Long-anticipated initial data from two large phase 3 pivotal clinical trials that studied a combination of Ophthotech’s proprietary anti-PDGF drug Fovista and Genentech’s Lucentis (ranibizumab) for wet AMD showed that the combination produced no significant benefit in visual acuity over Lucentis monotherapy at 12 months.
The news hit stakeholders hard. A highly positive 449-patient phase 2b trial of the Ophthotech combo had led many in the retina community to believe that an anti-PDGF/anti-VEGF combination would usher in the next generation of more durable and efficacious treatments for wet AMD. On Wall Street, Ophthotech shares immediately fell from $38 to less than $7. But just last week, the Point72 hedge fund spent $70 million to acquire 1.8 million shares in Ophthotech, equal to a 5% ownership stake.
The rationale behind anti-PDGF/anti-VEGF combinations is that the anti-PDGF agent has the ability to break down the barrier containing pericytes that protect VEGF, thus enabling the anti-VEGF agent to be more effective in eliminating the unwanted VEGF. Several companies have been active in this area of research, including Regeneron and Allergan. However, a Regeneron combination of its own proprietary anti-PDGF and its anti-VEGF Eylea failed in a phase 2 clinical trial.
As expected, Ophthotech was not happy with the results.
“We are very disappointed in the results from these trials, particularly for patients afflicted with wet AMD,” commented David R. Guyer, MD, CEO of Ophthotech in a release. “We are thankful to the patients and clinical investigators and their staff for participating in the trials. We will continue to analyze the data from these two studies to better understand the trial results.”
Both Dr. Guyer and Ophthotech President Samir Patel, MD, are considered pioneers in the development of retina drugs, having successfully shepherded the anti-VEGF aptamer Macugen through the FDA approval process when they were principals of Eyetech Corporation a decade ago.
The two clinical trials (OPH1002 and OPH1003) were international, multicenter, randomized, double-masked, controlled phase 3 studies evaluating the safety and efficacy of 1.5 mg of Fovista administered in combination with Lucentis compared to Lucentis monotherapy. In each trial, patients were randomized to one of two approximately equal sized treatment groups. The two phase 3 trials enrolled an aggregate of 1,248 patients with wet AMD. The results from the two trials’ databases were unmasked and analyzed concurrently.
The combined analysis showed that patients receiving Fovista combination therapy gained a mean of 10.24 letters of vision at 12 months as described by the Early Treatment of Diabetic Retinopathy Study (ETDRS) standardized chart; for the patients receiving Lucentis monotherapy, there was a mean gain of 10.01 ETDRS letters, a difference of 0.23 ETDRS letters.
In OPH1002, consisting of 619 treated patients, subjects receiving Fovista combination therapy gained a mean of 10.74 letters of vision at 12 months on the ETDRS standardized chart, compared to a mean gain of 9.82 ETDRS letters in patients receiving Lucentis monotherapy, a resulting difference of 0.92 ETDRS letters. In OPH1003, consisting of 626 treated patients, subjects receiving Fovista combination therapy gained a mean of 9.91 letters of vision at 12 months on the ETDRS standardized chart, compared to a mean gain of 10.36 ETDRS letters in patients receiving Lucentis monotherapy, a resulting difference of -0.44 ETDRS letters. None of these results of the prespecified primary efficacy analysis were statistically significant.
In the phase 3 trials, the anti-PDGF and anti-VEGF drugs were administered 30 minutes apart. However, in a small investigator-sponsored trial, Pravin Dugel, MD, of Retinal Consultants of Arizona, administered the anti-PDGF a day before he injected the anti-VEGF. This “pretreatment” protocol demonstrated encouraging results in a difficult-to-treat patient cohort, Dr. Dugel reported, and may offer some hope for future studies of the Fovista/anti-VEGF combination.
Ophthotech has a third ongoing phase 3 trial underway in which combinations of Fovista and Eylea and Fovista and Avastin (Genentech) are being studied in comparison to Eylea and Avastin monotherapy. No data from that trial have been released. RP