aflibercept (intravenous, cancer), Regeneron/Sanofi
Table of Contents
Snapshot...........................................................................................................................................
2
Development Profile..........................................................................................................................
2
Literature Review..............................................................................................................................
13
Development Status..........................................................................................................................
20
Drug Names......................................................................................................................................
24
Sales and Forecasts..........................................................................................................................
25
Clinical Trials..................................................................................................................................
27
Deals and Patents............................................................................................................................
30
SWOT Analysis.................................................................................................................................
35
Change History.................................................................................................................................
36
Created: 02-Apr-2013
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aflibercept (intravenous, cancer), Regeneron/Sanofi
SNAPSHOT
Drug Name
aflibercept (intravenous, cancer), Regeneron/Sanofi
Key Synonyms
aflibercept; Zaltrap
Originator Company
Regeneron Pharmaceuticals Inc
Active Companies
Sanofi; Regeneron Pharmaceuticals Inc
Inactive Companies
Aventis SA
Highest Status
Launched
Active Indications
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
Inactive Indications
Age related macular degeneration;Ascites;Pancreas tumor;Psoriasis;B-cell
lymphoma;Metastatic pancreas cancer;Breast tumor;Diabetic
retinopathy;Cancer;Ovary tumor
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
Technologies
Antibody fragment; Receptor fusion; Immunoglobulin-G; Intravenous
formulation; Infusion; Solution; Biological therapeutic; Protein recombinant
Last Change Date
01-Apr-2013
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 5fluorouracil, 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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2
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 agerelated 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, activecontrolled, 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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NON-SMALL-CELL LUNG CANCER
SECOND-LINE
PHASE III
In August 2007, a phase III global, randomized, double-blind, placebo-controlled, parallel group, efficacy
study (VITAL; NCT00532155; EFC10261) was initiated for second-line treatment of metastatic NSCLC.
Patients (expected n = 900) were to receive docetaxel with either aflibercept or placebo. The primary
endpoint was superiority of aflibercept over placebo [824576], [830785], [836023]. By February 2010,
enrollment had been completed [1075959]. In March 2011, sanofi-aventis and Regeneron reported that the
913-patient trial failed to achieve the primary endpoint; aflibercept (6 mg/kg every 3 weeks) plus docetaxel
(75 mg/m2) did not meet the prespecified criteria of improvement in overall survival compared to docetaxel
plus placebo. However, improvements were observed in key secondary endpoints including, progression
free survival and an overall objective response rate (23.3% compared to 8.9% in the docetaxel plus placebo
group). Compared to the docetaxel plus placebo group, treatment-emergent adverse events in the
aflibercept plus docetaxel arm (with greater than 10% incidence) included stomatitis, weight loss,
hypertension, epistaxis and dysphonia [1175277].
PHASE II
In December 2005, an open-label, non-randomized phase II study (ARD6123; NCT00284141) was initiated
in US and Canadian patients (expected n = 94) with advanced or metastatic platinum- and erlotinib-resistant
NSCLC. Patients were to receive 4 mg/kg iv aflibercept every 2 weeks and the primary endpoint was
response rate. Secondary endpoints were duration of response, PFS, overall survival, quality of life and
safety [680404]. In June 2007, clinical data from the trial were presented at the 43rd ASCO meeting in
Chicago, IL. A total of 94 patients were treated of which 54 were evaluable. There were 2 partial responses
and 34 patients with stable disease (SD), 6 of whom had SD for over 120 days. The drug was well tolerated
with the most common adverse event being dyspnea [797259].
FIRST-LINE
In November 2008, an open-label, phase I/II study (NCT00794417; VGFT-ST-0708, TCD10767) of
aflibercept in combination with pemetrexed and cisplatin was initiated in US and Canada in patients
(estimated n = 62) with advanced cancer. In January 2012, the study was completed [1301992]. In June
2012, data were presented from this phase II, single-arm, multicenter study in previously untreated
advanced/metastatic non-squamous NSCLC patients (n = 42) at the 48th ASCO meeting in Chicago, IL. Of
the 38 patients evaluable for response, the objective response rate and median progression-free survival
were 26.3% and 149 days, respectively (primary endpoint). Stable disease was observed in 24 patients. A
mean reduction of 20% from baseline over time in tumor burden was observed. The study was closed
prematurely due to three confirmed cases of reversible posterior leukoencephalopathy syndrome, and this
combination would not be explored further in NSCLC [1296093].
PROSTATE CANCER
In August 2007, a phase III, global, randomized, double-blind, placebo-controlled, parallel-group, efficacy
study (NCT00519285; VENICE) in metastatic HRPC was initiated. Patients (expected n = 1200) were to
receive first-line therapy of docetaxel and prednisone with either aflibercept or placebo. The primary
endpoint was overall survival; the trial was due to complete in June 2012 [824576], [830785], [959144],
[1075439]. In November 2009, an interim analysis of the trial was expected to be conducted by an
independent data monitoring committee in mid-2011[1054032]. By February 2010, enrollment had been
completed [1075959]. In July 2011, an independent data monitoring committee recommended the 1224patient trial continue as planned, following an interim analysis [1206061]. In April 2012, Sanofi reported that
aflibercept had not improved overall survival in the 1224-patient trial; at that time, data were expected to be
presented later that year [1277900]. In February 2013, similar data were presented at the Genitourinary
Cancers Symposium in Orlando, FL. Results showed no statistically significant difference between results
from the aflibercept treatment group and placebo group; median overall survival was 22.1 versus 21.2
months, respectively. The percentage of patients who had to discontinue treatment due to reported adverse
events was also higher in the aflibercept group [1384169], [1384354].
By December 2011, phase I studies in prostate cancer were underway in Japan [1255386].
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PANCREATIC CANCER
In August 2007, a phase III study in metastatic pancreatic cancer was planned. Patients (expected n = 650)
were to receive first-line therapy of gemcitabine with aflibercept or placebo [830785]. The study (VANILLA;
NCT00574275) was initiated in December 2007 [880542], [959144], [1263826]. In April 2009, the trial was
over 50% enrolled [1004413]. In September 2009, the trial was discontinued as the independent data
monitoring committee did not expect the drug would increase overall survival compared with gemcitabine
plus placebo. The trial data would be analyzed and patients taking aflibercept could continue to have access
to the drug at the discretion of the study investigators [1041345].
OVARIAN CANCER
PHASE III
In June 2006, a phase II/III study (AVE0005A/3001; NCT00327444) was initiated in an expected 54 US,
European and Canadian patients with advanced ovarian cancer with recurrent symptomatic malignant
ascites. Patients were to receive iv aflibercept every 2 weeks and the primary endpoint was time to repeat
paracentesis. Secondary endpoints were ascites impact measures, 60-day paracentesis frequency, safety,
tumor assessments and quality of life [680406]. In June 2009, data were reported demonstrating the primary
endpoint of an improvement in mean time-to-first repeat paracentesis was met with a mean of 55 days from
baseline procedure in the aflibercept group compared with 23 days for those receiving placebo. However, of
55 patients enrolled, four fatalities were thought to be treatment-related and included cases of intestinal
perforation, dyspnea and pneumonia. sanofi-aventis and Regeneron decided not to submit the data for
approval [1017305].
PHASE II
In October 2006, a non-randomized, open-label, uncontrolled phase II trial (NCT00396591; ARD6772) was
initiated in patients with ovarian cancer and symptomatic malignant ascites in the US, Italy and Sweden. The
subjects were to receive iv aflibercept every 2 weeks. The primary endpoint was time-to-repeat paracentesis
and secondary endpoints included survival, PFS and safety [755866].
Also in October 2006, an NCI-sponsored, phase II trial (NCT00390234) of aflibercept in patients (n = 82)
with metastatic gynecologic soft tissue sarcoma was recruiting patients in the Princess Margaret Hospital.
The primary outcome was the incidence of disease stabilization, as measured by 6-month PFS [739929]. In
May 2009, preliminary clinical data from this trial were presented at the 45th ASCO meeting in Orlando, FL.
Aflibercept (4 mg/kg iv every 2 weeks) was administered to patients with leiomyosarcoma of the uterus (n =
27) and patients with carcinosarcoma of the uterus (n = 17). Six-month survival rates were 77% in the
leiomyosarcoma group and 27% in the carcinosarcoma group. Aflibercept demonstrated modest efficacy in
the leiomyosarcoma group (nine patients with stable disease, no responses), and accrual to the second
stage of the trial was underway in this group. Only one patient in the carcinosarcoma group exhibited stable
disease, and accrual was continuing in the first stage of the trial. Aflibercept was generally well tolerated,
and demonstrated an acceptable safety profile [1013012].
In June 2006, a randomized, double-blind phase II study (ARD6122; NCT00327171) was initiated in US,
European, Australian and Canadian patients (expected n = 200) with advanced platinum-, topotecan- or
doxorubicin-resistant ovarian adenocarcinoma. Patients were to receive 2 or 4 mg/kg iv aflibercept every 2
weeks and the primary endpoint was response rate. Secondary endpoints were safety, pharmacokinetics,
immunogenicity, markers of drug activity and quality of life [680405]. In April 2007, a total of 127 patients
were off study with 35 continuing treatment, at that time an independent data monitoring committee
recommended the trial continue. There were 84 partial responses and 30% of patients had a meaningful
decline. A total of 138 subjects achieved stable disease at 4 weeks, and a further 7 by 30 weeks, with 29%
observing a complete clearance of ascites. The drug demonstrated an acceptable safety profile with the
most common adverse event being hypertension [796411]. In June 2007, similar data were reported at the
43rd ASCO meeting in Chicago, IL [801157]. In September 2007, results were reported from this study
showing that aflibercept had a response rate of 8%, with 40% of subjects achieving tumor control of over 3
months [830785].
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PHASE I
In February 2006, clinical data were presented at the GTCBio's Third Annual Cancer Drugs Research &
Development Conference in San Francisco, CA. In ovarian cancer patients treated with 4 mg/kg every 2
weeks for 4 cycles, tumor burden and ascites were reduced. Side effects included hypertension and
proteinuria [651778].
SMALL CELL LUNG CANCER
An NCI-sponsored phase II trial (NCT00828139) was initiated in May 2009; the trial was to evaluate
aflibercept in combination with topotecan compared to topotecan alone in patients with platinum-treated
extensive-stage SCLC. The primary endpoint was PFS at 3 months. The trial was designed to enroll 172
patients and complete in June 2012 [1304585].
BREAST CANCER
In February 2008, a study in first-line therapy of metastatic breast cancer was in preparation [875929];
however, no development has been reported since that time.
GLIOMA
By October 2006, the open-label, single-arm, phase II trial (NCT00369590; NABTC-0601) in temozolomideresistant glioblastoma multiforme or anaplastic glioma patients (n = 45) had begun patient recruitment in the
US; the trial was still listed as ongoing in July 2009 [739935], [1075508]. Data were reported at the 44th
ASCO meeting in Chicago, IL in June 2008. Although most toxicities were manageable, 43% and 25% of
anaplastic glioma and glioblastoma multiforme patients had to be removed from the study due to toxicity
(patients were dosed on 4 mg/kg iv q2weeks). The 6-month PFS endpoint was not met; median PFS for
patients who did not come off study was 26 weeks for anaplastic glioma, and 9 weeks for glioblastoma
[911051].
MULTIPLE MYELOMA
In January 2007, a phase II trial (NCT00437034; NYWCCC-7521) was initiated in patients (expected n = 50)
with multiple myeloma in the US. The primary endpoint was overall response rate, and secondary endpoints
included PFS and overall survival. The study was still recruiting in December 2012 [785208].
B-CELL NON-HODGKINS LYMPHOMAS
In March 2008, a phase I trial (NCT00644124) in patients with previously untreated B-cell non-Hodgkins
lymphomas was initiated in combination with rituximab and CHOP. The trial was expected to enroll 50
patients and completed in October 2011 [1020660]. Data were presented at the 46th ASCO meeting in
Chicago, IL, by which time 25 patients had been treated with 3 or 6 mg/kg iv aflibercept. Both doses were
generally well tolerated, with grade 1/2 reversible dysphonia the most common drug-related adverse event.
Complete and partial response rates of 80% and 20% were seen. At that time, further development of the
drug in lymphoma was under discussion [1104344].
OTHER SOLID TUMORS
PHASE II
In May 2009, clinical data were presented at the 45th ASCO meeting in Orlando, FL. Results from a phase II
study (NCT00450255) showed aflibercept demonstrated clinical activity in metastatic melanoma of
cutaneous or ocular origin, a partial response was reported in one patient (PFS = 293+ days) and 20
patients had stable disease [1010025].
In November 2006, a phase II trial (NCT00407485; CCC-PHII-76) was initiated in subjects (expected n = 40)
with cancer of the bladder, urethra, renal pelvis and ureter in the US. The primary endpoints were PFS and
response rate, and secondary endpoints included safety. The study was ongoing in April 2009 [785219].
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By August 2006, the companies were finalizing plans with the National Cancer Institute Cancer Therapy
Evaluation Program (CTEP) to conduct a minimum of 10 further cancer trials [681938]. These included
phase II trials for metastatic breast cancer (NCT00369655) [687414], temozolomide-resistant glioblastoma
multiforme or anaplastic glioma (NCT00369590) [687406] and metastatic or unresectable kidney cancer
(NCT00357760) [739933].
