학제간연구 | Interdisciplinary Studies in Gambling | 跨学科研究
- date : 2015-05-20 01:10|hit : 1955
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- Article] Aflibercept - AVE 0005, AVE 005, AVE0005, VEGF trap - Regeneron, VEGF trap (R1R2), VEGF trap-eye
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DocNo of ILP: 3959
Doc. Type: Article
Title: Aflibercept - AVE 0005, AVE 005, AVE0005, VEGF trap - Regeneron, VEGF trap (R1R2), VEGF trap-eye
Authors: [Anonymous]
Full Name of Authors: [Anonymous]
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Abstract: Aflibercept is a fully human recombinant fusion protein composed of the second Ig domain of VEGFR1 and the third Ig domain of VEGFR2, fused to the Fc region of human IgG(1). Aflibercept is in clinical development with Regeneron Pharmaceuticals and sanofi-aventis for the treatment of cancer, while Regeneron and Bayer are developing the agent for eye disorders. Aflibercept binds to all VEGF-A isoforms as well as placental growth factor (PIGF), thereby preventing these factors from stimulating angiogenesis. Blockade of VEGF can also prevent blood vessel formation and vasuclar leakage associated with wet age-related macular degeneration (AMD). Aflibercept is a member of Regeneron's proprietary family of 'Trap' product candidates that catch, hold and block (i.e. trap) certain harmful cytokines or growth factors. Regeneron and Bayer HealthCare entered into a collaboration agreement in October 2006 to develop and commercialize aflibercept for the treatment of eye disorders outside the US. The companies will share equally in profits from this market, while Regeneron will retain exclusive commercialization lights and profits from sales in the US.([1]) Regeneron and sanofi-aventis amended their aflibercept collaboration agreement to include Japan. Under the terms of the amended agreement, reported in December 2005, the two companies will jointly develop and commercialize aflibercept worldwide in all indications, except for intraocular delivery to the eye. sanofi-aventis paid $US25 million to Regeneron for the inclusion of Japan and will pay milestone payments linked to Japanese regulatory approvals, plus royalties on Japanese sales. sanofi-aventis will lead Japanese development and will pay all development costs; however, Regeneron will repay 50% of these expenses out of profits generated through the commercialization of aflibercept.([2]) sanofi-aventis reaffirmed its commitment to the aflibercept programme in oncology in January 2005, while the exclusive rights to develop and commercialize the agent for eye diseases through local delivery systems reverted to Regeneron. A $US25 million clinical development milestone payment to Regeneron was also triggered in connection with this agreement.([3]) Aventis (now sanofi-aventis) and Regeneron entered into a global (excluding Japan) agreement in September 2003 to jointly develop and commercialize aflibercept. Under the terms of the agreement, Aventis was to pay Regeneron $US125 million and fund development costs. An additional early clinical milestone payment of $US25 million was also outlined in the agreement. The two companies will share promotional tights equally, and profits globally. Aventis will also pay Regeneron up to $US360 million at identified milestones related to the receipt of marketing approvals for up to eight indications in Europe and the US. The companies initially agreed to jointly develop aflibercept in oncology, ophthalmology and possibly in other indications.([4]) Originally, aflibercept was being developed under a research and development alliance between Regeneron and Procter & Gamble. However, in 2000 this agreement was restructured and Regeneron regained all rights. An NCI-sponsored phase II trial (NCT00407654) of aflibercept, involving 80 patients with previously treated metastatic colorectal cancer, is also underway in the US and Canada. The trial was initiated in October 2006 and is evaluating the efficacy of aflibercept in this patient group, as measured by objective tumour response and progression-free survival at 4 months. In September 2006, a phase II trial in 82 patients with locally advanced, unresectable or metastatic gynaecological soft tissue sarcoma was initiated by NCI and Regeneron in the US and Canada. This ongoing trial (NCT00390234) will