aflibercept (intravenous, cancer), Regeneron/Sanofi Table of Contents

aflibercept (intravenous, cancer), Regeneron/Sanofi
Table of Contents
2Snapshot...........................................................................................................................................
2Development Profile..........................................................................................................................
13Literature Review..............................................................................................................................
20Development Status..........................................................................................................................
24Drug Names......................................................................................................................................
25Sales and Forecasts..........................................................................................................................
27Clinical Trials..................................................................................................................................
30Deals and Patents............................................................................................................................
35SWOT Analysis.................................................................................................................................
36Change History.................................................................................................................................
02-Apr-2013Created:
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aflibercept (intravenous, cancer), Regeneron/Sanofi
SNAPSHOT
aflibercept (intravenous, cancer), Regeneron/SanofiDrug Name
aflibercept; ZaltrapKey Synonyms
Originator Company Regeneron Pharmaceuticals Inc
Active Companies Sanofi; Regeneron Pharmaceuticals Inc
Inactive Companies Aventis SA
Highest Status Launched
Peritoneal tumor; Multiple myeloma; Metastatic colorectal cancer; Fallopian
tube cancer; Hormone refractory prostate cancer; Glioma; Solid tumor;
Advanced solid tumor; Small-cell lung cancer; Prostate tumor; Melanoma;
Metastatic non small cell lung cancer; Non-small-cell lung cancer; Colorectal
tumor
Active Indications
Age related macular degeneration;Ascites;Pancreas tumor;Psoriasis;B-cell
lymphoma;Metastatic pancreas cancer;Breast tumor;Diabetic
retinopathy;Cancer;Ovary tumor
Inactive Indications
Target-based Actions VEGF-B ligand inhibitor; Placenta growth factor ligand inhibitor; VEGF ligand
inhibitor; VEGF-A ligand inhibitor
Other Actions Systemic antipsoriatic product; Anticancer; Angiogenesis inhibitor; Metastasis
inhibitor
Antibody fragment; Receptor fusion; Immunoglobulin-G; Intravenous
formulation; Infusion; Solution; Biological therapeutic; Protein recombinant
Technologies
01-Apr-2013Last Change Date
DEVELOPMENT PROFILE
SUMMARY
Regeneron and licensee Sanofi (formerly Aventis, then sanofi-aventis) have developed and launched
aflibercept (AVE-0005; ziv-aflibercept; systemic VEGF Trap; Zaltrap), a recombinant decoy receptor
comprising portions of VEGF receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1,
that block VEGF and placental growth factor (PlGF). The product is indicated in combination with 5-
fluorouracil, leucovorin and irinotecan (FOLFIRI) for the treatment of metastatic colorectal cancer (mCRC)
that is resistant to or has progressed following an oxaliplatin-containing regimen [1313124], [1365866].
In August 2012, the product was launched in the US for the treatment of mCRC that was resistant to or had
progressed following an oxaliplatin-containing regimen, in combination with FOLFIRI [1313124], [1334180].
In February 2013, the product was approved in the EU for second-line mCRC [1365866]; launch was
expected later in 1Q13 [1355187].
Development in first-line CRC is also ongoing; a phase II study began in January 2009 [987192].
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Aflibercept is also being developed for other cancer indications, including for the second-line treatment of
non-small-cell lung cancer (NSCLC), and first-line metastatic hormone-resistant prostate cancer (HRPC). In
August 2007, phase III studies in second-line NSCLC and first-line metastatic HRPC were initiated
[824576], [836023], [959144]; in February 2008, filings for NSCLC and HRPC were expected in 2010 and
2011, respectively [875929]. In March 2011, the companies reported that the phase III VITAL study for
NSCLC failed to achieve its primary endpoint [1175277]. In April 2012, the HRPC trial failed to meet its
primary endpoint [1277900]. In March 2007, a phase I trial in solid tumors was initiated in Japan; the study
was still recruiting in November 2009 [809137]. In September 2012, a phase Ib trial was initiated in
combination with REGN-910 in the US and Canada in patients with advanced solid malignancies. The trial
was to complete in June 2014 [1334180], [1334482].
Several other cancer indications are being investigated in NCI-sponsored trials. In August 2006, a phase II
trial began in the US in glioma; the study was ongoing in July 2009 [1075468]. A phase II trial in multiple
myeloma began in January 2007, which was ongoing in December 2012 [785208]. By May 2009, a phase II
study in melanoma had been initiated [1010025]; at that time, a phase I trial in gynecological tumors was
also underway [1013025]. In May 2009, a phase II trial in small cell lung cancer was initiated [1304585].
