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Fovista combined with monthly Lucentis shows no benefit over anti-VEGF monotherapy
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Ophthotech Corporation announced that Fovista did not meet its primary endpoint of mean change in visual acuity in two phase 3 clinical trials comparing combination treatment of Fovista, an anti-PDGF, plus Lucentis, an anti-VEGF, with Lucentis monotherapy alone for treatment of wet age-related macular degeneration.
“We are very disappointed in the results from these trials, particularly for patients afflicted with wet AMD,” David R. Guyer, MD, chief executive officer of Ophthotech, said in a company press release, which reported that no benefit was observed when the anti-PDGF was added to a monthly regimen of Lucentis (ranibizumab, Genentech).
The two clinical trials were international, multicenter, randomized, double-masked controlled phase 3 studies, which together included 1,248 patients.
The combined results of the two trials (OPH1002 and OPH1003) showed patients receiving 1.5 mg pegpleranib (Fovista) with monthly injections of ranibizumab gained a mean 10.24 letters of vision on the Early Treatment of Diabetic Retinopathy Study (ETDRS) standardized chart at 12 months, compared to a mean gain of 10.01 ETDRS letters for the ranibizumab monotherapy, a difference of 0.23 letters, which was not statistically significant.
Neither were any statistically significant differences seen when results of OPH1002 and OPH1003 were analyzed separately, according to the press release. The OPH1002 trial included 619 patients. The cohort receiving combination therapy gained a mean of 10.74 ETDRS letters, compared to a mean gain of 9.82 ETDRS letters in patients receiving ranibizumab monotherapy. The OPH1003 trial included 626 patients. The cohort receiving the combination therapy gained a mean of 9.91 ETDRS letters compared to mean gain of 10.36 ETDRS letters in patients receiving ranibizumab monotherapy.
“We will continue to analyze the data from these two studies to better understand the trial results," Guyer said in the release.
Editor's note: This article was updated to clarify patient numbers in the study groups.
Perspective
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Pravin U. Dugel, MD
My first thought, and likely that of the vast majority of my colleagues, was shock and disappointment. Most of us expected this to be the first successful combination therapy.
After that initial period of shock and disappointment, there were two thoughts that I had. The first thought was that this system actually works. This is exactly the way our rigorous scientific system is supposed to function. As frustrated as we get with the FDA, there is a very good reason why it requires multi-center prospective parallel studies for a registration trial. It is crucial to have a new drug undergo that kind of rigor. In this case, the system worked. What worked was that science prevailed in telling us what may be approved and what may not be approved.
My second thought is the following: although almost all of us agree that anti-VEGFA monotherapy has reached its ceiling, we have to step back and realize that the ceiling is quite high in clinical trials. It gave me pause to realize how difficult it is to have an incremental improvement in visual acuity from our current anti-VEGFA monotherapy. However, there is an important difference between these clinical trials and real life data. In real life, it is clear that we have an unsustainable treatment strategy with suboptimal long-term results. This disconnect (or delta) between clinical trial results and real life data is alarming and must be addressed.
The next step, of course, is to thoroughly examine the phase 3 study data and find out what caused this result. When you look at this in retrospect, everything was done properly. There was a very good scientific basis to consider anti-PDGF combination therapy. The early preclinical and clinical studies were encouraging. The phase 2B study was the largest phase 2B study ever done in retina, with excellent and scientifically valid results. It certainly justified going into this phase 3 stage.
Scientifically, in retrospect I do not know that anything should have been done differently. However, we do have two very good companies, Regeneron and Ophthotech, who have now failed in their studies targeting the same mechanism with anti-PDGF drugs. It makes me wonder about the future of anti-PDGF combination therapy. Although it is too early to predict the fate of anti-PDGF drugs … this outcome necessitates a prolonged and honest recapitulation.
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