The prospective, randomized, double-masked study enrolled 449 patients with subfoveal neovascular AMD and randomly assigned them 1:1:1 into three arms to receive monthly intravitreal injections of Fovista 0.3 mg plus ranibizumab 0.5 mg (Lucentis, Genentech), Fovista 1.5 mg plus ranibizumab 0.5 mg, or sham plus ranibizumab 0.5 mg. There were no significant safety issues identified during the 6-month trial.
Mean change in ETDRS visual acuity from baseline to week 24 was assessed as the primary efficacy endpoint. The results showed a dose-response benefit for Fovista and statistically significant superiority (p = 0.019) comparing the combination of Fovista 1.5 mg and ranibizumab versus sham plus ranibizumab. Mean gain in ETDRS visual acuity was 10.6 letters for patients treated with the higher dose of Fovista in combination with ranibizumab and 6.5 letters for controls receiving ranibizumab monotherapy.
The 62% additional benefit in visual acuity gain achieved with the anti-PDGF/anti-VEGF regimen is generating tremendous excitement among retinal specialists about its potential to bring an advance in treatment for patients with exudative AMD. There are several factors strengthening their optimism, including the large size of the phase IIb study, the consistency with which the combination approach demonstrated statistically significant superiority to ranibizumab monotherapy in secondary efficacy and subgroup analyses, and the presence of a solid physiologic rationale underlying use of concomitant anti-PDGF/anti-VEGF therapy and providing a scientific basis for the observed results.
"The introduction of anti-VEGF agents was a huge step forward in our treatment of neovascular AMD, but we found within a few years that as good as it was, anti-VEGF therapy had the drawback of requiring ongoing monthly injections to maintain its benefit," said Pravin U. Dugel, MD, managing partner, Retinal Consultants of Arizona, Phoenix, and an investigator in the phase IIb trial. "Consequently, few patients receiving ranibizumab in clinical practice were achieving the vision gains recorded in the pivotal MARINA and ANCHOR trials.
"Anti-PDGF therapy with Fovista addresses the pathology through another mechanism that allows regression of the neovascular membrane and a greater functional benefit," he added. "The 62% greater gain in visual acuity achieved with the combination is astonishing and something we would have previously thought was unattainable."
Donald J. D'Amico, MD, professor and chairman, Department of Ophthalmology, Weill Cornell Medical College, New York, described the additional visual acuity gain with the combination over an already successful therapy as "nothing less than spectacular."
"Anti-PDGF therapy with Fovista attacks a different target [from] anti-VEGF therapy in treating exudative AMD," Dr. D'Amico said. "Importantly, Fovista is not just a longer-acting anti-VEGF agent or one that is used in a different route of administration, but it delivers a unique mechanism that appears to be complementary with anti-VEGF therapy.
"Fovista added to ranibizumab is like having a gasoline additive that substantially extends fuel economy without any evidence of deleterious effects," he said. "The results achieved with the combination are beyond what we would have expected to achieve in an initial efficacy trial, and if they can be sustained in the definitive phase III trials, we will see a new treatment paradigm for exudative AMD."
Dr. Dugel is also encouraged by the lack of any safety signals found with the combination regimen.
"Although this is just a phase IIb study, it is extraordinary in that it is the largest phase II study ever conducted in retina and perhaps in all of ophthalmology," he said. "Having data from a trial enrolling more than 440 patients builds confidence in the study results."
Samir Patel, MD, co-founder, chief executive officer, and president of Ophthotech, said, "We believe the statistical strength and clinical significance of this trial is great news for patients. Given the exciting news from this trial, Ophthotech will devote all its resources to bring Fovista (1.5 mg anti-PDGF) to market."
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