PHASE I
In September 2012, an open-label, multicenter, ascending, multi-dose phase Ib trial (NCT01688960; R910ST-1114) was initiated in combination with REGN-910 in the US and Canada in patients (expected n = 40)
with advanced solid malignancies. The trial was to complete in June 2014 [1334180], [1334482].
In June 2010, at the 46th ASCO meeting in Chicago, IL, data were presented from a phase I study of
aflibercept in combination with pemetrexed and cisplatin in patients with advanced solid tumors. Patients
received three doses of aflibercept (2, 4 and 6 mg/kg) in combination with a fixed dose of pemetrexed (500
mg/m2) plus cisplatin (75 mg/m2). Partial response, stable disease and progressive disease were seen in 2,
11 and 2 patients, respectively. The combination was well tolerated and aflibercept 6 mg/kg q3w was
determined as the recommended phase II dose in this combination regimen [1104105].
In November 2009, data from a phase I study in patients with advanced solid malignancies were presented
at the 21st AACR-NCI-EORTC International Conference in Boston, MA. It was found that the recommended
dose of aflibercept was 6 mg/kg when given in combination with docetaxel, and 5-fluorouracil q3w
[1057976].
In May 2009, data from a phase I study in recurrent ovarian, fallopian tube and primary peritoneal cancer
patients, were presented at the 45th ASCO meeting in Orlando, FL. Female subjects received iv afilbercept
at one of three dose levels (2, 4 or 6 mg/kg) plus docetaxel (75 mg/m2) for 21 days as one cycle. After one
cycle, pharmacokinetics was safe, two patients showed confirmed responses and another had a near partial
response. After 4 and 13 cycles, 2 patients discontinued treatment. Combination therapy with afilbercept (6
mg/kg q3w) was safe [1013025].
By October 2008, it was disclosed in the 46th annual meeting of the Japan Society of Clinical Oncology in
Nagoya, Japan, that the drug was being studied in a phase I trial as a second-line therapy for advanced
stomach cancer [966674].
In March 2007, a randomized, open-label, uncontrolled phase I trial (NCT00479076; TED10089) was
initiated in patients (expected n = 22) with advanced solid tumors in Japan. The subjects were to receive oral
S-1 and iv aflibercept every 2 weeks. The primary endpoint was the recommended phase II dose of
aflibercept in combination with S-1 in Japanese patients with solid tumors. Recruitment was ongoing in
November 2009 [809137].
In May 2006, data from a phase I study evaluating the aflibercept plus irinotecan, 5-fluorouracil, and
leucovorin (LV5FU2-CPT11) combination in patients with advanced solid tumors were presented at the 42nd
ASCO meeting in Atlanta, GA. Patients were treated with doses ranging up to 4 mg/kg of the aflibercept.
The compound could be safely combined with LV5FU2-CPT11 at the dose levels studied. At that time, the
maximum tolerated doses in this study had not yet been reached, and dose escalation was continuing
[681938].
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In May 2005, data from a phase I trial were presented at the 41st ASCO meeting in Orlando, FL. Sequential
dose cohorts of three to seven patients received an iv infusion of aflibercept (0.3 to 4 mg/kg) every 2 weeks.
Patients who developed dose-limiting toxicity were subsequently entered in an extension study with
continuing treatment at the same or lower dose. Data were collected from 23 patients with a wide range of
advanced solid tumors. Treatment with aflibercept was well tolerated at all dose levels; the most common
adverse events were mild to moderate. Anti-aflibercept antibodies were not detected in plasma. At the 2 to 4
mg/kg dose levels, steady-state concentrations were at or near saturation, and free levels of aflibercept were
in excess of bound levels throughout the biweekly cycles. Furthermore, at the 2 to 4 mg/kg dose range,
decreased tumor perfusion was observed within 24 h. The study concluded that tumor reduction and
prolonged stable disease were seen at the 1 to 4 mg/kg doses; a partial response was achieved at the
4mg/kg dose [601683], [601710], [603203]. Data from this trial were also presented in June 2003, at the 39th
ASCO meeting in Chicago, IL. At this time it was reported that nine of the 23 patients had stable disease
after 6 weeks of administration and the therapy was well tolerated at all dose levels [491964], [496170]. In
September 2003, similar data were presented at the SRI Angiogenesis meeting in Cambridge, MA [509103].
In November 2005, further data from this study were presented at the 17th AACR-NCI-EORTC conference
in Philadelphia, PA. At this time, 30 patients with advanced solid tumors had been treated. The MTD had not
been reached and dose escalation was ongoing [634957].
In May 2005, Regeneron and sanofi-aventis began a safety and tolerability study of aflibercept in
combination with oxaliplatin/5-fluorouracil/leucovorin (FOLFOX4) for treating advanced solid malignancies
[601097]. By May 2006, data from this study had been reported at the 42nd ASCO meeting in Atlanta, GA.
In this phase I trial, patients were in combination with chemotherapy in doses ranging up to 4.0 mg/kg of
aflibercept. The drug could be safely combined with FOLFOX4 at the dose levels studied. At that time, the
MTD had not yet been reached, and dose escalation was continuing [681938]. Final data were presented at
the 44th ASCO meeting in June 2008. Dose-escalation had reached 5 mg/kg, however there was one fatal
posterior leukoencephalopathy at this dose. In 18 patients treated at 4 mg/kg, adverse events included one
DVT, on GI hemorrhage, and one fatal hemorrhagic stroke. Febrile neutropenia was seen in two patients,
and Grade 3 proteinuria in 18.8%. Five patients had a prolonged clinical benefit at 24 weeks. The dose of 4
mg/kg was selected for further development in this setting [912703].
MISCELLANEOUS TUMORS
By February 2007, aflibercept at 4 mg/kg iv biweekly for four doses had shown complete resolution of
malignant ascites and reduction of advanced ovarian adenocarcinoma. At double this dose, it showed
efficacy in advanced NSCLC. In each case, patients had been treated unsuccessfully with standard
chemotherapy [765668].
In September 2006, an NCI-sponsored, phase I trial (NCT000823213) of aflibercept in 25 relapsed or
refractory advanced solid tumor or non-Hodgkin's lymphoma cancer patients was recruiting at the Memorial
Sloan-Kettering Cancer Centre (MSKCC). For the study, cohorts of 3 to 6 patients would receive escalating
doses of iv aflibercept until reaching the MTD. Once determined, 6 patients would receive iv MTD for 3
months [739895]. At that time, a further NCI-sponsored phase I trial (NCT00082823), was also recruiting 25
patients to receive repeated MTD iv aflibercept, every 14 days for 3 months, dependent on the absence of
disease progression or toxicity [739847].
In January 2006, Regeneron presented clinical data at JP Morgan's 24th Annual Healthcare Conference in
San Francisco, CA, showing that patient blood samples demonstrated trapping of VEGF and that a single
dose of aflibercept decreased perfusion and vascular permeability. The compound produced responses in
patients previously treated with multiple chemotherapy regimens. Adverse events were similar to those
observed in bevacizumab studies, with hypertension and proteinuria being the main adverse events
[645230].
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10
In April 2004, Regeneron, in collaboration with Aventis, initiated a phase I trial to assess the safety and
tolerability of iv aflibercept in cancer. The study was to evaluate increasing dose levels of aflibercept in
patients with advanced solid tumors or non-Hodgkin's lymphoma [532729]. In June 2004, data were
presented at the 40th ASCO meeting in New Orleans, LA. Objective partial or complete responses had not
yet been achieved; however, 14 of 23 evaluable patients achieved stable disease for at least 10 weeks,
including six patients treated with the 0.8 mg/kg dose. These patients entered a long-term study [543400].
Similar data were presented in September 2004 at the 16th EORTC-NCI-AACR meeting in Geneva,
Switzerland. By this time 38 patients had been enrolled into the trial. The maximum tolerated dose was not
reached in this study. No patients demonstrated an objective, partial or complete response; however, 18 of
35 patients achieved stable disease for at least 10 weeks. This included 9 of 12 patients who were treated
with more than or equal to 0.8 mg/kg/week. Treatment-related drug limiting toxicities included grade 3
leukopenia, grade 3 proteinuria and grade 3 and 4 thromboembolic events. Dose-related adverse events
included hypertension and grade 1 hoarseness and anorexia. A total of 9 of 11 patients administered the
800 microg/kg dose every week or biweekly maintained stable disease. One patient continued to receive
the drug for over 1 year [562697].
In November 2002, phase I data were presented at the 14th EORTC-NCI-AACR meeting in Frankfurt,
Germany. Patients with refractory solid tumors (other than squamous cell carcinoma of lung) or lymphoma,
who had failed prior curative chemotherapy and standard chemotherapy, were divided into two cohorts of six
patients, each dosed sc with either 25 or 50 microg/kg aflibercept. A series of six weekly injections at the
same dose were resumed following a 4-week rest period. By this time, adverse events had included grade I
to II proteinuria (reversible), fatigue and constipation. Two patients with renal cell carcinoma (administered
15 doses at 25 microg/kg and 17 doses at 50 microg/kg respectively) had stable disease, whereas disease
progressed in all remaining patients. At this time, additional data on the higher dose levels were required
before phase II trials could commence, and the schedule was being repeated with dose groups of three
patients receiving 1 to 800 microg/kg aflibercept [471327], [471226]. Similar data were presented in
February 2004 at the New Targets and Innovative Strategies in Cancer Treatment: One year of Progress
[524997].
An open-label phase I trial in patients with advanced tumors, was initiated in New York, NY, in November
2001. The aim of this study was to evaluate aflibercept at increasing dose levels [431126]. The trial was a
dose-escalation study, in which subjects received a weekly, self-administered sc injection. In August 2003,
Regeneron was planning an iv phase of this study for later in the year [500010].
MISCELLANEOUS STUDIES
In January 2012, meta-analyses of data from the VELOUR, VITAL and VANILLA studies were presented at
the 2012 ASCO Gastrointestinal Cancer Symposium in San Francisco, CA. Adding aflibercept to concurrent
chemotherapies did not increase the risk of venous thromboembolic events. The risk of grade 3 to 4 antiVEGF class adverse events was increased when but was only statistically significant for hypertension,
proteinuria and hemorrhage [1260968]. In June 2012, similar data were presented at the 48th ASCO
meeting in Chicago, IL [1299208].
PRECLINICAL
CANCER
In April 2011, preclinical data were presented at the 102nd AACR meeting in Orlando, FL. The combination
of aflibercept plus docetaxel was significantly more effective when compared with single agents in
immunodeficient SCID mice bearing sc HT1080 tumors, however no added benefit was observed with the
combination of aflibercept and gemcitabine. There was a dramatic decrease in the number of proliferating
tumor cells with both combination regimens [1176780]. Further data reported at the same meeting showed
that aflibercept decreased vascular perfusion by 59% after 24 h in C6 rat glioma tumors and 32% after 24 h
Colo205 human colon tumors, but no decrease was observed in HT1080 human fibrosarcoma tumors. Coadministration of aflibercept with a blocking Dll4 antibody decreased vascular perfusion by 30% in C6, 77%
in Colo205 and 54% in HT1080, while co-administration with an anti-Ang2 antibody produced a 13%
decrease in perfusion of Colo205 tumors. The changes in perfusion correlated with long-term tumor growth
inhibition. Combinations of aflibercept plus anti-Dll4 or anti-Ang2 antibodies were more potent in all tumor
types compared to the monotherapies [1176767].
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In April 2008, preclinical data were presented at the 99th AACR annual meeting in San Diego, CA, from a
study in a range of tumor mouse models, showing that the drug was well tolerated at doses between 2.5
and 40 mg/kg/day and displayed a broad spectrum of anticancer activity [893702].
In October 2007, preclinical data testing aflibercept in combination with the cytotoxic agents 5-FU and
irinotecan were presented a the 19th AACR-NCI-EORTC International Conference in San Francisco, CA. In
three-arm study single agent cytotoxic, single agent afilbercept, and the combination were tested for dose
response effects. The combination of aflibercept (sc twice weekly) with 5-FU (iv weekly) for a 3-week
treatment period in mice bearing early stage murine mammary adenocarcinoma MA13/C, showed aflibercept
alone to be as active as the highest non-toxic dose of 5-FU (90 mg/kg/dose). Aflibercept at 10, 25 and 40
mg/kg/dose produced a log CK of 1.3, 1.5, 1.4, respectively. A 40-mg/kg/dose of aflibercept plus 90mg/kg/dose 5-FU produced a 2.7 log CK, proving synergy whilst maintaining safety. In mice bearing
advanced stage human colon carcinoma HCT 116 (155 mg tumor burden) aflibercept alone at 40
mg/kg/dose produced a 1.7 log CK and irinotecan produced 1.8 log CK at a 12.4 mg/kg/dose. In combination
(sc aflibercept 40 mg/kg/dose and iv irinotecan 20.2 mg/kg/dose tumor cell kill was improved synergistically
by more than 1 log and was well tolerated [840299].
In January 2006, in vitro data presented at JP Morgan's 24th Annual Healthcare Conference in San
Francisco, CA, showed that aflibercept had a higher affinity for VEGF than bevacizumab [645230].