The drug was also previously being developed in other cancer settings. In June 2006, a phase II/III study in
advanced ovarian cancer with symptomatic malignant ascites began; however in June 2009, development
was presumed to be discontinued [1017305]. In December 2007, a phase III study in metastatic pancreatic
cancer was initiated [880542], [959144]; however, in September 2009, the trial was discontinued and by
October 2009, the indication no longer appeared in the company's pipeline [1041345], [1063525]. In
February 2008, a phase III study for breast cancer was planned [875929]; however no development has
been reported since that time. The drug was also previously also being investigated for the potential
treatment of psoriasis, but by February 2004, this indication was no longer listed [521119], [411378]. In
March 2008, a phase I trial in B-cell non-Hodgkins lymphoma began in France [1020660]; results were
presented in June 2010, by which time further development in lymphoma was under discussion [1104344];
no further development was reported.
The companies were previously developing systemic aflibercept for ophthalmic indications including age-
related macular degeneration (AMD) and diabetic macular edema (DME). Phase I trials in wet AMD
[526831] and DME [567459] began in 2004; however, in January 2005, the companies decided not to
pursue systemic delivery for eye diseases due to a potential risk of hypertension, and Regeneron began
development of a separate intravitreal formulation [579058].
The US label contains a boxed warning highlighting the risk of severe and possibly fatal hemorrhage,
gastrointestinal perforation and compromised wound healing [1313124], [1313316].
PATENTS AND GENERICS
The compound patent expires in 2020 in the US, EU and Japan [1269852].
In November 2010, Regeneron filed a suit against Genentech, seeking a declaratory judgment that
Regeneron's VEGF trap products did not infringe Genentech's Davis-Smyth patents. Genentech filed
counterclaims that Regeneron's previous and planned activities infringed four patents and requested
damages and other relief. A second, similar suit regarding the Davis-Smyth patents was filed by Genentech
in December 2011. By February 2012, Regeneron had also taken action against Genentech in Germany, the
UK and Italy [1267527].
REGULATORY
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THE US
COLORECTAL CANCER
In October 2011, a US filing was submitted for second-line mCRC [1235900]. In April 2012, the FDA
granted the filing Priority Review, for use of aflibercept in combination with irinotecan-fluoropyrimidine-based
chemotherapy for previously treated mCRC. At that time, an action date was expected in August 2012
[1277900]; by July 2012, the FDA issued a PDUFA date of August 4, 2012 [1310811]. In August 2012, the
FDA approved the product, in combination with FOLFIRI, for the treatment of patients with mCRC that was
resistant to or had progressed following an oxaliplatin-containing regimen; at that time, launch was planned
for 3Q12 [1313124]; later that month, the drug was launched in the US [1334180].
OVARIAN CANCER
In February 2008, a regulatory filing for the third-line treatment of advanced ovarian cancer was expected in
2008 [875929]; however, in June 2009, the companies decided not to submit phase II data for accelerated
approval of advanced ovarian cancer with symptomatic malignant ascites due to four fatalities in the trial.
The companies would instead focus on completion of the phase III program for metastatic CRC, NSCLC,
pancreatic and prostate cancers [1017305].
OTHER CANCERS
In February 2008, filings for the second-line treatment of NSCLC were expected in 2010, and filings for the
first-line treatment of hormone-refractory prostate cancer and pancreatic cancer were expected in 2011
[875929].
EUROPE
COLORECTAL CANCER
In November 2011, a filing was submitted for second-line CRC [1269852]; the filing was accepted for review
by the EMA at the end of 2011 [1269852]. In November 2012, the EMA's CHMP issued a positive opinion
recommending approval of aflibercept in combination with FOLFIRI chemotherapy for the treatment of
patients with mCRC that was resistant to or had progressed following an oxaliplatin-containing regimen
[1341506], [1341857], [1341879]. In February 2013, Sanofi expected first European launches in 1Q13
[1366737]. In February 2013, the product was approved in the EU in combination with FOLFIRI for mCRC
that was resistant to or had progressed following an oxaliplatin-containing regimen [1365866].
