By Cheryl Guttman Krader
By Cheryl Guttman Krader
Reviewed by Pravin U. Dugel, MD
Phoenix-Patients with wet age-related macular degeneration (AMD) may benefit from treatment that combines anti-platelet-derived growth factor (PDGF)/anti-vascular endothelial growth factor (VEGF) therapy.
Results from a large phase IIb randomized clinical trial show combination therapy with E10030 (Fovista, Ophthotech), an investigational 50kD DNA aptamer directed against PDGF-B (subunit B), plus ranibizumab (Lucentis, Genentech) is superior to ranibizumab monotherapy for treating neovascular AMD.
“There is no doubt that anti-VEGF monotherapy treatment is effective for neovascular AMD, but there is equally no doubt that chronic anti-VEGF monotherapy treatment induces resistance, and that is why we have to treat perhaps indefinitely,” said Pravin U. Dugel, MD, study investigator and managing partner, Retinal Consultants of Arizona, Phoenix.
“It makes good physiologic sense to combine anti-PDGF and anti-VEGF agents, and this is well-supported in the oncology literature,” he said. “If the results of the Fovista phase IIb neovascular AMD study are confirmed in a larger pivotal phase III trial, the combined approach has the potential to change dramatically and profoundly our treatment model for patients with neovascular AMD.”
The rationale for the anti-PDGF combination is based on evidence that anti-VEGF monotherapy treatment induces PDGF upregulation, pericyte recruitment, and neovascular membrane maturation. These pericytes form a protective armor around the neovascular complex, but are stripped away with the addition of an anti-PDGF agent, thereby rendering the neovascular complex more vulnerable to anti-VEGF therapy.
The E10030 phase IIb trial of anti-PDGF combination therapy randomly assigned 449 treatment-naive patients equally into three treatment arms to receive ranibizumab plus E10030 0.3 mg, ranibizumab plus E10030 1.5 mg, or ranibizumab monotherapy.
“There are two important things to note about the study,” Dr. Dugel said. “It was designed as a superiority study, and it was the largest phase II superiority study ever done in retina.”
Both the 0.3-mg and 1.5-mg E10030 combination groups met their pre-specified primary endpoint by achieving superior mean visua acuity improvement from baseline to week 24 compared with ranibizumab monotherapy The vision improvement at week 24 was 10.6 letters in the 1.5mg E10030 combination group, 8.8 letters in the 0.3mg E10030 combination group, and 6.5 letters in the ranibizumab monotherapy group.
“The data for visual acuity improvement also showed a classic dose response and continued divergence of the efficacy curves over time,” Dr. Dugel said.
Pre-specified subgroup analyses were performed to determine whether any particular patient subgroup(s) drove the superior results for the combination treatment. With patients stratified by neovascular membrane size or baseline vision, the combination arms were always superior to ranibizumab monotherapy.
Combination treatment was also superior to control in an analysis of the disappearance of subretinal hyperreflective material as seen on optical coherence tomography (OCT), and a comparison of the two combination groups showed a clear and predictable dose-related effect.
“We were especially interested in this parameter that was felt to represent the entire lesion and lesion components,” Dr. Dugel said.
When the relationship of OCT thickness and vision was studied, regardless of the initial lesion thickness, the combination arms always proved superior. When fluorescein angiograms were studied, there was a consistent and predictable relationship between lesion regression and vision improvement.
The safety data showed no differences in the rate or type of ocular adverse events or serious systemic adverse events among the three study arms, and mean IOP was not significantly different even though patients received two injections in the combination groups.OT
Pravin U. Dugel, MD
Dr. Dugel is a consultant to and minor shareholder in Ophthotech. This article was adapted from Dr. Dugel’s presentation at Retina 2012 during the annual meeting of the American Academy of Ophthalmology.