ZALTRAP (ziv-aflibercept) Approved in the EU for Patients with Previously Treated Metastatic Colorectal Cancer

Tue Feb 5, 2013 1:05am EST

* Reuters is not responsible for the content in this press release.

For best results when printing this announcement, please click on the link
below:

http://pdf.reuters.com/pdfnews/pdfnews.asp?i=43059c3bf0e37541&u=urn:newsml:reuters.com:20130205:nPnNY53942

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  /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.[1]

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 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.   

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 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.

* Bleeding/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.  
* 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.

* 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.  
* 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.

* Discontinue ZALTRAP in patients with compromised wound healing.  
* Suspend 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.  
* 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.

* 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.  
* 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®  (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.  
* Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA)
occurred more frequently in patients treated with ZALTRAP.

* 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.  
* 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.  
* Suspend ZALTRAP®  (ziv-aflibercept) 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.

* 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 patients.  
* 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 greater than or equal to 1.5 x 109/L.

* Incidence of severe diarrhea and dehydration is increased in patients treated
with ZALTRAP/FOLFIRI.

* 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 patients.  
* The incidence of diarrhea is increased in patients greater than or equal to 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 experiences ongoing neurologic sequelae or death.

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®  (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.  
* 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® 
(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.  
* 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.

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 
(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.

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.

 Contacts:                                                                     
                                                                               
 Sanofi                                                                        
 Media Relations                                Investor Relations             
 Marisol Peron                                  Sebastien Martel               
 Tel. : + (33) 1 53 77 45 02                    Tel. : + (33) 1 53 77 45 45    
 marisol.peron@sanofi.com                       ir@sanofi.com                  
                                                                               
 Lauren Musto                                                                  
 Oncology Division Communications                                              
 Tel: 1 (617) 768-1993; Mobile 1(781) 572-1147                                 
 lauren.musto@sanofi.com                                                       
                                                                               
 Regeneron                                                                     
 Corporate Communications                       Investor Relations             
 Peter Dworkin                                  Michael Aberman M.D.           
 Tel. : 1 (914) 847-7640                        Tel. : 1 (914) 847-7799        
 peter.dworkin@regeneron.com                    michael.aberman@regeneron.com  


[1]   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

 

SOURCE  Regeneron Pharmaceuticals, Inc.

Comments (0)
This discussion is now closed. We welcome comments on our articles for a limited period after their publication.