Regeneron Pharmaceuticals Inc. and partner Bayer HealthCare AG kicked off their pivotal program for VEGF Trap-Eye with a Phase III trial comparing the drug to Lucentis (ranibizumab, Genentech Inc.) in wet age-related macular degeneration (wet AMD).
"In many ways, they are the same," Regeneron's Chief Scientific Officer George Yancopoulos said of VEGF Trap-Eye and Lucentis. Both are biologics, based on antibody-like technologies and inhibit VEGF. But VEGF Trap-Eye "binds and blocks 1-to-2 orders of magnitude more tightly than Lucentis," which means it "might do a better job of binding and sopping up VEGF," Yancopoulos told BioWorld Today.
The randomized, double-blind, Phase III trial - dubbed VIEW 1 - is expected to enroll 1,200 patients with the neovascular form of wet AMD. Patients will receive 0.5 mg or 2 mg of VEGF Trap-Eye every four weeks, 2 mg of VEGF Trap-Eye every eight weeks, or 0.5 mg of Lucentis every four weeks. The study is designed to establish VEGF Trap-Eye's noninferiority compared to Lucentis based on a primary endpoint of the proportion of patients who maintain or improve their vision at the end of one year.
Yancopoulos noted, however, that "doing a noninferior approach doesn't preclude showing superiority."
The trial is being conducted under a special protocol assessment, and its initiation triggers a milestone payment from Bayer. Tarrytown, N.Y.-based Regeneron signed a deal worth up to $320 million with Leverkusen, Germany-based Bayer in 2006, agreeing to split profits from the wet AMD drug's sales outside of the U.S. but retaining all U.S. rights. (See BioWorld Today, Oct. 20, 2006.)
Although the trial's primary endpoint will be evaluated after one year, patients will be treated and monitored for a second year. Yancopoulos said a second, similar Phase III trial will be initiated before the end of 2007 but declined to provide a timeline to regulatory filings or approval.
Before it can think about approval, Regeneron will have to show that VEGF Trap-Eye is at least as good as Lucentis. Lucentis was approved on data from two Phase III trials showing that 95 percent of Lucentis-treated patients maintained their vision after one year, and more than a third experienced a clinically significant improvement as measured by at least three lines (or 15 letters) on the study eye chart. In one trial, patients showed an average improvement of 6.6 letters from baseline at two years, and in the other trial, they gained 11.3 letters over baseline after one year.
Interim data from a Phase II trial of VEGF Trap-Eye showed a statistically significant reduction in retinal thickness compared with baseline after 12 weeks as well as a statistically significant improvement in visual acuity. Patients from five dose groups showed an overall improvement of 5.9 letters after 12 weeks. Final data are expected this quarter. (See BioWorld Today, March 28, 2007.)
Michael Aberman, analyst with Credit Suisse Securities LLC, said there is a "very high probability" that VEGF Trap-Eye will show noninferiority, at least in the every-four-week dosing. If Regeneron's drug can show noninferiority when dosed once every eight weeks, Aberman predicted it could "become the drug of choice and get more than 50 percent of the market share compared to Lucentis and Avastin."
Avastin (bevacizumab), Genentech's VEGF inhibitor for cancer, is used off-label for wet AMD because it is significantly less expensive than Lucentis. Aberman estimated Avastin has about half of the wet AMD market. Other competitors include Macugen (pegaptanib sodium, OSI Pharmaceutical Inc.) and Visudyne (verteporfin, QLT Inc. and Novartis AG), both of which have suffered declining sales since Lucentis's launch.
With the VEGF Trap-Eye Phase III program up and running, Regeneron is now preparing to initiate a Phase III trial with aflibercept, its VEGF Trap candidate for oncology. The trial will combine aflibercept with chemotherapy in colorectal, non-small-cell lung, prostate, pancreatic and gastric tumors. If the drug proves successful, Regeneron and partner Sanofi-Aventis Group could position it against Avastin, which is approved for colorectal and lung cancers.
Beyond its two VEGF programs, Regeneron is developing the anti-inflammatory IL-1 Trap drug rilonacept. The company completed a rolling biologics license application in June seeking approval for the drug in cryopyrin-associated periodic syndrome.
An exploratory trial in gout is ongoing, and Regeneron expects to advance to a safety and efficacy trial in gout this quarter as well as begin an exploratory trial in another indication by the end of the year. (See BioWorld Today, June 11, 2007.)
In addition to the Trap programs, Regeneron plans to advance the first fully human monoclonal antibody derived from its VelocImmune technology into the clinic in the fourth quarter, with subsequent antibodies to follow at a rate of two per year beginning next year.