In April 2005, preclinical data were presented at the 96th AACR meeting in Anaheim, CA. In rat aortic
explants, aflibercept inhibited VEGF-induced angiogenesis at picomolar concentrations. In mice with B16
melanomas implanted subcutaneously, aflibercept (2.5, 10, 25 and 40 mg/kg sc, twice-weekly for 3 weeks)
produced 2.4, 3.9, 5 and 5.4 log cell kill values, respectively. In mice with MA13/C xenografts, aflibercept
(2.5 to 40 mg/kg) was administered alone or in combination with 5-fluorouracil (34 to 145 mg/kg). Each
agent was active when administered alone (1.4 and 1.3 log cell kill, respectively), while the combination
proved synergistic, producing a log cell kill value of 2.7 [593521]. In an athymic mouse U-87 tumor model,
aflibercept alone (2.5 or 10 mg/kg, every third day for 3 weeks), radiation alone (three doses of 5 Gy), and
combination of radiation with of low- or high-dose aflibercept slowed the doubling time of tumors to 4.7, 9.5,
6.5, 10.4 and 17 days, respectively, compared with 3.1 days in controls. These results indicate a stronger
effect of aflibercept in combination with radiation than that of high-dose aflibercept alone or radiation alone
[593894]. In November 2005, similar data were presented at the 17th AACR-NCI-EORTC conference in
Philadelphia, PA [634951].
Data presented at the 95th AACR in Orlando, FL in March 2004 indicated that the combination of aflibercept
and paclitaxel dramatically reduced tumor burden and ascites in mice, while the animals remained visually
indistinguishable from non tumor-bearing mice receiving vehicle alone [531117].
In November 2003, preclinical data were presented at the 15th AACR-NCI-EORTC meeting in Boston, MA,
from a study evaluating the effect of aflibercept on tumor growth delay (TGD) in response to ionizing
radiation in the clinically relevant U87 human glioblastoma model, which expresses high levels of VEGF. U87 cells were injected sc into the right hind limb (5 x 10(5) cells in 0.1 ml PBS) of athymic NCR NUM mice
and allowed to grow until reaching a diameter of 4 to 5 mm before treatment. TGD was determined using
time in days for the tumor to grow to 1000 mm3. The drug was administered at 25 mg/kg (high) and 2.5
mg/kg (low), given every 3 days for up to 3 weeks, using the same schedule with and without a single dose
of radiation of 10 Gy. Control tumors had an average TGD of 10 days whereas low-dose aflibercept
increased TGD by 10 days. A single dose of radiation of 10 Gy increased TGD 10 days over that of control
whereas radiation plus low-dose aflibercept increased TGD 20 to 25 days over that of control. High-dose
aflibercept increased TGD 40 days over that of control but did not show any increased benefit when
combined with radiation. These results show indicate that aflibercept alone is an effective inhibitor of tumor
growth in the U87 glioblastoma model and that low-dose aflibercept in combination with single dose radiation
has an enhanced effect on tumor cell kill [514567].
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12
In June 2003, Regeneron published data showed aflibercept shrunk growing tumors and their metastases in
a mouse model of anaplastic Wilms tumor. Tumor shrinkage appeared to be caused by the collapse and
eventual elimination of blood vessels within the tumors. Collapse of tumor blood vessels was seen within a
day of treatment initiation and was followed by marked tumor regression over a period of a few weeks,
including regression of lung micrometastases, present at the start of treatment. On examination, treated
tumors had a virtual absence of blood vessels by day 36. The kidneys returned to an almost normal
appearance by day 36. While the number of established metastases had not significantly changed with
treatment, the tumors were much smaller in the aflibercept-treated lungs [492907]. Similar data were
presented in February 2004 at the New Targets and Innovative Strategies in Cancer Treatment: One Year of
Progress meeting in Nice, France [524997].
In May 2003, preclinical data were presented at the Growth Factor Receptors meeting in Philadelphia, PA.
Reduction in tumor growth was seen in murine melanoma, human A673 rhabdomyosarcoma and rat C6
glioma tumor models when administered twice-weekly doses of 25 mg/kg or 2.5 mg/kg aflibercept [495949].
Similar data were presented in February 2004 at the New Targets and Innovative Strategies in Cancer
Treatment: One Year of Progress meeting in Nice, France [524997].
In February 2003, preclinical data were presented at the SMi Angiogenesis conference in London, UK. The
compound aflibercept was effective in blocking the growth of different tumor types in mice. Vascular
remodeling was acheived, with various sc tumor types reverting to normal vasculature morphologies
following treatment [479492].
In August 2002, Regeneron published two preclinical studies which compared aflibercept to three
approaches to blocking angiogenesis: a mAb that binds and blocks VEGF, a mAb that binds and blocks the
VEGF receptor, and an RNA-based fluoropyrimidine aptamer that binds and blocks VEGF. The studies,
which also examined multiple tumor types, suggested that aflibercept may be the most potent of the VEGF
blockers tested and could be used to achieve a greater degree of VEGF blockade. One study indicated that
a greater degree of VEGF blockage may dramatically and differentially modify the progress of vessel growth
in tumors. With partial VEGF blockage, new vessel growth is inhibited while existing blood vessels that
fueled early tumor growth remain intact. In contrast, it appears that the more complete blockage achieved by
aflibercept eventually leads to regression of the existing vessels as well, and tumor growth is significantly
more inhibited [461572].
In March 2001, data were presented at the Angiogenesis Euro conference in Paris, France. The compound
aflibercept was reported to have in vivo antitumor activity through the generation of smaller tumors devoid of
blood vessels [407696].
PSORIASIS
Tests in animal models of psoriasis performed before December 2000 suggested that aflibercept may be a
useful therapy [411378]. Data presented to the Angiogenesis Euroconference in Paris, France in March
2001, demonstrated efficacy in a mouse model of psoriasis. Clinical trials in either cancer or psoriasis were
planned at this time [407696]. However, in February 2004, the psoriasis indication was not listed for the
program [521119].
ADDITIONAL INFORMATION
Aflibercept blocks placental growth factor (PIGF) receptor binding [557257], [601710] and was developed
using Regeneron's Trap technology platform. The drug is a fusion protein of a soluble decoy receptor
comprising portions of VEGF receptors 1 and 2 [504344], [531117].
LITERATURE REVIEW
Sin Lau, Daniela D Rosa and Gordon Jayson, Cancer Research UK Department of Medical Oncology,
Christie Hospital, Withington, Manchester M20 4BX, United Kingdom
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13
Submission date: 6 July 2005
Publication date: 18 August 2005
INTRODUCTION
Angiogenesis, the formation of new blood vessels, is a process that is critical during both normal
physiological development and in various pathological states such as cancer and retinal neovascularization.
Throughout cancer progression, the growth of tumor cells is dependent on the delivery of oxygen and
nutrients, as well as the removal of waste metabolic products. Solid tumors up to ~ 2 mm3 are able to feed
off nearby pre-existing vascular structures. However, the development of a blood supply is required for
tumors to further increase in size. Thus, the disruption of angiogenesis has long been recognized as a
means of treating cancer [614462].
The onset of tumor angiogenesis involves a change in the balance of stimulatory and inhibitory influences
[614462]. Most human tumors remain in situ for a long period of time (ranging from months to years) in an
avascular, quiescent status. In this phase the tumor may contain a few million cells. When a subgroup of
cells within the tumor switches to an angiogenic phenotype by changing the local equilibrium between
positive and negative regulators of angiogenesis, leading to neovascularization, the tumor starts to grow
rapidly and becomes clinically detectable [614462]. Many molecules have been implicated as positive
regulators of angiogenesis, acting either directly or indirectly, including vascular endothelial growth factor
(VEGF), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), platelet-derived growth factor
(PDGF), matrix metalloproteinases (MMPs), placental growth factor (PlGF) and angiopoietin-1 and -2 (Ang-1
and Ang-2) [614463].
The VEGF family comprises a number of glycoprotein growth factors that include VEGF-A, VEGF-B, VEGFC, VEGF-D, placental growth factor-1 (PlGF-1) and PlGF-2. The first of these, VEGF-A, which was originally
identified as vascular permeability factor but is now more usually referred to as VEGF, appears to have a
critical role in the angiogenic process. The VEGF-A gene contains eight exons and undergoes variable
splicing to produce several isoforms named according to their amino acid sequence length, thereby
generating VEGF121, VEGF145, VEGF165, VEGF189 and VEGF206. These isoforms exhibit different
characteristics with respect to their secretion into and sequestration within the extracellular matrix (ECM).
For example, VEGF121 diffuses well in the interstitium because it does not bind to ECM heparan-sulfate
proteoglycans. In contrast, VEGF165 does bind to ECM proteoglycans and is released from the matrix
slowly [614463].
The exposure of cells to hypoxia stimulates the expression of VEGF. As a response to hypoxia the
transcription factor hypoxia-inducible factor-1 (HIF-1alpha) is produced, which binds to a site within the
promoter region of VEGF and enhances transcription [407820]. The mutant ras oncogene, which is
commonly expressed in human cancers, also has an up-regulatory effect of VEGF expression [216924]. The
regulation of VEGF splicing may be a critical switch from an anti-angiogenic to a pro-angiogenic phenotype.
VEGF165 appears to be the predominant isoform produced by tumors and thus a likely candidate for
targeting with anti-angiogenic therapies. VEGF165b is an endogenous splice variant that is expressed as
protein in normal cells and tissues and circulates in human plasma [612376]. It binds to VEGF receptor 2
(VEGFR-2) with the same affinity as VEGF165 but does not activate it or stimulate downstream signaling
pathways. In addition, it prevents VEGF165-mediated VEGFR-2 phosphorylation and signaling in cultured
cells. VEGF165b is not angiogenic and inhibits VEGF165-mediated angiogenesis in rabbit cornea and rat
mesentery. Tumors that express VEGF165b grow more slowly than VEGF165-expressing tumors, indicating
that a switch in splicing from VEGF165 to VEGF165b can inhibit tumor growth [612376].
The biological effects of VEGF are mediated by VEGF receptor 1 (VEGFR-1) and VEGFR-2, which are
localized on endothelial cell surface receptors, and VEGF receptor 3 (VEGFR-3), which is expressed within
lymphatic vessels [614463]. These receptors consist of an extracellular ligand-binding region that contains
seven immunoglobulin-like domains, a transmembrane region and an intracellular split tyrosine kinase
domain. Ligand binding with VEGF results in receptor dimerization, autophosphorylation and activation of
the kinase domains leading to an intracellular signaling cascade. The second and third domains of the Fmslike tyrosine kinase receptor (Flt-1) provide the binding site for VEGF [420914]. When the receptor-binding
properties of VEGF121 and VEGF165 were compared, VEGF165 bound to a class of VEGF receptors that
was not recognized by VEGF121 [614471]. This receptor, neuropilin-1, lacks any intrinsic functional
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14
intracellular domain and probably acts as a co-receptor for VEGFR-2.
In animals, blockade of the VEGF pathway has been achieved by many different means, including the use of
antibodies targeted against VEGF [133839] or its receptors [614473], soluble decoy receptors that prevent
VEGF from binding to its normal receptors [614474], [614475] and small molecule inhibitors of the tyrosine
kinase activity of the VEGFRs [321926]. Development of these compounds as both scientific tools and
therapeutic agents has led to a more complete understanding of the actions of VEGF, and a number of
these drugs have since progressed into clinical trials. By targeting VEGF with the humanized monoclonal
antibody bevacizumab (Avastin), the promise of anti-angiogenic therapy has finally been realized. In a
landmark phase III clinical trial in patients with metastatic colorectal cancer, the addition of bevacizumab to
standard irinotecan-based chemotherapy resulted in significant improvements in overall survival,
progression-free survival and overall response rate [541911]. Other clinical trials of bevacizumab
demonstrated a survival benefit in non-small cell lung cancer [614954] and an improvement in progressionfree survival in metastatic renal [508055] and breast cancers [614955]. Taken together, these trials provide
the proof of concept that anti-angiogenic therapy, and specifically targeting the VEGF pathway, can be of
clinical benefit in treating cancer. However, trials with small molecule inhibitors targeting the tyrosine kinase
activity of the VEGFRs have failed to achieve primary endpoints in initial randomized studies, for example
semaxanib (which was previously being developed by SUGEN Inc) [614478] and lapatinib (GlaxoSmithKline
plc) [614481].
Sanofi-Aventis and Regeneron Pharmaceuticals Inc are developing systemic VEGF Trap (AVE-0005) for the
potential treatment of cancer. VEGF Trap is a protein that specifically disrupts VEGF signaling by acting as a
soluble decoy receptor. Its activity is dependent upon binding to and then sequestering circulating VEGF
thereby preventing the binding of VEGF to its target receptors. By doing so, the process of angiogenesis is
reduced [614463].
Systemic VEGF Trap was previously being developed for the potential treatment of age-related macular
degeneration (AMD) and diabetic macular edema. Currently an intravitreal formulation is being tested for
AMD [579058], however this evaluation will discuss only studies with the systemic VEGF Trap for
oncological indications.
