reported in 0.5% of 3795 patients treated with ZALTRAP monotherapy or in combination with chemotherapy. Confirm diagnosis of RPLS with MRI and discontinue ZALTRAP in patients who develop RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae or death.
• The most common adverse reactions (all grades, ≥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 (≥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.
PREGNANCY AND NURSING MOTHERS
• ZALTRAP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Females and males of reproductive potential should use highly effective contraception during and up to a minimum of 3 months after the last dose of treatment.
• It is not known whether ZALTRAP is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Please click here for full Prescribing Information for ZALTRAP® (ziv-aflibercept) Injection for Intravenous Infusion, including Boxed WARNING, and visit: www.ZALTRAP.com or call 1-855-ZALTRAP.
About Colorectal Cancer
According to the American Cancer Society, more than 143,000 new cases of colorectal cancer were diagnosed in 2012, and more than 51,000 people died from it. 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.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.
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, rare diseases, consumer healthcare, emerging markets and animal health. Sanofi is listed in Paris (EURONEXT: SAN) and in New York (NYSE: SNY). Sanofi is the holding company of a consolidated group of subsidiaries and operates in the United States as Sanofi US. For more information on Sanofi US, please visit http://www.sanofi.us or call 1-800-981-2491.
About Regeneron Pharmaceuticals
Regeneron is a leading science-based biopharmaceutical company based in Tarrytown, New York that discovers, invents, develops, manufactures, and commercializes medicines for the treatment of serious medical conditions. Regeneron markets medicines for eye diseases, colorectal cancer, and a rare inflammatory condition and has product candidates in development in other areas of high unmet medical need, including hypercholesterolemia, rheumatoid arthritis, and asthma. For additional information about the company, please visit www.regeneron.com.
Sanofi Forward Looking Statements
This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, as amended. Forward-looking statements are statements that are not historical facts. These statements include projections and estimates and their underlying assumptions, statements regarding plans, objectives, intentions and expectations with respect to future financial results, events, operations, services, product development and potential, and statements regarding future performance. Forward-looking statements are generally identified by the words “expects”, “anticipates”, “believes”, “intends”, “estimates”, “plans” and similar expressions. Although Sanofi’s management believes that the expectations reflected in such forward-looking statements are reasonable, investors are cautioned that forward-looking information and statements are subject to various risks and uncertainties, many of which are difficult to predict and generally beyond the control of Sanofi, that could cause actual results and developments to differ materially from those expressed in, or implied or projected by, the forward-looking information and statements. These risks and uncertainties include among other things, the uncertainties inherent in research and development, future clinical data and analysis, including post marketing, decisions by regulatory authorities, such as the FDA or the EMA, regarding whether and when to approve any drug, device or biological application that may be filed for any such product candidates as well as their decisions regarding labelling and other matters that could affect the availability or commercial potential of such product candidates, the absence of guarantee that the product candidates if approved will be commercially successful, the future approval and commercial success of therapeutic alternatives, the Group’s ability to benefit from external growth opportunities, trends in exchange rates and prevailing interest rates, the impact of cost containment policies and subsequent changes thereto, the average number of shares outstanding as well as those discussed or identified in the public filings with the SEC and the AMF made by Sanofi, including those listed under “Risk Factors” and “Cautionary Statement Regarding Forward-Looking Statements” in Sanofi’s annual report on Form 20-F for the year ended December 31, 2011. Other than as required by applicable law, Sanofi does not undertake any obligation to update or revise any forward-looking information or statements.
Regeneron Forward-Looking Statements
This news release includes forward-looking statements that involve risks and uncertainties relating to future events and the future performance of Regeneron, and actual events or results may differ materially from these forward-looking statements. These statements concern, and these risks and uncertainties include, among others, the nature, timing, and possible success and therapeutic applications of Regeneron’s products, product candidates and research and clinical programs now underway or planned, including without limitation ZALTRAP® (ziv-aflibercept), unforeseen safety issues resulting from the administration of products and product candidates in patients, the likelihood and timing of possible regulatory approval and commercial launch of Regeneron’s late-stage product candidates, determinations by regulatory and administrative governmental authorities which may delay or restrict Regeneron’s ability to continue to develop or commercialize Regeneron’s products and drug candidates, competing drugs that may be superior to Regeneron’s products and drug candidates, uncertainty of market acceptance of Regeneron’s product and drug candidates, unanticipated expenses, the costs of developing, producing, and selling products, the potential for any license or collaboration agreement, including Regeneron’s agreements with the Sanofi Group and Bayer HealthCare, to be canceled or terminated without any product success, and risks associated with third party intellectual property and pending or future litigation relating thereto. A more complete description of these and other material risks can be found in Regeneron's filings with the United States Securities and Exchange Commission, including its Form 10-K for the year ended December 31, 2011 and its Form 10-Q for the quarter ended September 30, 2012. Regeneron does not undertake any obligation to update publicly any forward-looking statement, whether as a result of new information, future events, or otherwise, unless required by law.
Posted: January 2013