evaluate the efficacy of aflibercept, as measured by progression-free survival and tumour response rate. Regeneron and sanofi-aventis are conducting a phase II trial of intravenously (IV) administered aflibercept in patients with advanced ovarian cancer who have recurrent symptomatic malignant ascites (SMA). The trial (NCT00327444) began in July 2006 and was continuing to recruit a total of 54 patients at centres in the US, Canada, India and the EU (Austria, Belgium, Hungary, Spain and the UK) in April 2007. In October 2006, the companies initiated a second small phase II trial of aflibercept (NCT00396591) in 15 patients with malignant ascites associated with ovarian cancer. The study will assess the efficacy, safety, pharmacokinetics and immunogenicity of aflibercept IV given every 2 weeks in the US and EU (Italy and Sweden) and was recruiting patients in May 2007. Regeneron and sanofi-aventis are also conducting a single-agent phase II study of aflibercept in non-small-cell lung adenocarcinoma (NSCLA). The open-label, single-arm study (NCT00284141) has completed enrolment of approximately 100 patients with platinum- and erlotinib-resistant, locally advanced or metastatic NSCLA to receive aflibercept (4.0 mg/kg IV) in the US, France and Canada. Results from the first 37 evaluable patients have been reported showing aflibercept was generally well tolerated and two partial reponses were noted.([5,6]) Regeneron has completed an open-label phase I trial in patients with solid tumours and non-Hodgkin's lymphoma (NHL) at three sites in the US. The study enrolled 38 patients with incurable, relapsed or refractory solid tumours who received subcutaneous injections. In total, the trial enrolled patients with 15 different types of cancer who were treated with seven subcutaneous doses of aflibercept over 10 weeks. In June 2004, Regeneron presented results from this study showing that the aflibercept was well tolerated and had a good safety profile. The maximum tolerated dose was not established. The company has not conducted any further trials in this indication with aflibercept as a monotherapy, although the NCI has ongoing trials of aflibercept in patients with solid tumours and NHL (e.g. NCT0008283).([7]) In May 2005, Regeneron announced initiation of a phase I safety and tolerability study with aflibercept in combination with the FOLFOX-4 regimen (oxaliplatin, 5-fluorouracil and leucovorin) in patients with advanced solid tumours. As at August 2006, the maximum tolerated dose had not been reached and dose-escalation was continuing in this study.([8,9]) The NCI/Regeneron trial in patients with metastatic or unresectable kidney cancer began in September 2007 with continued recruitment in April 2008. This trial (NCT00357760) is anticipated to recruit 120 patients in the US to evaluate the efficacy of two doses of aflibercept. Regeneron and Bayer inititiated a phase III trial of aflibercept in approximately 1200 patients with the neovascular form of wet AMD in August 2007. The non-inferiority, VIEW 1 (VEGF Trap: Investigation of Efficacy and safety in Wet age-related macular degeneration) study will evaluate the safety and efficacy of intravitreal aflibercept at doses of 0.5 mg and 2.0 mg administered at 4-week dosing intervals, and 2.0 mg at an 8-week dosing interval, compared with 0.5 mg ranibizumab administered every 4 weeks. The randomized, double-blind trial will be conducted at more than 200 centres throughout the US and Canada, pursuant to a Special Protocol Assessment (SPA) issued by the the US FDA. Patients will continue to be treated and followed for an additional year, after the first year of treatment. The VIEW 1 study is the first in a phase III global development programme in wet AMD, which is expected to be conducted in the US, Europe and other nations. Regeneron received a $US20 million milestone payment from Bayer HealthCare in August 2007 following dosing of the first patient.([10,11]) A second phase III trial (VIEW 2) in wet AMD began with the first patient dosed in May 2008. The VIEW 2 trial will enrol approximately 1200 patients from the EU, Asia Pacific, Japan and Latin America. This study will evaluate the safety and efficacy of aflibercept at 0.5 mg and 2.0 mg administered at 4-week intervals and 2.0 mg at an 8-week dosing interval, including one additional 2.0 mg dose at week 4. Patients randomized to the ranibizumab arm of the trial will receive a 0.5 mg dose every 4 weeks. The primary endpoint will be the proportion of patients treated with aflibercept who maintain vision at the end of I year compared with ranibizumab patients.