SYNTHESIS AND SAR
The original VEGF Trap protein was a fusion product of the first three immunoglobulin (Ig) domains of
VEGFR-1 and the constant portion (Fc) of human IgG1. This construct had demonstrable activity in various
rodent-based studies of angiogenesis and served as a useful laboratory tool. The antitumor effects of
VEGFR1-Fc and VEGFR-2 were then found to be dose-dependent and VEGFR-1-Fc was efficacious at a
concentration ~ 500-fold lower than for a similar VEGFR-2 construct; however, it was disadvantaged by a
poor pharmacokinetic profile, which required frequent administrations at very high doses to achieve effective
concentrations [614474], [614475], [614482]. A consequence of this was an unacceptable toxicity profile
compared with the VEGFR2-Fc. Therefore, attempts were made to enhance the pharmacokinetic profile of
the soluble decoy receptor whilst maintaining its high affinity binding characteristics. Based on the
hypothesis that the high positive charge of the protein promoted attraction to the negatively charged
proteoglycans within the ECM, modifications were made to the basic regions that lay within the first Ig
domain and the basic region made up of ten amino acid residues within the third Ig domain [512546]. These
modified fusion proteins were less positively charged and demonstrated reduced binding to the ECM and a
superior maximum concentration (Cmax) and area under curve (AUC). Further modifications to minimize the
interactions with extracellular matrix resulted in the development of a parent VEGF TrapR1R2 molecule,
which combined the high affinity second Ig domain of VEGFR-1 and the high affinity third Ig domain of
VEGFR-2 with the Fc region of IgG1. The resultant VEGF Trap (referred to hereafter as the modified VEGF
Trap or simply as VEGF Trap) had a smaller negative charge and an improved pharmacokinetic profile.
CHO cells were used to produce the VEGF Trap variants, although details of the purification were not
disclosed [512546].
PRECLINICAL DEVELOPMENT
The ability of VEGF Trap to bind VEGF in vitro was confirmed in preliminary analyses. The modified VEGF
Trap had a higher binding affinity (Kd ~ 1 pM) than parental VEGF Trap (Kd ~ 5 pM). An assay to detect
VEGF-induced VEGFR-2 phosphorylation demonstrated that either VEGF Trap molecule (tested at a 1.5fold molar excess to VEGF) was able to completely block any detectable activation of VEGFR-2. Modified
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15
and parental VEGF Trap inhibited VEGF-induced proliferation in 3-day growth assays in a cell line
containing a chimeric VEGFR-2/TrkB receptor with approximate IC50 values of 0.5 nM and 1.5 nM,
respectively [512546].
Having demonstrated the superiority of VEGF Trap to its parent molecule, tumor growth inhibitory activity
was investigated. In murine tumor models subcutaneous injections of VEGF Trap (2.5 and 25 mg/kg twiceweekly) for 2 to 3 weeks significantly inhibited the growth of mouse B16F10 melanoma (p = 0.01), human
A673 rhabdomyosarcoma (p = 0.06) and rat C6 glioma (p < 0.0001) cells. In the vehicle-treated mice, C6
tumors were highly vascularized and much larger compared with mice treated with 2.5 and 25 mg/kg VEGF
Trap, where the tumors were greatly stunted and largely avascular, respectively. Both VEGF Trap doses
resulted in large areas of necrosis. Near-complete blockage of tumor-associated angiogenesis was achieved
at the higher dose of VEGF Trap whereas at the lower dose, complete blockage was slightly less effective.
In order to visualize the vasculature, the tumors were sectioned and immunostained with antibodies to
platelet-endothelial cell adhesion molecule [512546].
The same effect was demonstrated in nude athymic mice bearing xenografts derived from four human
pancreatic cell lines, BxPC3, T3M4, COLO-357 and PANC-1. Twice-weekly injections of control buffer or
VEGF Trap (25 mg/kg) were initiated 2 days after subcutaneous injection of cancer cells. No significant
differences in tumor growth were detected either in VEGF Trap-treated or control-treated mice at the end of
week 1. However, VEGF Trap-treated mice showed a 97% inhibition of the growth of COLO-357 and PANC1 tumors after 5 and 6 weeks respectively, 92% inhibition of BxPC3 tumors after 6 weeks and 89% inhibition
of T3M4 tumors after 2 weeks by comparison with control mice [582679].
The effects of VEGF Trap on tumor vessel formation were compared with those of two other anti-VEGF
agents: pegaptanib, an RNA-based fluoropyrimidine polyethylene glycol-conjugated aptamer targeting
VEGF165, and A.4.6.1 (Genentech Inc), the parental anti-VEGF monoclonal antibody that was developed to
become bevacizumab [472985]. In a neuroblastoma xenograft murine model, tumor growth inhibition was
induced by all of the agents tested, as compared with controls. However, statistical significance was only
achieved with twice-weekly intraperitoneal dosing with VEGF Trap (500 microg), which inhibited tumor
growth by 81%. The lower dose of VEGF Trap (100 microg) inhibited tumor growth by 70%. In VEGF Traptreated animals, sparse microvessel density and poor co-option of established vessels were observed. The
association of this pattern of vascular development with tumor growth inhibition suggested that the reduced
levels of VEGF, induced by the anti-VEGF antibody or 100 microg VEGF Trap, were able to sustain existing
co-opted vessels but were insufficient for angiogenesis, with tumor growth still being supported to a limited
extent. However, compared to controls, the greater degree of VEGF blockade induced by 500 microg VEGF
Trap given twice-weekly resulted in decreases in microvessel density (54%, p = 0.037), total vessel length
(42%, p = 0.01), vessels ends (63%, p < 0.004) and branches points or nodes (80%, p < 0.004), with a
79.3% reduction in the mean tumor weight (p < 0.0002) [512542].
A recent study investigated VEGF Trap in mouse xenografts of six Ewing's sarcoma family of tumors (ESFT)
cell lines. A significant correlation was observed between microvessel density and the expression of VEGF,
but not other over-expressed growth factors. Twice-weekly administration of VEGF Trap delayed
subcutaneous tumor growth of ESFT RD-ES cells at both high (25 mg/kg) and low (2.5 mg/kg) doses
compared with the controls (both p = 0.001). VEGF Trap also inhibited the growth of A673 tumors but only at
the higher (25 mg/kg) dose (p = 0.0005) [613363].
In murine models, VEGF Trap also decreased the volume of metastatic deposits in the lung [512542] and
inhibited formation of ascites in murine models [582688]. Lung metastases decreased in size 36 days after
twice-weekly treatment with VEGF Trap (500 microg, ip). The size of pulmonary lesions was quantified at
days 0 and 36 by diameter, volume and individual cell count. The diameter, volume and cell count per
metastasis decreased on average by 80% (225.2 +/- 35.4 to 89.2 +/- 8.4 microm, p = 0.0005), 78% (0.0023
+/- 0.0009 to 0.00018 +/- 0.0001 mm3, p = 0.0004) and 83% (115.3 +/- 16.9 to 20.1 +/- 7.2, p = 0.0002)
respectively [512542].
VEGF Trap has also demonstrated activity in combination with paclitaxel in a mouse model of ovarian
cancer, dramatically reducing tumor burden and ascites. Female athymic nude mice (n = 40) were divided
into four groups and inoculated intraperitoneally with OVCAR-3 cells. After 2 weeks, the first group was
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16
treated with subcutaneous VEGF Trap twice-weekly (undisclosed dose) and intraperitoneal paclitaxel threetimes per week for 2 weeks. Other groups were administered VEGF Trap or paclitaxel alone, or vehicle as a
control. VEGF Trap in combination with paclitaxel resulted in a 97.7% (p < 0.01) reduction in OVCAR-3
tumor volume, VEGF Trap alone resulted in a 55.7% (p < 0.05) reduction and paclitaxel alone resulted in a
54.8% (p < 0.05) reduction compared with controls. There was no significant development of ascites in the
combined treatment group or the group treated with VEGF Trap. Paclitaxel alone reduced ascites by 85.5%
(p < 0.01) [531117].
Controlled preclinical studies in diseases other than cancer have also shown that VEGF Trap inhibited
choroidal [512544] and corneal neovascularization [512551], and suppressed the development of
retinopathy [512552]. Choroidal neovascularization was induced in C57BL/6 mice by laser photocoagulation.
VEGF Trap (25 mg/kg) or Fc fragment were administered 1 day prior to laser and on days 2, 5, 8 and 11
after laser. VEGF Trap-treated mice had smaller areas of neovascularization, with complete or nearcomplete inhibition compared with mice treated with the Fc fragment. In some mice given VEGF Trap (4.92
microg) in one eye and the Fc fragment (4.92 microg) in the other eye by intraocular injection in both cases,
a statistically significant reduction was observed in the mean area of neovascularization in VEGF Trapinjected eyes compared to the Fc fragment-injected eyes (p < 0.0001) [512544]. Corneal neovascularization
was induced by application of NaOH and mechanical debridement of the corneal epithelium in adult male
C57BL/6 mice. VEGF Trap was administered subcutaneously (12.5 mg/kg) on days 0, 7 and 14 when reepithelialization of the cornea was complete. VEGF Trap inhibited corneal neovascularization during and for
4 weeks following treatment cessation. Conjuntivalization of the cornea was inhibited, as evidenced by a
30% reduction in the number of globet cells. Corneal inflammation and edema were also reduced [512551].
In a mouse model of oxygen-induced retinopathy, 25 mg/kg of VEGF Trap was administered by
intraperitoneal injection. The treated retinas were evaluated after being flat mounted and stained with
fluorescent Griffonia simplicifolia lectin B4 to visualize the vasculature. The contralateral eyes were
embedded, sectioned and stained with hematoxylin and eosin, as controls. The treatment almost completely
blocked the development of vascular tufts penetrating the inner limiting membrane of the retina as well as
chaotic sprouting of vessels on the surface of the retina [512552].
VEGF Trap has also shown potential in psoriasis. In a study in K14-VEGF transgenic mice that overexpress
VEGF in the epidermis, generating a skin phenotype that resembles human psoriasis, systemic treatment
with VEGF Trap (25 mg/kg) every 3 days for 12 days produced a moderate to pronounced macroscopic
improvement in skin lesions, which correlated with histological improvement [512545].
Recombinant VEGF165 (10 microg) administration as a single intravenous bolus to rats resulted in acute
hypotension. A reduction in baseline systolic blood pressure of ~ 40% was observed, which was at a
maximum at 5 min and slowly returned to normal by approximately 30 min. To further characterize the length
of time in which VEGF Trap remained active, 5 mg/kg of the construct was injected prior to induction of
hypotension. Rats were monitored for 1, 3 and 7 days. At 1 and 3 days, this single dose of VEGF Trap
effectively blocked VEGF-induced acute hypotension. Further analysis revealed a Kd value of 1 to 10 pM for
VEGF121 and ~ 45 pM for PlGF-2 [512546].
METABOLISM AND PHARMACOKINETICS
Initial experiments with the modified VEGF Trap demonstrated superior pharmacokinetic characteristics
compared with parent VEGF Trap. Following a single 4 mg/kg subcutaneous injection of VEGF Trap in mice,
the Cmax value was 16 microg/ml and the AUC value was 36.28 microg.days/ml, compared with a Cmax
value of 0.05 microg/ml and AUC value of 0.04 microg.days/ml for the parent construct [512546].
The efficacy of VEGF Trap was compared with that of the monoclonal antibody IMC-1C11 (ImClone
Systems Inc), a known antagonist of VEGFR-2. A higher dose of IMC-1C11 was required to inhibit tumor
growth in the B16F10 melanoma model. Additionally, IMC-1C11 accumulated in serum to levels ~ 60-fold
higher than VEGF Trap. Circulating levels of IMC-1C11 and VEGF Trap in treated mice were 2442 +/- 272
microg/ml (40 mg/kg dose) and 40 +/- 8 microg/ml (3.2 mg/kg dose) respectively [512546].
In a phase I trial in patients with relapsed or refractory solid tumors, subcutaneously administered VEGF
Trap (800 microg/kg) had an elimination half-life of 25 days. Steady state serum levels of ~ 14 microg/ml and
7 to 8 microg/ml were achieved following twice- and once-weekly doses of 800 microg/kg, respectively.
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© 2013 Thomson Reuters All rights reserved
17
Preclinical experiments suggested that the minimum effective dose was 10 microg/ml [543400].
A similar pharmacokinetic study of intravenously administered VEGF Trap (0.3, 1 and 2 mg/kg every 2
weeks) in patients with relapsed or refractory solid tumors showed a proportional increase in peak total
VEGF Trap serum concentration within the first two dose levels [603203].
TOXICITY
No significant toxicities have been reported in preclinical studies.
CLINICAL DEVELOPMENT
An open-label study of single, escalating doses of VEGF Trap was conducted in patients with relapsed or
refractory solid tumors or lymphoma. One (or two) doses of subcutaneous VEGF Trap were administered to
patients (n = 38 in total), followed 4 weeks later by six weekly (0.025, 0.05, 0.1, 0.2, 0.4 and 0.8 mg/kg) or
six twice-weekly (0.8 mg/kg) doses [491964], [543400], [562697]. The maximum tolerated dose was not
reached, but no dose-related adverse effects were observed. No patients developed anti-VEGF Trap
antibodies (including those treated for >/= 6 months). No partial or complete responses were observed, but
17 of the 35 evaluable patients (including 8 of the 12 patients who had been treated with 800 microg/kg
VEGF Trap once-weekly or twice-weekly) achieved stable disease for at least 10 weeks [562697]. Patients
with renal cell carcinoma were specifically noted to have achieved stable disease for up to 15 weeks
[491964].
Another phase I trial involved intravenous administration of VEGF Trap (0.3, 1, 2, 3 and 4 mg/kg) every 2
weeks to patients (n = 27) with advanced solid tumors, including ovarian, kidney and colon cancers. No
patients had developed antibodies to VEGF Trap and the maximum tolerated dose had not been reached by
the time of publication, but dose escalations were to continue [601710], [603203]. At the time of publication,
one patient had achieved a partial response with disappearance of ascites, two patients had minor
responses and one patient had maintained stable disease for over 11 months [601710]. Specifically, one
patient with metastatic renal cell carcinoma maintained stable disease for over 6 months and a minor
response was observed in another patient with advanced uterine leiomyosarcoma, both had been treated
with 1 mg/kg VEGF Trap [603203].
