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Combining anti-PDGF, anti-VEGF potential next step in stalling wet AMD progression
The anti-platelet-derived growth factor agent inhibits the proliferation of pericytes.
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CHICAGO — An antiplatelet-derived growth factor combined with ranibizumab outperformed ranibizumab monotherapy in treating neovascular age-related macular degeneration, a speaker said here.
During Retina Subspecialty Day preceding the joint meeting of the American Academy of Ophthalmology and Asia-Pacific Academy of Ophthalmology, OSN Retina/Vitreous Board Member Pravin U. Dugel, MD, presented results of a phase 2 clinical trial comparing Fovista (Ophthotech) combined with Lucentis (ranibizumab, Genentech) and ranibizumab alone.
Anti-platelet-derived growth factor (anti-PDGF) combined with ranibizumab may change the landscape of neovascular AMD treatment, Dugel said.
“At the end of the day, it makes good sense to combine anti-PDGF with anti-VEGF. There are good data in the oncology field to support that,” Dugel said. “If these results are confirmed in a larger pivotal trial, it has the potential to dramatically and profoundly change our treatment model for patients with neovascular macular degeneration.”
Pravin U. Dugel
Agent of action
“There’s no doubt whatsoever that anti-VEGF treatment is effective in patients with neovascular macular degeneration,” Dugel said. “There’s equally no doubt whatsoever that chronic anti-VEGF treatment induces resistance. The cause of the resistance is fairly well known and well defined in the oncology literature.”
Prolonged anti-VEGF treatment induces PDGF, which regulates pericytes, or cells associated with the walls of newly formed small blood vessels.
“It is these pericytes that are stimulated by PDGF that form a protective barrier around the neovascular complex,” Dugel said.
Dugel described the mechanism of action as the inhibition of PDGF. Fovista is an aptamer that targets PDGF and inhibits the proliferation of pericytes, he said.
“The combination of anti-PDGF with anti-VEGF makes good physiologic sense. The goal is to have the anti-PDGF strip the pericytes from the neovascular complex, rendering it more vulnerable to anti-VEGF therapy. Fovista has been shown in lab studies to be very effective in binding to and stripping pericytes from the neovascular complex,” he said.
Study design and methods
The prospective, randomized clinical trial included 449 patients. One group received 0.5-mg ranibizumab in combination with 0.3-mg Fovista, a second group received ranibizumab combined with 1.5-mg Fovista, and a third group received ranibizumab alone.
Injections were administered every 4 weeks for 24 weeks.
The study was the largest phase 2 superiority study ever done in retina, Dugel said.
“There are two things of note in the trial design,” he said. “Although this was a phase 2 study, it resembled a phase 3 study in the number of recruited patients. Secondly, I’d like to point out to you that, unlike a lot of recent studies … this was not a non-inferiority study but, rather, a superiority study.”
The primary endpoint was improvement in visual acuity at 24 weeks. Secondary endpoints were improvement in visual acuity at 12 weeks, number of patients gaining 15 letters or more at 12 weeks and 24 weeks, and reduction in size of the neovascular complex at 24 weeks.
Baseline demographic features were similar in all three study arms.
Combination superior
Study results showed that both combination treatment arms met the pre-specified primary endpoint of superiority, Dugel said. Efficacy improved 62% in the 1.5-mg Fovista combination arm compared with the ranibizumab monotherapy arm.
“There was a classic dose response curve that showed sustained superiority,” Dugel said. “Importantly, there was an improvement over time, meaning that at the end of the study, the curves were most divergent.”
Additionally, visual improvement was greater in the combination treatment groups, Dugel said.
Results showed median size of the neovascular membrane was 1.21 disc areas and mean size of the membrane was 1.78 disc areas, Dugel said.
“No matter how we sliced it, no matter what baseline lesion size we looked at, across the board, the combination arm always proved superior,” he said.
Optical coherence tomography findings showed a strong dose-related disappearance of subretinal hyper-reflective material, representing the neovascular lesion complex, at 24 weeks.
In addition, the combination treatment arms had superior visual acuity, regardless of the baseline macular thickness.
The association between regression of the neovascular complex and improvement in visual acuity was strongest in the combination treatment arms, Dugel said.
“Finally, we looked at the safety data,” he said. “Whether we looked at the ocular adverse events or whether we looked at the serious systemic adverse events, there was no difference in the three treatment arms. And, despite two injections, there was also no difference in the mean intraocular pressure.” – by Matt Hasson