([12,13]) Regeneron has completed a 12-week, phase II trial in patients with wet AMD, to evaluate the safety and efficacy of intravitreal aflibercept using different doses and dose regimens. Two patient groups received monthly doses of 0.5 or 2.0 mg, and three groups received quarterly doses of 0.5, 2.0 or 4.0 mg (baseline and week 12). Analysis of data demonstrated that all five doses of aflibercept met the primary study endpoint of a statistically significant reduction in retinal thickness after 12 weeks and 32 weeks of treatment compared with baseline. The study commenced in April 2006 and enrolled 157 patients at sites in the US. Preliminary phase I trial results in 21 patients have also been presented.([14-16]) Additionally, Regeneron has conducted a phase I trial of aflibercept in five patients with diabetic macular oedema (DME) in the US. Results presented in May 2007 indicated that a single 4 ring injection resulted in a marked decrease in mean central retinal thickness and mean macular volume throughout the 6-week observation period. The VEGF Trap-Eye was generally well tolerated, and there were no drug-related serious adverse events.([17]) Regeneron plans to conduct advanced studies of the VEGF Trap-Eye in DME. Previously, sanofi-aventis and Regeneron had been collaborating on the development of aflibercept for eye diseases through local delivery systems. However, the exclusive rights to develop and commercialize aflibercept for eye diseases through local delivery systems reverted to Regeneron in January 2005. Additionally, Regeneron chose to pursue intravitreal inection, as a route of administration, instead of systemic delivery.([18]) Results from an earlier phase I trial assessing the safety and tolerability of intravenous infusions of aflibercept in patients with wet AMD have been reported. Preliminary results from the trial showed that the efficacy endpoint was met. Furthermore, systemic delivery of aflibercept was associated with a dose-dependent increase in blood pressure.([19])
Cate of OECD: Basic medicine
Year of Publication: 2008
Business Area: other
Detail Business: medicine & science
Country: New Zealand
Study Area:
Name of Journal: DRUGS IN R&D
Language: English
Country of Authors:
Press Adress:
Email Address:
Citaion:
Funding:
Lists of Citation: *AV REG PHARM INC, 2003, AV REG ENT GLOB PART; *BAY HEALTHCARE AG, 2008, BAY REG DOS 1 PAT 2; *BAY HEALTHCARE AG, 2008, BAY REG START ADD PH; *BAY HEALTHCARE RE, 2006, BAY HEALTHCARE REG C; Byrne AT, 2003, CLIN CANCER RES, V9, P5721; DUPONT J, 2003, 39 ANN M AM SOC CLIN, P194; DUPONT J, 2004, EJC SUPPLEMENTS, V2, P43, DOI 10.1016/S1359-6349(04)80140-X; Huang JZ, 2003, P NATL ACAD SCI USA, V100, P7785, DOI 10.1073/pnas.1432908100; *JH WILM EYE I, 2003, INJ PREV BLIND BLOOD; MASSARELLI E, 2007, J CLIN ONCOLOGY S, V25, P416; *REG PHARM INC, 2007, REG ANN POS PRIM END; *REG PHARM INC, 2005, REG REP 4 QUART FULL; *REG PHARM INC, 2004, REG REP POS PREL RES; *REG PHARM INC, 2006, REG REP 4 Q FULL YEA; *REG PHARM INC, 2007, VEGF TRAP EYE PHAS 2; *REG PHARM INC, 2005, CLIN PRECL STUD VEGF; *REG PHARM INC, 2006, REG REP POS PHAS 1 D; *REG PHARM INC, 2005, REG VEGF TRAP DEM PO; *REG PHARM INC, 2005, SAN AV REG PHARM EXP; *REG PHARM INC, 2006, REG VEGF TRAP DEM PO; *REG PHARM INC, 2007, REG REC 20 MILL MIL; *REG PHARM INC, 2007, REG REP 2 QUART FIN; *REG PHARM INC BAY, 2007, REG BAY HEALTHCARE I; *REG PHARM INC BAY, 2008, REG BAY HEALTHCARE A; *SANOF AV, 2005, SAN AV REG PHARM REA
Number of Citaion: 25
Publication: ADIS INT LTD
City of Publication: AUCKLAND
Address of Publication: 41 CENTORIAN DR, PRIVATE BAG 65901, MAIRANGI BAY, AUCKLAND 1311, NEW ZEALAND
ISSN: 1174-5886
29-Character Source Abbreviation: DRUGS R&D
ISO Source Abbreviation: Drugs R&D
Volume: 9
Version: 4
Start of File: 261
End of File: 269
DOI:
Number of Pages: 9
Web of Science Category: Pharmacology & Pharmacy
Subject Category: Pharmacology & Pharmacy
Document Delivery Number: 328UM
Unique Article Identifier: WOS:000257823700006
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