A further phase I trial has recently been initiated that will evaluate the safety, tolerability and efficacy of
escalating doses of VEGF Trap administered in combination with FOLFOX4 (oxaliplatin, 5-fluorouracil and
leucovorin) chemotherapy. The study will also assess objective response rate, duration of response and time
to tumor progression. The multicenter trial will include patients with advanced solid malignancies that are
metastatic or unresectable and suitable for treatment with FOLFOX4, such as metastatic colorectal cancer.
Further details from the trial have yet to be released [601097].
SIDE EFFECTS AND CONTRAINDICATIONS
In the phase I study of subcutaneously administered VEGF Trap, grade 1 and 2 toxicities included reversible
proteinuria, fatigue and constipation [491964]. Grade 3 or 4 adverse events included hypertension (n = 2),
proteinuria (n = 1), afebrile neutropenia (n = 1), pulmonary embolism (n = 1) and hypertension (n = 4).
Serious dehydration and hypotension were recorded in a patient in the 0.1 mg/kg dose group. At the time
there was radiological evidence of cerebral ischemia but following rehydration the symptoms resolved and
an MRI scan did not detect cerebral ischemia. Another patient on the 0.8 mg/kg twice-weekly dose was
diagnosed with a pulmonary embolism; however, a review of baseline radiological investigations showed
that this had been present prior to treatment. Other severe events included a patient with proteinuria and
another with leukopenia, both of which resolved on discontinuation of treatment [543400], [562697].
Side effects in patients administered intravenous VEGF Trap included fatigue (n = 9), pain (n = 4) and
constipation (n = 4), which were mild to moderate in severity. Hypertension was also observed occasionally.
The majority of adverse events were manageable and reversible [601710], [603203]. One patient had doselimiting arthralgia, fatigue and voice changes and another had a non-dose-limiting transient elevation in
alanine transaminase levels. Two patients experienced potentially drug related grade 3 adverse events, but
no grade 4 or 5 adverse events were encountered [603203].
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© 2013 Thomson Reuters All rights reserved
18
PATENT SUMMARY
Regeneron holds several patents relating to VEGF Trap. The first application by Regeneron and Columbia
University claiming the use of VEGF Trap for the treatment of tumors (WO-2004110490) was published in
December 2004. In February 2005, PCT applications were filed claiming the use of VEGF Trap for the
treatment of cancer, in synergistic combination with an antiproliferative agent (WO-2005011734) and in
combination with radiation therapy (WO-2005016369).
Several non-oncological indications have also been claimed. In October 2004, Regeneron filed a PTC
application (WO-2004087206) disclosing the use of VEGF Trap in the treatment of diabetes, and in
December 2004 published WO-2004106378 (together with the Schepens Eye Research Institute), detailing
the use of VEGF Trap for prevention of corneal transplant rejection. Regeneron also published an
application in January 2005 disclosing the use of VEGF Trap in the treatment of AMD (WO-2005000895).
A PTC application was filed in December 2004 by The Board of Trustees of the Leland Stanford Junior
University claiming the use of VEGF Trap in inhibiting pregnancy and treating abnormal gynecological
bleeding (WO-2004103159).
CURRENT OPINION
Over the past decade, the treatment of cancer has witnessed a revolution with the era of 'targeted therapy'.
Advances in molecular cell biology have begun to uncover the numerous growth factors, their corresponding
cell surface receptors and associated intracellular signaling pathways, each of which has offered a potential
target for novel therapy. The angiogenesis pathway has been recognized as a potential target for therapy for
over 30 years. This clinical promise has finally been realized with the licensing of bevacizumab for the
treatment of metastatic colorectal cancer. This validates not only the principle of anti-angiogenic therapy but
also proves that specifically targeting VEGF can be of therapeutic benefit. It also begs the question of
whether bevacizumab can be improved on and whether an agent that targets VEGF can more effectively
produce even greater clinical benefits.
Development of the modified VEGF Trap protein from its parent compound yielded a soluble decoy receptor
with a superior pharmacokinetic profile whilst still maintaining a high binding affinity, thereby representing a
paradigm of rational design. The observation that the original VEGF Trap molecule required frequent high
dosing suggested that it was being retained within the ECM due to its high positive charge. This hypothesis
was supported by the removal of the highly charged areas and the accompanying improvement in
bioavailability. Subsequent in vitro assays confirmed that VEGF Trap had improved binding affinity for VEGF
and was a potent inhibitor of VEGFR-2 activation.
The preclinical data for VEGF Trap demonstrate significant antitumor activity in a number of tumor models.
Additional analyses within these studies have also, uniformly, detected the suppression of pathological
neoangiogenesis within the tumors. Two studies showed that the anti-angiogenic effect produced by VEGF
Trap was dose dependent [472985], [512546]. In one study this resulted in the persistence of co-opted host
vasculature that was abrogated by the lower dose, suggesting that low levels of VEGF are sufficient to
maintain this pre-angiogenic state. A comparison was also performed with a monoclonal anti-VEGF antibody
that demonstrated similar efficacy to the lower dose of VEGF Trap. Although it would be tempting to suggest
that VEGF Trap (at the higher dose) is superior to A.4.6.1 (the monoclonal anti-VEGF antibody that
preceded bevacizumab), this would be premature. A number of reasons that could account for the apparent
difference in efficacy would need to be addressed, such as pharmacokinetic considerations (different dosing
regimens or half-lives) and biological factors (additional activity of VEGF Trap against the murine host
VEGF).
The results of the two phase I trials of VEGF Trap in patients with refractory or relapsed cancer are
encouraging. The drug appears to be well tolerated with a side-effect profile consistent with other inhibitors
of VEGF. When subcutaneously administered two serious adverse events were reported and only one was
likely to be drug related. When intravenously administered only one dose limiting adverse event was
reported within the first two cohorts. The lack of any anti-drug antibody formation or acute allergic reactions
was also advantageous. Compared with data from the phase III bevacizumab trial [541911], VEGF Trap
appears to produce similar rates of grade 2 to 3 proteinuria and manageable hypertension.
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© 2013 Thomson Reuters All rights reserved
19
VEGF Trap was associated with disease stabilization in a number of patients and this was more prevalent at
the higher doses, which is consistent with biological activity. It is perhaps disappointing, however, that given
the promising preclinical data only one partial response has thus far been observed. There are many
possible reasons for this and the lack of such responses may not necessarily be a reflection of the activity of
VEGF Trap. Indeed, responses have not generally been seen in the phase I studies of anti-VEGF
antibodies; rather it is the high prevalence of stable disease that is consistent with the phase I trial of, for
example, bevacizumab [420916].
The clinical benefit produced by bevacizumab is, on the whole, observed when it is combined with
conventional cytotoxic chemotherapy and not as a single agent. One hypothesis for the mode of action of
anti-angiogenic agents is that they promote vascular normalization and thus facilitate the delivery of
systemic cytotoxic agents to the tumor. The apparent synergy between VEGF Trap and paclitaxel in the
OVCAR-3 mouse model also makes a strong case for combination therapy [531117]. This makes the finding
that VEGF Trap appeared not to interfere with normal revascularization in the retinopathy model very
interesting [512552]. By inhibiting pathological angiogenesis but allowing ordered revascularization, VEGF
Trap in combination with traditional cytotoxic drugs may provide support for the normalization hypothesis
and become a potent anticancer therapy.
At present numerous anti-angiogenic agents are being investigated as potential cancer therapies. These
include other antibodies that target VEGF, antibodies that target the VEGFRs, small molecule inhibitors of
VEGFR, and ribozymes targeting VEGFR mRNA. Apart from bevacizumab, only vatalanib (Novartis AG's
small molecule VEGFR tyrosine kinase inhibitor) is currently undergoing phase III clinical trials, namely
CONFIRM-1 and CONFIRM-2 for patients with metastatic colorectal cancer. Preliminary results for
CONFIRM-1 indicate that the addition of vatalanib to standard FOLFOX4 chemotherapy in the first line
metastatic setting has not significantly improved progression-free survival following central radiological
review. However, a preplanned analysis based on investigator review did demonstrate a statistically
significant 17% reduction in risk of progression. Overall survival data were not available [603203].
Based on these initial results the strategy of targeting VEGF rather than its receptor appears to have validity.
This may reflect the fact that VEGF maintains angiogenesis through other receptors such as VEGFR-1; we
know that there is a synergy between VEGFR-1 and VEGFR-2. Thus the ability of VEGF Trap to bind the
ligands for VEGFR-1 and VEGFR-2 should increase the clinical potential of the molecule, through a more
comprehensive suppression of VEGFR activation and thus more effective inhibition of pathological
angiogenesis.
DEVELOPMENT STATUS
CURRENT DEVELOPMENT STATUS
Company
Indication
Country
Development Status
Date
Regeneron
Pharmaceuticals Inc
Metastatic colorectal cancer
US
Launched
31-Aug-2012
Sanofi
