ZALTRAP® (ziv-aflibercept) Approved in the EU for Patients with Previously
Treated Metastatic Colorectal Cancer
First and only agent to statistically significantly improve survival in
combination with FOLFIRI chemotherapy after an oxaliplatin regimen
PARIS and TARRYTOWN, N.Y., Feb. 5, 2013
PARIS and TARRYTOWN, N.Y., Feb. 5, 2013 /PRNewswire/ --Sanofi (EURONEXT: SAN
and NYSE: SNY) and Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today
announced that the European Commission (EC) has granted marketing
authorization in the European Union for ZALTRAP 25mg/ml concentrate for
solution for 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. This decision was based on the efficacy and safety results of the
VELOUR Phase 3 trial.
"ZALTRAP is an important addition to the metastatic colorectal cancer
treatment landscape and helps to fill a critical treatment gap," said Eric Van
Cutsem, M.D., Ph.D., University Hospitals Leuven, Belgium and lead
investigator of the VELOUR study. "ZALTRAP is the first and only agent to
demonstrate a survival improvement in a Phase 3 trial in patients previously
treated with an oxaliplatin-based regimen who are being treated with FOLFIRI
for their metastatic disease."
"I would like to thank the physicians, patients, and their families for their
support in moving ZALTRAP through the clinical trial process leading to
approval in Europe," said Debasish Roychowdhury, M.D., Senior Vice President
and Head, Sanofi Oncology. "We are thrilled to provide a new therapy that
further extends the lives of patients with metastatic colorectal cancer and
look forward to working with European health authorities to ensure patients
have access to ZALTRAP."
In Europe, colorectal cancer is the most common cancer in both men and women
and is the second leading cause of cancer death. In 2008, there were 436,000
new cases diagnosed and 212,000 deaths from colorectal cancer.
Commenting on the marketing authorization, George D. Yancopoulos, M.D., Ph.D.,
Chief Scientific Officer of Regeneron and President of Regeneron Laboratories,
added: "The European approval of ZALTRAP provides a new option to address the
unmet medical need in this patient population. There continues to be a need
to develop new cancer therapies and Regeneron and Sanofi are committed to
finding novel investigational treatments and combinations."
ZALTRAP received approval from the U.S. Food and Drug Administration (FDA) in
August 2012 after a Priority Review, and marketing authorization applications
for ZALTRAP are under review with other regulatory agencies worldwide.
About the VELOUR Phase 3 Study
The ZALTRAP approval was based on data from the pivotal Phase 3 VELOUR trial,
a 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
of the trial 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 alone (p=0.0001).
The most common adverse reactions (all grades,greater than or equal to20%
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.
About ZALTRAP^® (ziv-aflibercept)
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), as shown in preclinical studies. 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 US, ZALTRAP is a registered trademark of Regeneron Pharmaceuticals, Inc.
In the US, ZALTRAP is approved with the US proper name ziv-aflibercept. The
World Health Organization (WHO) recommended international non-proprietary name
for ZALTRAP is aflibercept. Marketing authorization applications for ZALTRAP
are also under review other regulatory agencies worldwide.
IMPORTANT SAFETY INFORMATION FOR
ZALTRAP^® (ziv-aflibercept) INJECTION FOR INTRAVENOUS INFUSION
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.
oBleeding/hemorrhage (all grades) occurred in 38% of ZALTRAP^®
(ziv-aflibercept)/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.
oMonitor patients for signs and symptoms of bleeding.
Do not initiate ZALTRAP in patients with severe hemorrhage.
Discontinue ZALTRAP in patients who develop severe hemorrhage.
oGI perforation including fatal GI perforation can occur in patients
oAcross 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.
oMonitor patients for signs and symptoms of GI perforation.
Discontinue ZALTRAP in patients who experience GI perforation.
oZALTRAP 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.
oDiscontinue ZALTRAP in patients with compromised wound healing.
oSuspend ZALTRAP for at least 4 weeks prior to elective surgery and do
not initiate/resume ZALTRAP^® (ziv-aflibercept) until at least 4
weeks after major surgery and surgical wound is fully healed.
oFor 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.
oFistula 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
oAn increased risk of Grade 3-4 hypertension has been observed in patients
oThere 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.
oMonitor 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
oArterial thromboembolic events (ATE), including transient ischemic attack,
cerebrovascular accident, and angina pectoris, occurred more frequently in
patients who have received ZALTRAP^® (ziv-aflibercept). 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.
oSevere proteinuria, nephrotic syndrome, and thrombotic microangiopathy
(TMA) occurred more frequently in patients treated with ZALTRAP.
oProteinuria 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.
oMonitor 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
oSuspend ZALTRAP^® (ziv-aflibercept) when proteinuria greater than or
equal to 2 grams/24 hours and resume ZALTRAP when proteinuria <2
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.
oGrade 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
oMonitor CBC with differential count at baseline and prior to
initiation of each cycle of ZALTRAP. Delay administration of
ZALTRAP/FOLFIRI until neutrophil count is greater than or equal to
1.5 x 10^9/L.
oIncidence of severe diarrhea and dehydration is increased in patients
treated with ZALTRAP/FOLFIRI.
oGrade 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
oThe incidence of diarrhea is increased in patients greater than or
equal to 65 years of age compared to patients ˂65 years of age.
oRPLS (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 experiences
ongoing neurologic sequelae or death.
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^® (ziv-aflibercept)/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^®
(ziv-aflibercept)/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
PREGNANCY AND NURSING MOTHERS
oZALTRAP 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.
oIt 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.
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 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, asthma, and atopic dermatitis. For additional information about
the company, please visit www.regeneron.com.
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include among other things, the uncertainties inherent in research and
development, future clinical data and analysis, including post marketing,
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whether and when to approve any drug, device or biological application that
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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
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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
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these and other material risks can be found in Regeneron's filings with the
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the year ended December 31, 2011 and its Form 10-Q for the quarter ended
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Media Investor Relations
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Oncology Division Communications
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Corporate Communications Investor Relations
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 ESMO Consensus Guidelines for management of patients with colon and
rectal cancer. A personalized approach to clinical decision making. Annals of
Oncol. 2012; 23: 2470-2516
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