PREMARKETING
COLORECTAL CANCER
FIRST-LINE TREATMENT
PHASE II
By May 2008, a study in first-line therapy of CRC was in preparation [907488]. In January 2009, enrollment
in the phase II AFFIRM trial began. Patients would receive aflibercept in combination with FOLFOX
(leucovorin, 5-fluorouracil and oxaliplatin) [987192]. The multinational, randomized, open-label, active-
controlled, parallel-assignment, efficacy study (NCT00851084; AFFIRM) was to compare treatment with
modified FOLFOX6 and modified FOLFOX6 plus aflibercept in 230 patients. The primary endpoint was
progression-free survival (PFS) rate, with secondary endpoints of overall survival, PFS and overall response
rate. The study was due to complete in September 2011 [1075398]. By July 2011, enrollment had been
completed [1119304], [1210789]. In February 2012, results were reported. PFS at 1 year was similar for
patients who received aflibercept plus FOLFOX and patients who received FOLFOX only [1260944].
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SECOND-LINE TREATMENT
PHASE III
In November 2007, a global, multicenter, randomized, double-blind, placebo-controlled, parallel-group,
phase III efficacy study (NCT00561470; VELOUR; EFC10262) began in patients who had previously failed
an oxaliplatin-based treatment for metastatic CRC (n = 1226). The study was to evaluate aflibercept in
combination with folinic acid, 5-FU and irinotecan (FOLFIRI) compared with placebo plus FOLFIRI. The
primary endpoint was overall survival, with secondary endpoints of PFS, tumor response rate, safety and
immunogenicity [880542], [959144], [1075390], [1186513]. In September 2010, an independent data
monitoring committee recommended that the trial could continue with no modifications [1129505]. By
February 2011, enrollment had been completed [1168877]. In April 2011, the company reported that the
trial met its primary endpoint of improving overall survival [1186513]. In June 2011, data were presented at
the European Society of Medical Oncology World Congress on Gastrointestinal Cancer in Barcelona, Spain.
Combination of aflibercept and FOLFIRI significantly improved overall survival (13.5 versus 12.06 months)
and progression-free survival (6.9 versus 4.67 months); a similar effect was observed whether or not
patients had received prior bevacizumab therapy. Deaths due to adverse events during study treatment
occurred in 2.4% of patients in the aflibercept arm compared with 1.0% of patients in the placebo arm
[1197619], [1305016]. In September 2011, prespecified subgroup analysis data were presented at the
European Multidisciplinary Cancer Congress in Stockholm, Sweden. In the aflibercept arm, the median
overall survival was 12.5 and 13.9 months for patients with (n =186) or without prior bevacizumab therapy (n
= 426), respectively compared with 11.7 and 12.4 months, respectively for placebo. The median PFS in
patients with or without bevacizumab prior treatment was 6.7 and 6.9 months, and 3.9 and 5.4 months for
aflibercept and placebo, respectively. A consistent improvement in OS and PFS was observed regardless of
prior treatment with bevacizumab [1222598]. These data were presented at the 48th ASCO meeting in
Chicago, IL in June 2012 [1296528]. Also at the meeting, data were presented from an estimation of mean
overall survival, using patient level data; logistical parameters gave a mean OS benefit of 2.9 months with
aflibercept/FOLFIRI compared with 1.4 months using median survival [1299214]. Also in June 2012, an
analysis of the VELOUR study was presented at the 14th World Congress on Gastrointestinal Cancer in
Barcelona, Spain. The mean overall survival was greater for patients receiving aflibercept by approximately
1.4 to 9.8 months, compared with placebo for all subgroups [1304842]. In August 2012, further data were
reported demonstrating an improvement in the overall response rate for aflibercept plus FOLFIRI compared
with FOLFIRI alone (19.8 versus 11.1%, respectively) [1313124]. In October 2012, similar data were
published [1329371], [1329485].
PHASE II
In October 2006, a phase II trial (NCT00407654; PMH-PHL-050) was initiated in patients (expected n = 80)
with CRC in the US. The primary endpoints were objective responses and PFS, and secondary endpoints
included overall survival [785216]. The study was still recruiting in March 2007 [769947]. In October 2007,
data from this study were presented at the 19th AACR-NCI-EORTC International Conference in San
Francisco, CA. Follow-up data were available for 50 out of 51 patients. In the bevacizumab-naive group (n =
24), no partial responses were observed but 8 patients had stable disease, with 4 cases lasting over 4
months. In the patient group previously treated with bevacizumab (n = 27), 1 patient had a partial response
and 12 had stable disease (6 cases lasting over 4 months). The most common grade 3 toxicities were
fatigue, hypertension, headache and biochemical changes (hyperglycemia, increased liver enzymes,
cytopenia and proteinuria) [843863]. The study was ongoing in April 2009 [785216].
PHASE I
By December 2011, phase I studies in CRC were underway in Japan [1255386].
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