Metastatic colorectal cancer
US
Launched
31-Aug-2012
Regeneron
Pharmaceuticals Inc
Metastatic colorectal cancer
EU
Registered
05-Feb-2013
Sanofi
Metastatic colorectal cancer
EU
Registered
05-Feb-2013
Regeneron
Pharmaceuticals Inc
Colorectal tumor
Australia
Phase 3 Clinical
20-Nov-2007
Regeneron
Pharmaceuticals Inc
Colorectal tumor
New Zealand Phase 3 Clinical
20-Nov-2007
Regeneron
Pharmaceuticals Inc
Colorectal tumor
South Africa
20-Nov-2007
Phase 3 Clinical
Return to Table of Contents
© 2013 Thomson Reuters All rights reserved
20
Company
Indication
Country
Regeneron
Pharmaceuticals Inc
Colorectal tumor
South America Phase 3 Clinical
Development Status
Date
20-Nov-2007
Regeneron
Pharmaceuticals Inc
Colorectal tumor
South Korea
Phase 3 Clinical
20-Nov-2007
Regeneron
Pharmaceuticals Inc
Hormone refractory prostate
cancer
Canada
Phase 3 Clinical
21-Aug-2007
Regeneron
Pharmaceuticals Inc
Hormone refractory prostate
cancer
Europe
Phase 3 Clinical
21-Aug-2007
Regeneron
Pharmaceuticals Inc
Hormone refractory prostate
cancer
Far East
Phase 3 Clinical
21-Aug-2007
Regeneron
Pharmaceuticals Inc
Hormone refractory prostate
cancer
Israel
Phase 3 Clinical
21-Aug-2007
Regeneron
Pharmaceuticals Inc
Hormone refractory prostate
cancer
South America Phase 3 Clinical
21-Aug-2007
Regeneron
Pharmaceuticals Inc
Hormone refractory prostate
cancer
Turkey
Phase 3 Clinical
21-Aug-2007
Regeneron
Pharmaceuticals Inc
Hormone refractory prostate
cancer
US
Phase 3 Clinical
21-Aug-2007
Regeneron
Pharmaceuticals Inc
Metastatic non small cell lung
cancer
Europe
Phase 3 Clinical
19-Sep-2007
Regeneron
Pharmaceuticals Inc
Metastatic non small cell lung
cancer
Far East
Phase 3 Clinical
19-Sep-2007
Regeneron
Pharmaceuticals Inc
Metastatic non small cell lung
cancer
South America Phase 3 Clinical
19-Sep-2007
Regeneron
Pharmaceuticals Inc
Metastatic non small cell lung
cancer
US
Phase 3 Clinical
19-Sep-2007
Regeneron
Pharmaceuticals Inc
Non-small-cell lung cancer
Canada
Phase 3 Clinical
03-Jun-2007
Sanofi
Colorectal tumor
Australia
Phase 3 Clinical
20-Nov-2007
Sanofi
Colorectal tumor
New Zealand Phase 3 Clinical
20-Nov-2007
Sanofi
Colorectal tumor
South Africa
Phase 3 Clinical
20-Nov-2007
Sanofi
Colorectal tumor
South America Phase 3 Clinical
20-Nov-2007
Sanofi
Colorectal tumor
South Korea
Phase 3 Clinical
20-Nov-2007
Sanofi
Hormone refractory prostate
cancer
Canada
Phase 3 Clinical
21-Aug-2007
Sanofi
Hormone refractory prostate
cancer
Europe
Phase 3 Clinical
21-Aug-2007
Sanofi
Hormone refractory prostate
cancer
Far East
Phase 3 Clinical
21-Aug-2007
Sanofi
Hormone refractory prostate
cancer
Israel
Phase 3 Clinical
21-Aug-2007
Sanofi
Hormone refractory prostate
cancer
South America Phase 3 Clinical
21-Aug-2007
Sanofi
Hormone refractory prostate
cancer
Turkey
Phase 3 Clinical
21-Aug-2007
Sanofi
Hormone refractory prostate
cancer
US
Phase 3 Clinical
21-Aug-2007
Sanofi
Metastatic non small cell lung
cancer
Europe
Phase 3 Clinical
19-Sep-2007
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© 2013 Thomson Reuters All rights reserved
21
Company
Indication
Country
Development Status
Date
Sanofi
Metastatic non small cell lung
cancer
Far East
Phase 3 Clinical
19-Sep-2007
Sanofi
Metastatic non small cell lung
cancer
South America Phase 3 Clinical
19-Sep-2007
Sanofi
Metastatic non small cell lung
cancer
US
Phase 3 Clinical
19-Sep-2007
Sanofi
Non-small-cell lung cancer
Canada
Phase 3 Clinical
03-Jun-2007
Regeneron
Pharmaceuticals Inc
Glioma
US
Phase 2 Clinical
09-Oct-2006
Regeneron
Pharmaceuticals Inc
Melanoma
US
Phase 2 Clinical
31-May-2009
Regeneron
Pharmaceuticals Inc
Multiple myeloma
US
Phase 2 Clinical
31-Jan-2007
Sanofi
Glioma
US
Phase 2 Clinical
09-Oct-2006
Sanofi
Melanoma
US
Phase 2 Clinical
31-May-2009
Sanofi
Multiple myeloma
US
Phase 2 Clinical
31-Jan-2007
Sanofi
Small-cell lung cancer
US
Phase 2 Clinical
27-May-2009
Regeneron
Pharmaceuticals Inc
Advanced solid tumor
Canada
Phase 1 Clinical
30-Sep-2012
Regeneron
Pharmaceuticals Inc
Advanced solid tumor
US
Phase 1 Clinical
30-Sep-2012
Regeneron
Pharmaceuticals Inc
Fallopian tube cancer
US
Phase 1 Clinical
31-May-2009
Regeneron
Pharmaceuticals Inc
Peritoneal tumor
US
Phase 1 Clinical
31-May-2009
Regeneron
Pharmaceuticals Inc
Solid tumor
Japan
Phase 1 Clinical
12-Mar-2007
Sanofi
Advanced solid tumor
Canada
Phase 1 Clinical
30-Sep-2012
Sanofi
Advanced solid tumor
US
Phase 1 Clinical
30-Sep-2012
Sanofi
Colorectal tumor
Japan
Phase 1 Clinical
19-Dec-2011
Sanofi
Fallopian tube cancer
US
Phase 1 Clinical
31-May-2009
Sanofi
Peritoneal tumor
US
Phase 1 Clinical
31-May-2009
Sanofi
Prostate tumor
Japan
Phase 1 Clinical
19-Dec-2011
Sanofi
Solid tumor
Japan
Phase 1 Clinical
12-Mar-2007
Regeneron
Pharmaceuticals Inc
Age related macular
degeneration
US
Discontinued
10-Jan-2005
Regeneron
Pharmaceuticals Inc
Ascites
US
Discontinued
11-Jun-2009
Regeneron
Pharmaceuticals Inc
Diabetic retinopathy
US
Discontinued
10-Jan-2005
Regeneron
Pharmaceuticals Inc
Metastatic pancreas cancer
US
Discontinued
11-Sep-2009
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© 2013 Thomson Reuters All rights reserved
22
Company
Indication
Country
Development Status
Date
Regeneron
Pharmaceuticals Inc
Ovary tumor
Canada
Discontinued
11-Jun-2009
Regeneron
Pharmaceuticals Inc
Ovary tumor
Europe
Discontinued
11-Jun-2009
Regeneron
Pharmaceuticals Inc
Ovary tumor
US
Discontinued
11-Jun-2009
Sanofi
Age related macular
degeneration
US
Discontinued
10-Jan-2005
Sanofi
Ascites
US
Discontinued
11-Jun-2009
Sanofi
Diabetic retinopathy
US
Discontinued
10-Jan-2005
Sanofi
Ovary tumor
Canada
Discontinued
11-Jun-2009
Sanofi
Ovary tumor
Europe
Discontinued
11-Jun-2009
Sanofi
Ovary tumor
US
Discontinued
11-Jun-2009
Sanofi
Pancreas tumor
France
Discontinued
11-Sep-2009
Regeneron
Pharmaceuticals Inc
B-cell lymphoma
France
No Development Reported
11-Dec-2012
Regeneron
Pharmaceuticals Inc
Breast tumor
US
No Development Reported
12-Feb-2010
Regeneron
Pharmaceuticals Inc
Psoriasis
US
No Development Reported
05-Feb-2004
Sanofi
B-cell lymphoma
France
No Development Reported
11-Dec-2012
Sanofi
Breast tumor
France
No Development Reported
12-Feb-2010
HISTORICAL DEVELOPMENT STATUS
Company
Indication
Country
Development Status
Date
Regeneron
Pharmaceuticals Inc
Metastatic colorectal cancer
US
Registered
03-Aug-2012
Sanofi
Metastatic colorectal cancer
US
Registered
03-Aug-2012
Regeneron
Pharmaceuticals Inc
Metastatic colorectal cancer
US
Pre-registration
31-Oct-2011
Sanofi
Colorectal tumor
EU
Pre-registration
30-Nov-2011
Sanofi
Metastatic colorectal cancer
US
Pre-registration
31-Oct-2011
Regeneron
Pharmaceuticals Inc
Ascites
US
Phase 3 Clinical
30-Jun-2006
Regeneron
Pharmaceuticals Inc
Colorectal tumor
Europe
Phase 3 Clinical
20-Nov-2007
Regeneron
Pharmaceuticals Inc
Colorectal tumor
US
Phase 3 Clinical
20-Nov-2007
Regeneron
Pharmaceuticals Inc
Metastatic pancreas cancer
US
Phase 3 Clinical
31-Dec-2007
Return to Table of Contents
© 2013 Thomson Reuters All rights reserved
23
Company
Indication
Country
Development Status
Date
Regeneron
Pharmaceuticals Inc
Ovary tumor
Canada
Phase 3 Clinical
30-Jun-2006
Regeneron
Pharmaceuticals Inc
Ovary tumor
Europe
Phase 3 Clinical
30-Jun-2006
Sanofi
Ascites
US
Phase 3 Clinical
30-Jun-2006
Sanofi
Colorectal tumor
Europe
Phase 3 Clinical
20-Nov-2007
Sanofi
Colorectal tumor
US
Phase 3 Clinical
20-Nov-2007
Sanofi
Ovary tumor
Canada
Phase 3 Clinical
30-Jun-2006
Sanofi
Ovary tumor
Europe
Phase 3 Clinical
30-Jun-2006
Sanofi
Pancreas tumor
France
Phase 3 Clinical
12-Feb-2008
Regeneron
Pharmaceuticals Inc
Non-small-cell lung cancer
US
Phase 2 Clinical
31-Dec-2005
Regeneron
Pharmaceuticals Inc
Ovary tumor
US
Phase 2 Clinical
24-Feb-2006
Sanofi
Non-small-cell lung cancer
Canada
Phase 2 Clinical
31-Dec-2005
Sanofi
Ovary tumor
US
Phase 2 Clinical
24-Feb-2006
Aventis SA
Age related macular
degeneration
US
Phase 1 Clinical
09-Mar-2004
Aventis SA
Cancer
US
Phase 1 Clinical
08-Sep-2003
Regeneron
Pharmaceuticals Inc
Age related macular
degeneration
US
Phase 1 Clinical
09-Mar-2004
Regeneron
Pharmaceuticals Inc
B-cell lymphoma
France
Phase 1 Clinical
12-Mar-2008
Regeneron
Pharmaceuticals Inc
Cancer
US
Phase 1 Clinical
29-Nov-2001
Regeneron
Pharmaceuticals Inc
Diabetic retinopathy
US
Phase 1 Clinical
28-Oct-2004
Sanofi
Age related macular
degeneration
US
Phase 1 Clinical
20-Aug-2004
Sanofi
B-cell lymphoma
France
Phase 1 Clinical
12-Mar-2008
Sanofi
Cancer
US
Phase 1 Clinical
20-Aug-2004
Sanofi
Diabetic retinopathy
US
Phase 1 Clinical
28-Oct-2004
Regeneron
Pharmaceuticals Inc
Age related macular
degeneration
US
Discovery
28-May-2002
Regeneron
Pharmaceuticals Inc
Cancer
Japan
Discovery
22-Dec-2005
Regeneron
Pharmaceuticals Inc
Cancer
US
Discovery
04-Aug-2000
Regeneron
Pharmaceuticals Inc
Psoriasis
US
Discovery
01-Dec-2000
Sanofi
Cancer
Japan
Discovery
22-Dec-2005
Return to Table of Contents
© 2013 Thomson Reuters All rights reserved
24
DRUG NAMES
Names
VEGF Trap, Regeneron/sanofi-aventis
Type
VEGF antagonist (cancer), Regeneron/sanofi-aventis
AVE-0005
Research Code
aflibercept
INN, USAN
VEGF trap
aflibercept (intravenous, cancer), Regeneron/Sanofi
VEGF Trap, Regeneron/Aventis
aflibercept (intravenous, cancer), Regeneron/sanofiaventis
Zaltrap
Trade Name
ziv-aflibercept
VEGF antagonist (cancer), Regeneron/Aventis
systemic VEGF Trap (cancer), Regeneron/sanofiaventis
Return to Table of Contents
© 2013 Thomson Reuters All rights reserved
25
SALES AND FORECASTS
CHARTS
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© 2013 Thomson Reuters All rights reserved
26
COMMENTARY
CONSENSUS SALES INFORMATION
Consensus forecast data for Sanofi and Regeneron are presented; however, no Consensus forecast data
beyond 2017 for Regeneron are currently available.
REGIONAL DEVELOPMENT AND MARKETING RIGHTS
Regeneron and sanofi-aventis (now Sanofi) jointly hold worldwide development and marketing rights, under
an agreement signed in September 2003. The companies agreed to codevelop VEGF trap in oncology,
ophthalmology and possibly in other indications in all regions except Japan [504344]. Sanofi-aventis
returned rights in ophthalmology indications in January 2005 [579058]. The agreement between the
companies for cancer indications was expanded in December 2005 to include Japan [642522].
