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Dark Horse Fovista Challenges Regeneron's Eylea in Wet AMD

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By Catherine Shaffer
Staff Writer

Stellar Phase IIb results reported by Ophthotech Corp. for Fovista have harshed Regeneron Pharmaceuticals Inc.'s mellow just six weeks after the highly successful launch of competing product Eylea (aflibercept opthalmic solution).

Regeneron's stock (NASDAQ:REGN) fell 12.5 percent, or $15.97, to close at $111.88 Wednesday on news that Opthotech's Fovista showed a 62 percent added benefit in combination with Lucentis (ranibizumab, Roche AG) compared to Lucentis alone in neovascular age-related macular degeneration (wet AMD).

In spite of the selloff, analysts pointed out that the trial results support use of Fovista, an anti-platelet-derived growth factor (anti-PDGF) agent, in combination with an antivascular endothelial growth factor (anti-VEGF) drug, and that Eylea could ultimately be the preferred option for that combo treatment.

The real threat to Eylea is a Fovista/Lucentis combination product that locks Eylea out. Hence, the trial results could set off a bidding war between Roche and Regeneron for possession of Fovista.

"This is an extremely large market and is growing at a brisk pace," Ophthotech CEO Samir Patel told BioWorld Today. "We're entering a new era of combination therapy. . . . We'll just wait and see what is the most efficacious way to proceed forward."

Patel said there are options to use Fovista with multiple anti-VEGF agents and that flexibility bodes well for the market. He gave no clues as to whether there may be a deal with Roche or what the ultimate design of the Fovista Phase III trial will be.

The randomized, controlled Phase IIb study assessed efficacy and safety of Fovista 0.3 mg in combination with Lucentis 0.5 mg; Fovista 1.5 mg with Lucentis 0.5 mg; or sham with Lucentis 0.5 mg. Patients in the 1.5-mg Fovista/0.5-mg Lucentis group gained a mean of 10.6 letters of vision on the ETDRS standardized chart after 24 weeks of treatment, compared to 6.5 letters for patients receiving Lucentis monotherapy.

There were no significant safety issues for either treatment group.

Regarding the dosing and injection of two different drugs, Patel said, "You don't increase the treatment burden for patients and physicians. The injections are given pretty much right after each other."

The combination of an anti-PDGF drug with an anti-VEGF drug was expected to be synergistic. Wet AMD is characterized by the growth of new blood vessels covered by two types of cells: endotheliel cells and pericytic cells. The pericytic cells cover the endotheliel cells, Patel explained, producing factors that keep the endotheliel cells alive despite anti-VEGF therapy.

In administering an anti-PDGF drug, the vessels are stripped of pericytic cells, and when those pericytes are no longer protecting the endotheliel cells, the anti-VEGF agent can destroy them.

"The synergistic combination leads to benefit in visual outcome," Patel said.

Eylea, formerly known as VEGF Trap Eye, boosted Regeneron to profitability for the first time in its 24-year history, and has been nibbling away at Lucentis' market share since its approval. It was a major disruptor in the market dynamic between Lucentis and off-label Avastin (bevacizumab), and is considered by many to be the superior anti-VEGF product. (See BioWorld Today, April 27, 2012.)

However, two-year Phase III data suggested that Eylea offered only a modest benefit in head-to-head comparison with Lucentis. In the first year of the two studies, VIEW1 and VIEW2, patients were treated with three dosing regimens of Eylea – 0.5 mg every four weeks, 2 mg every four weeks or 2 mg every eight weeks following three initial monthly injections – compared to Lucentis 0.5 mg every four weeks.

In the second year, patients received the same dose per injection, but on an as-needed, or PRN, basis, at least once every 12 weeks, and then evaluated monthly.

In an integrated analysis of the data, patients treated with Eylea 2 mg every eight weeks had visual acuity gain of 7.6 letters at week 96 compared with 8.4 letters at week 52. In the Lucentis group, the gain in the monthly dosing group was 7.9 letters at week 96 compared to 8.7 letters at week 52.

Those results suggested that Lucentis and Eylea are on a roughly even footing in terms of efficacy in the competition to be Fovista's favored combination partner.

One of Eylea's differentiators from Lucentis was the eight-week dosing schedule, which cut in half the number of injections the patient needed to endure.

However, in combination with Fovista, that advantage may be irrelevant, depending on the dosing schedule needed for Fovista.

"The sky is not falling for Eylea," wrote Biren Amin, an equity analyst with Jefferies and Co. Inc. "We believe these [Phase IIb] data are strong and robust. However, we believe Fovista may be a useful addition to any anti-VEGF agent, including Eylea."

Amin cited anecdotal reports that Eylea has been effective in patients who were poorly controlled with Lucentis or Avastin, suggesting Eylea has greater potency. "We believe physicians will opt for the most effective anti-VEGF agent to pair potentially with Fovista."

Leerink Swann's Steve Yoo broke down the forthcoming scramble for control of Fovista: "Both Roche and Regeneron have vested interest in keeping Fovista as a standalone therapy off the market. If Fovista is priced so that it could be used in conjunction with Avastin, it could seriously degrade the market share of both Eylea and Lucentis. Roche obviously would like to exclusively partner/purchase Ophthotech so it can reverse the trend of Eylea rapdily gaining share in the AMD market. If Regeneron ends up with exclusive access to Fovista, it may be the end of Lucentis as a viable franchise since Lucentis cannot offer benefits in cost, efficacy nor convenience."

Yoo suggested that the optimal strategy for Ophthotech would be to carry out the Phase III trial using both Eylea and Lucentis, so that it can increase competitive bidding pressure between the two companies.

None of that is likely to be of benefit to patients, however. Pravin Dugel, managing partner of Retinal Consultants of Arizona, and one of the trial investigators, said "As a physician, I would like as much choice as possible."