CLINICAL TRIALS
Trials by Phase and Condition Studied
Phase 4
Clinical
Ongoing
All
Phase 3
Clinical
Ongoing
Phase 2
Clinical
Phase 1
Clinical
Phase
Unspecified
Total
All
Ongoing
All
Ongoing
All
Ongoing
All
Ongoing
All
3
4
3
6
1
2
0
0
7
12
0
0
0
0
0
5
0
1
0
6
0
0
0
4
0
1
0
0
0
5
0
0
0
1
0
2
0
0
0
3
0
0
0
0
3
0
0
0
3
0
0
0
0
1
2
0
0
1
2
0
0
0
0
0
2
0
0
0
2
0
0
1
0
1
0
0
0
2
Metastatic colorectal cancer
0
0
Solid tumor
0
0
Ovary tumor
0
0
Neoplasm
0
0
Non-Hodgkin lymphoma
0
0
0
Advanced solid tumor
0
0
Lymphoma
0
0
Fallopian tube cancer
0
0
0
Return to Table of Contents
© 2013 Thomson Reuters All rights reserved
27
Metastasis
0
0
0
0
0
1
0
1
0
0
0
2
0
0
0
0
2
0
0
0
0
0
2
0
0
0
0
0
0
2
0
0
0
2
0
0
0
1
0
1
0
0
0
2
0
0
0
0
2
0
0
0
0
0
2
0
0
0
0
2
0
0
0
0
0
2
0
0
1
1
0
0
0
0
1
1
0
0
1
1
0
0
0
0
1
1
0
0
0
1
0
0
0
0
0
1
0
0
0
1
0
0
0
0
0
1
0
0
0
1
0
0
0
0
0
1
0
0
0
1
0
0
0
0
0
1
0
0
0
1
0
0
0
0
0
1
0
0
0
1
0
0
0
0
0
1
0
0
0
1
0
0
0
0
0
1
Renal tumor
0
Cancer
0
Non-small-cell lung cancer
0
0
Melanoma
0
Ascites
0
Metastatic liver cancer
0
0
Rectal tumor
0
0
Small-cell lung cancer
0
0
Urethral disease
0
0
Metastatic breast cancer
0
0
Brain tumor
0
0
Thyroid tumor
0
0
Leiomyosarcoma
0
0
Soft tissue sarcoma
0
0
Return to Table of Contents
© 2013 Thomson Reuters All rights reserved
28
Metastatic pancreas cancer
0
0
0
1
0
0
0
0
0
0
0
1
0
0
0
0
0
0
1
0
0
0
1
0
0
0
0
1
0
0
0
0
0
1
0
0
1
0
0
0
0
0
1
1
0
0
0
0
0
0
0
1
0
0
0
1
0
0
0
0
0
1
0
0
0
1
0
0
0
0
0
1
0
0
0
1
0
0
0
0
0
1
0
0
1
0
0
0
0
0
1
0
0
1
0
0
0
0
0
1
0
0
0
1
0
0
0
0
0
1
0
0
0
1
0
0
0
0
0
1
0
0
0
1
0
0
0
0
0
1
0
0
0
1
0
0
0
0
0
1
0
0
1
0
0
0
0
0
1
Peritoneal tumor
0
Leukemia
0
Endometrioid carcinoma
0
0
0
Hormone refractory prostate cancer
0
0
0
Myeloproliferative disorder
0
0
Carcinoid tumor
0
0
Glioblastoma
0
0
Myelodysplastic syndrome
0
0
0
Metastatic esophageal cancer
0
0
0
Metastatic stomach cancer
0
0
Carcinosarcoma
0
0
Bladder cancer
0
0
Multiple myeloma
0
0
Acute myelogenous leukemia
0
0
0
Return to Table of Contents
© 2013 Thomson Reuters All rights reserved
29
Metastatic non small cell lung cancer
0
0
0
1
0
0
0
0
0
0
0
1
0
0
1
0
0
0
0
0
1
Central nervous system tumor
0
0
0
Total Trials by Phase and Status
Phase 4
Clinical
Ongoing
All
Phase 3
Clinical
Ongoing
Phase 2
Clinical
Phase 1
Clinical
Phase
Unspecified
Total
All
Ongoing
All
Ongoing
All
Ongoing
All
Ongoing
All
7
4
26
2
15
0
1
9
49
Total by Phase and Status
0
0
3
Phase Definitions
Phase 3 Clinical
Includes Phase 3, Phase 3b, Phase 3a, Phase 2/3 (where enrolment count is 300 or over)
Phase 2 Clinical
Includes Phase 2, Phase 2a, Phase 2b, Phase 1/2 (where enrolment count is 100 or over), Phase 2/3 (where enrolment count is
under 300 or not specified)
Phase 1 Clinical
Includes Phase 1, Phase 1a, Phase 1, Phase 1/2 (where enrolment count is under 100 or not specified), Phase 0
Return to Table of Contents
© 2013 Thomson Reuters All rights reserved
30
DEALS AND PATENTS
DEALS
Deals by Parent Company Chart
Deals by Parent Company Table
Company Name
Principal
Active Inactive
Partner
Total
Active Inactive
Regeneron Pharmaceuticals Inc
3
0
0
0
3
The Procter & Gamble Co
0
0
1
0
1
Sanofi
0
0
1
0
1
US Government
0
0
1
0
1
Return to Table of Contents
© 2013 Thomson Reuters All rights reserved
31
Deals by Type Chart
Deals by Type Table
Deal Type
Active
Inactive Total
Drug - Funding
1
0
1
Drug - Development/Commercialization License
1
0
1
Drug - Development Services
1
0
1
Return to Table of Contents
© 2013 Thomson Reuters All rights reserved
32
PATENTS
Patents by Parent Company Chart
Return to Table of Contents
© 2013 Thomson Reuters All rights reserved
33
Patents by Parent Company Table
Company Name
As Owner
As Third Party
Total
Regeneron Pharmaceuticals Inc
12
0
12
Sanofi
7
0
7
Ohio State University
0
1
1
Individual
1
0
1
Memorial Sloan-Kettering Cancer Center
1
0
1
Government of the Republic of Singapore
1
0
1
Friedrich-Alexander-Universitaet Erlangen-Nuernberg
0
1
1
Columbia University
1
0
1
University of California
1
0
1
Schepens Eye Research Institute
1
0
1
Patents by Drug Relationship Type Chart
Return to Table of Contents
© 2013 Thomson Reuters All rights reserved
34
Patents by Drug Relationship Type Table
Drug Relationship
Total
Component of Combination
6
New use
5
Product
2
General interest
2
Formulation
1
SWOT ANALYSIS
Anticancer angiogenesis inhibitors
Strengths
Weaknesses
Phase II AFFIRM data in first-line CRC
indicated that PFS at 1 year was not
significantly different in patients treated with
Zaltrap plus FOLFOX6 compared with
FOLFOX6 alone [1260944]
Improved overall survival in metastatic
colorectal cancer (CRC) when combined with
FOLFIRI compared with FOLFIRI alone in
the second-line setting, according to the
phase III VELOUR study (13.5 vs 12.06
months) [1197619], [1210789], [1305016]
Failed in a late-stage trial in prostate cancer;
the phase III VENICE trial did not
demonstrate improved overall survival in
metastatic androgen-resistant prostate
cancer [1277900]
A survival benefit was also consistently seen
in VELOUR in patients previously treated
with Avastin [1222598], [1305016]
Subgroup analysis of the VELOUR study
showed a benefit in patients with liver
metastases, where mortality was reduced by
35% [1305016]
The phase III trial VITAL study in second-line
non-small cell lung cancer failed to meet its
primary endpoint of improved overall survival
[1175277]
Higher affinity for VEGF than Avastin
observed in preclinical studies [645230]
The VANILLA trial in pancreatic cancer also
missed its endpoint of overall survival when
added to gemcitabine [1041345]
Conveniently dosed every 2 weeks
[1305016]
Development has been discontinued in
ovarian cancer after the drug caused the
death of four patients in a phase II trial
[1017305]
Common side effects in CRC patients in
combination with FOLFIRI include diarrhea,
fatigue, stomatitis and ulceration, nausea,
infection, hypertension, vomiting, decreased
appetite, decreased weight, epistaxis and
alopecia [1186513]
Return to Table of Contents
© 2013 Thomson Reuters All rights reserved
35
Opportunities
Threats
Regulatory risk; the magnitude of overall
survival benefit in second-line CRC (6
weeks) may not be viewed as clinically
meaningful in this setting [1197619],
[1210789], [1305016]
CRC is one of the leading forms of cancer,
with an estimated 147,000 people newly
diagnosed each year in the US alone
[1305019]
Up to 70% of CRC patients may be eligible
for second-line therapy [1305019]
Approval in NSCLC and prostate cancer
looks unlikely due to disappointing efficacy
[1277900], [1175277]
Avastin has provided significant validation for
VEGF inhibition as a cancer strategy
[656375]
For Zaltrap to be widely adopted in the
second-line CRC setting, it will need to
demonstrate a benefit in Avastinexperienced patients; the VELOUR trial was
not powered to demonstrate this, and
therefore another trial may be required
[1222598], [1305016]
Use in adjuvant CRC; clinical trials in this
setting could drive growth due to frequency
of patients undergoing surgery [1305018]
Avastin, which dominates first-line treatment
in CRC [656375]
Avastin was also successful in the AIO
study, which examined the drug in the
second-line in patients who are Avastinexperienced; this could limit Zaltrap's
commercial adoption as many physicians
would likely opt for continuous Avastin
therapy (first- and second-line) rather than
switching to a new agent with which
physicians have far less experience
[1291405], [1297868], [1298300]
The utility of the continuation of VEGF
inhibition after progression is not clear, which
could limit second-line use after first-line
Avastin [1305018]
Biosimilar Avastin; if approved, could capture
significant market share due to potentially
lower pricing [1305020]
Novel therapy options for second-line CRC
coming to the market, which may yield better
efficacy, fewer side effects and a
convenience benefit, such as ramucirumab
and regorafenib [1148364], [1304824]
CHANGE HISTORY
Return to Table of Contents
© 2013 Thomson Reuters All rights reserved
36
SUMMARY
Last Change Date
01-Apr-2013
Added Date
04-Aug-2000
CHANGE HISTORY DETAIL
Date
Update Type
Description
Consensus sales and forecast
data updated
Sanofi, 2015, 338.167 to 338.977
Consensus sales and forecast
data updated
573.878 to 569.08, 2018, Sanofi
Consensus sales and forecast
data updated
Sanofi, 2013, 124.989 to 125.475
Consensus sales and forecast
data updated
443.54 to 444.512, 2016, Sanofi
Consensus sales and forecast
data updated
Sanofi, 2017, 502.981 to 500.048
Consensus sales and forecast
data updated
2014, 231.335 to 231.983, Sanofi
Consensus sales and forecast
data updated
2017, Regeneron Pharmaceuticals Inc, 500 to
252.5
Consensus sales and forecast
data updated
2015, Regeneron Pharmaceuticals Inc, 407 to 273
Consensus sales and forecast
data updated
Regeneron Pharmaceuticals Inc, 2013, 154.85 to
106.567
Consensus sales and forecast
data updated
Regeneron Pharmaceuticals Inc, 2016, 450 to
227.5
Consensus sales and forecast
data updated
28.75 to 23.533, Regeneron Pharmaceuticals Inc,
2012
Consensus sales and forecast
data updated
2014, Regeneron Pharmaceuticals Inc, 312 to
209.667
Consensus sales and forecast
data updated
438.352 to 443.54, Sanofi, 2016
Consensus sales and forecast
data updated
Sanofi, 2014, 230.848 to 231.335
Consensus sales and forecast
data updated
Sanofi, 2017, 470.775 to 502.981
Consensus sales and forecast
data updated
Sanofi, 2018, 585.55 to 573.878
Consensus sales and forecast
data updated
2015, 336.113 to 338.167, Sanofi
Consensus sales and forecast
data updated
24.641 to 26.864, Sanofi, 2012
01-Apr-2013
25-Mar-2013
13-Mar-2013
Return to Table of Contents
© 2013 Thomson Reuters All rights reserved
37
13-Mar-2013
Consensus sales and forecast
data updated
Sanofi, 2013, 126.232 to 124.989
Consensus sales and forecast
data updated
2018, 778.14 to 585.55, Sanofi
Consensus sales and forecast
data updated
135.915 to 126.232, 2013, Sanofi
Consensus sales and forecast
data updated
2014, 243.298 to 230.848, Sanofi
Consensus sales and forecast
data updated
461.178 to 438.352, 2016, Sanofi
Consensus sales and forecast
data updated
2017, 508.817 to 470.775, Sanofi
Consensus sales and forecast
data updated
351.46 to 336.113, 2015, Sanofi
Consensus sales and forecast
data added
500, 2017, Regeneron Pharmaceuticals Inc
Consensus sales and forecast
data added
2016, 450, Regeneron Pharmaceuticals Inc
Consensus sales and forecast
data updated
2013, Regeneron Pharmaceuticals Inc, 144.7 to
154.85
Consensus sales and forecast
data updated
324 to 312, Regeneron Pharmaceuticals Inc, 2014
Consensus sales and forecast
data updated
29.5 to 28.75, 2012, Regeneron Pharmaceuticals
Inc
Consensus sales and forecast
data updated
2015, 414 to 407, Regeneron Pharmaceuticals Inc
Consensus sales and forecast
data added
2018, Sanofi, 778.14
Consensus sales and forecast
data updated
Sanofi, 2013, 108.68 to 135.915
Consensus sales and forecast
data updated
408.091 to 508.817, 2017, Sanofi
Consensus sales and forecast
data updated
Sanofi, 2016, 402.558 to 461.178
Consensus sales and forecast
data updated
201.538 to 243.298, 2014, Sanofi
Consensus sales and forecast
data updated
Sanofi, 2015, 299.325 to 351.46
Development profile section
source updates
Premarketing: Added [1384354], [1384169]
Consensus sales and forecast
data updated
2012, Sanofi, 25.16 to 24.641
Consensus sales and forecast
data updated
2015, 278.834 to 299.325, Sanofi
04-Mar-2013
01-Mar-2013
25-Feb-2013
19-Feb-2013
18-Feb-2013
Return to Table of Contents
© 2013 Thomson Reuters All rights reserved
38
18-Feb-2013
17-Feb-2013
Consensus sales and forecast
data updated
2014, Sanofi, 189.866 to 201.538
Consensus sales and forecast
data updated
2016, Sanofi, 371.951 to 402.558
Consensus sales and forecast
data updated
Sanofi, 105.049 to 108.68, 2013
Consensus sales and forecast
data updated
19.75 to 29.5, 2012, Regeneron Pharmaceuticals
Inc
Consensus sales and forecast
data updated
2014, 179.075 to 189.866, Sanofi
Consensus sales and forecast
data updated
2013, Sanofi, 100.053 to 105.049
Consensus sales and forecast
data updated
Sanofi, 2012, 20.967 to 25.16
Consensus sales and forecast
data updated
269.897 to 278.834, Sanofi, 2015
Consensus sales and forecast
data updated
406.164 to 408.091, Sanofi, 2017
Consensus sales and forecast
data updated
364.178 to 371.951, 2016, Sanofi
Consensus sales and forecast
data updated
237.222 to 269.897, Sanofi, 2015
Consensus sales and forecast
data updated
325.469 to 364.178, Sanofi, 2016
Consensus sales and forecast
data updated
2013, Sanofi, 87.828 to 100.053
Consensus sales and forecast
data updated
Sanofi, 152.216 to 179.075, 2014
Consensus sales and forecast
data updated
Sanofi, 18.481 to 20.967, 2012
Development profile section
source updates
Regulatory: Added [1366737]: Removed
[1355187]
Development profile section
source updates
Regulatory: Added [1365866]
Development profile section
source updates
Summary: Added [1355187], [1365866]: Removed
[1269852], [1341506], [1355153]
Development status:
company/indication/country trio
added
Sanofi, Registered, Metastatic colorectal cancer,
EU
Development status:
company/indication/country trio
added
Regeneron Pharmaceuticals Inc, Registered, EU,
Metastatic colorectal cancer
Development status:
company/indication/country trio
removed
Colorectal tumor, Sanofi, EU
12-Feb-2013
11-Feb-2013
07-Feb-2013
05-Feb-2013
Return to Table of Contents
© 2013 Thomson Reuters All rights reserved
39
Development status:
company/indication/country trio
removed
Colorectal tumor, Regeneron Pharmaceuticals Inc,
Europe
Development status:
company/indication/country trio
removed
Sanofi, Europe, Colorectal tumor
Consensus sales and forecast
data updated
Regeneron Pharmaceuticals Inc, 2015, 457 to 414
Consensus sales and forecast
data updated
Regeneron Pharmaceuticals Inc, 2013, 172.35 to
144.7
Consensus sales and forecast
data updated
21.5 to 19.75, Regeneron Pharmaceuticals Inc,
2012
Consensus sales and forecast
data updated
Regeneron Pharmaceuticals Inc, 2014, 362 to 324
Consensus sales and forecast
data updated
2014, 169.579 to 152.216, Sanofi
Consensus sales and forecast
data updated
Sanofi, 250.195 to 237.222, 2015
Consensus sales and forecast
data updated
Sanofi, 329.873 to 325.469, 2016
Consensus sales and forecast
data updated
2013, 100.357 to 87.828, Sanofi
Consensus sales and forecast
data updated
Sanofi, 18.028 to 18.481, 2012
Consensus sales and forecast
data updated
2017, 404.875 to 406.164, Sanofi
Consensus sales and forecast
data updated
2014, 360.8 to 362, Regeneron Pharmaceuticals
Inc
Consensus sales and forecast
data updated
2013, Regeneron Pharmaceuticals Inc, 163.7 to
172.35
Consensus sales and forecast
data updated
17.267 to 21.5, Regeneron Pharmaceuticals Inc,
2012
Consensus sales and forecast
data updated
2013, 77.995 to 100.357, Sanofi
Consensus sales and forecast
data updated
231.285 to 250.195, 2015, Sanofi
Consensus sales and forecast
data updated
2014, Sanofi, 139.084 to 169.579
Consensus sales and forecast
data updated
Sanofi, 2012, 8.453 to 18.028
Consensus sales and forecast
data updated
Sanofi, 398.782 to 404.875, 2017
Consensus sales and forecast
data updated
323.486 to 329.873, 2016, Sanofi
Development profile section
Summary: Added [1355153]
05-Feb-2013
02-Feb-2013
28-Jan-2013
25-Jan-2013
21-Jan-2013
08-Jan-2013
Return to Table of Contents
© 2013 Thomson Reuters All rights reserved
40
08-Jan-2013
07-Jan-2013
21-Dec-2012
source updates
Summary: Added [1355153]
Development profile section
source updates
Regulatory: Added [1355187]
Consensus sales and forecast
data updated
Sanofi, 2013, 100.891 to 77.995
Consensus sales and forecast
data updated
2015, 249.903 to 231.285, Sanofi
Consensus sales and forecast
data updated
15.975 to 8.453, 2012, Sanofi
Consensus sales and forecast
data updated
2016, Sanofi, 328.69 to 323.486
Consensus sales and forecast
data updated
Sanofi, 170.154 to 139.084, 2014
Consensus sales and forecast
data updated
Sanofi, 2015, 279.06 to 249.903
Consensus sales and forecast
data updated
2016, 357.506 to 328.69, Sanofi
Consensus sales and forecast
data updated
199.844 to 170.154, 2014, Sanofi
Consensus sales and forecast
data updated
88.678 to 100.891, Sanofi, 2013
Consensus sales and forecast
data updated
2012, Sanofi, 14.579 to 15.975
Development status:
company/indication pair status
change
Sanofi, B-cell lymphoma, France, Phase 1 Clinical
to No Development Reported
Development status:
company/indication pair status
change
Regeneron Pharmaceuticals Inc, B-cell lymphoma,
France, Phase 1 Clinical to No Development
Reported
Consensus sales and forecast
data updated
Sanofi, 2012, 14.29 to 14.579
Consensus sales and forecast
data updated
Sanofi, 2017, 382.271 to 398.782
Consensus sales and forecast
data updated
Sanofi, 2016, 338.818 to 357.506
Consensus sales and forecast
data updated
Sanofi, 2015, 259.101 to 279.06
Consensus sales and forecast
data updated
Sanofi, 2014, 181.525 to 199.844
Consensus sales and forecast
data updated
Sanofi, 2013, 80.964 to 88.678
Development profile section
source updates
Regulatory: Added [1341506], [1341857],
[1341879]: Removed [1284811]
Development profile section
Summary: Added [1341506]: Removed [1284811]
11-Dec-2012
07-Dec-2012
19-Nov-2012
Return to Table of Contents
© 2013 Thomson Reuters All rights reserved
41
19-Nov-2012
source updates
Summary: Added [1341506]: Removed [1284811]
Consensus sales and forecast
data updated
Regeneron Pharmaceuticals Inc, 2012, 59.733 to
17.267
Consensus sales and forecast
data updated
Regeneron Pharmaceuticals Inc, 2015, 500 to 457
Consensus sales and forecast
data updated
Regeneron Pharmaceuticals Inc, 2014, 400 to
360.8
Consensus sales and forecast
data updated
Regeneron Pharmaceuticals Inc, 2013, 200 to
163.7
Consensus sales and forecast
data updated
Sanofi, 2012, 14.346 to 14.29
Consensus sales and forecast
data updated
Regeneron Pharmaceuticals Inc, 2012, 84.6 to
59.733
Consensus sales and forecast
data updated
Sanofi, 2017, 306.187 to 382.271
Consensus sales and forecast
data updated
Sanofi, 2016, 324.387 to 338.818
Consensus sales and forecast
data updated
Sanofi, 2015, 260.366 to 259.101
Consensus sales and forecast
data updated
Sanofi, 2014, 194.632 to 181.525
Consensus sales and forecast
data updated
Sanofi, 2013, 79.866 to 80.964
Consensus sales and forecast
data updated
Sanofi, 2012, 14.346 to 14.29
Consensus sales and forecast
data updated
Regeneron Pharmaceuticals Inc, 2012, 84.6 to
59.733
Consensus sales and forecast
data updated
Sanofi, 2017, 306.187 to 382.271
Consensus sales and forecast
data updated
Sanofi, 2016, 324.387 to 338.818
Consensus sales and forecast
data updated
Sanofi, 2015, 260.366 to 259.101
Consensus sales and forecast
data updated
Sanofi, 2014, 194.632 to 181.525
Consensus sales and forecast
data updated
Sanofi, 2013, 79.866 to 80.964
Consensus sales and forecast
data updated
Sanofi, 2012, 14.346 to 14.29
Consensus sales and forecast
data updated
Regeneron Pharmaceuticals Inc, 2012, 84.6 to
59.733
Consensus sales and forecast
data updated
Sanofi, 2017, 306.187 to 382.271
15-Nov-2012
05-Nov-2012
04-Nov-2012
03-Nov-2012
Return to Table of Contents
© 2013 Thomson Reuters All rights reserved
42
Consensus sales and forecast
data updated
Sanofi, 2016, 324.387 to 338.818
Consensus sales and forecast
data updated
Sanofi, 2015, 260.366 to 259.101
Consensus sales and forecast
data updated
Sanofi, 2014, 194.632 to 181.525
Consensus sales and forecast
data updated
Sanofi, 2013, 79.866 to 80.964
Consensus sales and forecast
data updated
Sanofi, 2012, 14.346 to 14.29
Consensus sales and forecast
data updated
Regeneron Pharmaceuticals Inc, 2012, 84.6 to
59.733
Consensus sales and forecast
data updated
Sanofi, 2017, 306.187 to 382.271
Consensus sales and forecast
data updated
Sanofi, 2016, 324.387 to 338.818
Consensus sales and forecast
data updated
Sanofi, 2015, 260.366 to 259.101
Consensus sales and forecast
data updated
Sanofi, 2014, 194.632 to 181.525
Consensus sales and forecast
data updated
Sanofi, 2013, 79.866 to 80.964
Consensus sales and forecast
data updated
Sanofi, 2012, 14.346 to 14.29
Consensus sales and forecast
data updated
Regeneron Pharmaceuticals Inc, 2012, 84.6 to
59.733
Consensus sales and forecast
data updated
Sanofi, 2017, 306.187 to 382.271
Consensus sales and forecast
data updated
Sanofi, 2016, 324.387 to 338.818
Consensus sales and forecast
data updated
Sanofi, 2015, 260.366 to 259.101
Consensus sales and forecast
data updated
Sanofi, 2014, 194.632 to 181.525
Consensus sales and forecast
data updated
Sanofi, 2013, 79.866 to 80.964
Development profile section
source updates
Premarketing: Added [1334180], [1334482]
Development profile section
source updates
Summary: Added [1334180], [1334482]
Development profile section
source updates
Regulatory: Added [1334180]
Development status:
company/indication pair added
Sanofi, Advanced solid tumor, Phase 1 Clinical
03-Nov-2012
02-Nov-2012
26-Oct-2012
Return to Table of Contents
© 2013 Thomson Reuters All rights reserved
43
Development status:
company/indication pair added
Regeneron Pharmaceuticals Inc, Advanced solid
tumor, Phase 1 Clinical
Development status:
company/indication pair status
change
Sanofi, Metastatic colorectal cancer, Registered to
Launched
Development status:
company/indication pair status
change
Regeneron Pharmaceuticals Inc, Metastatic
colorectal cancer, Registered to Launched
Highest status change
Registered to Launched
Development profile section
source updates
Premarketing: Added [1329371], [1329485]
Development profile section
source updates
Premarketing: Added [1313124]
Development profile section
source updates
Summary: Added [1284811], [1313124],
[1313316]: Removed [1235900], [1310811],
[396972]
Development profile section
source updates
Regulatory: Added [1313124]
Development status:
company/indication pair status
change
Sanofi, Metastatic colorectal cancer, Preregistration to Registered
Development status:
company/indication pair status
change
Regeneron Pharmaceuticals Inc, Metastatic
colorectal cancer, Pre-registration to Registered
Highest status change
Pre-registration to Registered
Development profile section
source updates
Regulatory: Added [1310811]
Development profile section
source updates
Summary: Added [1310811]
20-Jul-2012
Development profile section
source updates
Patents and Generics: Added [1267527]
29-Jun-2012
Development profile section
source updates
Premarketing: Added [1304842]
Development profile section
source updates
Premarketing: Added [1305016]
Other action added
Systemic antipsoriatic product
Development profile section
source updates
Premarketing: Added [1304585]: Removed
[1086059], [1175557], [1236076], [739575],
[876053]
Development profile section
source updates
Summary: Added [1304585]: Removed [830785]
Development status:
company/indication pair added
Sanofi, Small-cell lung cancer, Phase 2 Clinical
Development status:
Regeneron Pharmaceuticals Inc, Metastatic
26-Oct-2012
09-Oct-2012
06-Aug-2012
26-Jul-2012
28-Jun-2012
27-Jun-2012
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© 2013 Thomson Reuters All rights reserved
44
company/indication pair added
pancreas cancer, Discontinued
Development status:
company/indication pair added
Regeneron Pharmaceuticals Inc, Metastatic non
small cell lung cancer, Phase 3 Clinical
Development status:
company/indication pair added
Regeneron Pharmaceuticals Inc, Metastatic
colorectal cancer, Pre-registration
Development status:
company/indication pair added
Sanofi, Metastatic non small cell lung cancer,
Phase 3 Clinical
Development status:
company/indication pair added
Sanofi, Metastatic colorectal cancer, Preregistration
Development status:
company/indication pair removed
Regeneron Pharmaceuticals Inc, Pancreas tumor
Development status:
company/indication pair status
change
Regeneron Pharmaceuticals Inc, Colorectal tumor,
Pre-registration to Phase 3 Clinical
Other action removed
Systemic antipsoriatic product
19-Jun-2012
Development profile section
source updates
Premarketing: Added [1296093], [1301992]
15-Jun-2012
Development profile section
source updates
Premarketing: Added [1296528], [1299208],
[1299214]
02-May-2012
Development profile section
source updates
Regulatory: Added [1284811]: Removed
[1261000]
Other action removed
Systemic antipsoriatic product
Technology added
Antibody fragment
Technology added
Immunoglobulin-G
Development profile section
added
Patents and Generics
Development profile section
source updates
Regulatory: Removed [1210789], [1210858]
Technology added
Solution
Development profile section
source updates
Premarketing: Added [1277900]: Removed
[1243277], [1261000]
Development profile section
source updates
Summary: Added [1277900]
Development profile section
source updates
Regulatory: Added [1277900]
Development profile section
source updates
Regulatory: Added [1269852]
Development profile section
source updates
Summary: Added [1269852]: Removed [1186513],
[1236076]
Development profile section
source updates
Premarketing: Added [1260968], [1263826]
27-Jun-2012
21-Apr-2012
11-Apr-2012
06-Apr-2012
09-Mar-2012
18-Feb-2012
Return to Table of Contents
© 2013 Thomson Reuters All rights reserved
45
Development profile section
source updates
Premarketing: Added [1260944], [1261000]
Development profile section
source updates
Regulatory: Added [1261000]
Target-based action removed
Phosphatidylinositol glycan synthesis F inhibitor
Development profile section
source updates
Premarketing: Added [1255386]
Development status:
company/indication pair added
Sanofi, Prostate tumor, Phase 1 Clinical
06-Dec-2011
Technology added
Infusion
26-Nov-2011
Development profile section
source updates
Premarketing: Added [1243277]: Removed
[1225130]
11-Nov-2011
Development profile section
source updates
Preclinical: Added [1176767]
Development profile section
source updates
Premarketing: Added [1236076]
Development profile section
source updates
Summary: Added [1235900], [1236076]: Removed
[1075390], [1210789]
Development profile section
source updates
Regulatory: Added [1235900]
Development status:
company/indication pair status
change
Sanofi, Colorectal tumor, Phase 3 Clinical to Preregistration
Development status:
company/indication pair status
change
Regeneron Pharmaceuticals Inc, Colorectal tumor,
Phase 3 Clinical to Pre-registration
Highest status change
Phase 3 Clinical to Pre-registration
09-Feb-2012
18-Jan-2012
04-Nov-2011
28-Oct-2011
Change history start date
04-Aug-2000
Drug added
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© 2013 Thomson Reuters All rights reserved
46