Combination Outperforms Ranibizumab Alone in AMD

CHICAGO — A marked reduction in vision loss was observed in patients with age-related macular degeneration (AMD) who were treated with the combination of an agent targeting platelet-derived growth factor (PDGF) plus ranibizumab in a prospective randomized controlled phase 2b study. The results were reported here at the American Academy of Ophthalmology 2012 Annual Meeting.

In the study of 449 patients with wet AMD, the novel anti-PDGF compound E10030 (Fovista), when given in combination with the anti-VEGF (vascular endothelial growth factor) agent ranibizumab, met the prespecified primary efficacy end point of mean vision gain, compared with ranibizumab alone, reported Pravin U. Dugel, MD, from Retinal Consultants of Arizona in Phoenix, who is clinical associate professor at the Doheny Eye Institute at the Keck School of Medicine, University of Southern California in Los Angeles.

Treatment with agents that target VEGF are vital in preventing AMD-related blindness, but chronic anti-VEGF treatment appears to induce resistance. There is a need to determine the source of this resistance, Dr. Dugel said during a meeting press briefing.

E10030 is an aptamer directed against PDGF subunit B, which regulates neovascular pericytes (cells associated with the walls of newly formed small blood vessels). The combination of an anti-PDGF agent plus an anti-VEGF agent results in maximal inhibition and regression of neovascularization, he said.

"From research in cancer patients, we know that if you give anti-VEGF treatment chronically, you upregulate PDGF, recruit pericytes, and cause neovascular membrane maturation," he explained.

"Pericytes protect the endothelium, and if you inhibit PDGF and then strip pericytes off the neovascular complex, it enhances vulnerability to anti-VEGF treatment," he pointed out. "Combining an anti-PDGF agent with an anti-VEGF agent makes good physiologic sense."

The phase 2b study comparing E10030 plus ranibizumab with ranibizumab alone involved 449 patients previously untreated for AMD. It is the largest phase 2b trial of retinal disease ever conducted, he noted.

Patients received ranibizumab plus E10030 0.3 mg or 1.5 mg or ranibizumab 0.5 mg alone. The primary study end point was mean change in visual acuity from baseline at week 24.

Patients who received the combination gained a mean of 10.6 letters of vision on the ETDRS (Early Treatment Diabetic Retinopathy Study) standardized chart, whereas those who received ranibizumab monotherapy gained a mean of 6.5 letters of vision (P = .019) — a 62% additional benefit. Both doses of E10030 met the primary end point. The mean change with the lower dose was 8.76 letters.

"We saw an early and sustained superiority and a classic dose–response curve," Dr. Dugel said. "The patients improved over time. The curves were most divergent at the end of the study," he reported.

On fluorescein angiogram, the investigators observed a relation between regression of the neovascular membrane and improvement in visual acuity; the combination was always superior.

All Subgroups Benefited

"We saw a consistency of data across all clinically relevant and prespecified subgroups," Dr. Dugel added.

This included analyses by baseline vision, lesion size, and the proportion of patients gaining 1, 2, 3, 4, or 5 lines of vision. The combination provided an average absolute benefit of 7.4% over ranibizumab monotherapy across all lines of vision gain, with the relative benefit greatest in patients gaining 4 or more and 5 or more lines of vision.

"No matter how you slice it, whatever the lesion size, the combination was superior, and for good versus poor baseline vision, the combination was also superior," he said.

There was no dose-limiting toxicity with the combination; all doses were well tolerated and there were no adverse events related to study drug. No differences emerged in intraocular pressure, despite the fact that the combination group required 2 injections, he said.

Once the results are confirmed in a phase 3 trial, Dr. Dugel explained, the drug "has the potential to dramatically and profoundly change how we treat patients with neovascular macular degeneration."

He added that if this compound is approved by the US Food and Drug Administration, he would use it in combination with an anti-VEGF agent from the outset of treatment.

"Given how this works, I would use it at all times in patients for whom I would use an anti-VEGF agent," he said. "What I don't know is when I would stop. The phase 3 trial will be 1 year, which may give some guidance as to when we would stop treatment."

Abdhish R. Bhavsar, MD, attending surgeon and retina-vitreous specialist at the Phillips Eye Institute in Minneapolis, Minnesota, who moderated the press briefing, advised "restraint in interpreting these phase 2 results."

"I have been an investigator in this area for a long time. I have seen many drugs that look promising in phase 2 studies, that, in phase 3, go kaput," he told Medscape Medical News. "There is positivity here and a glimmer of hope in these results, but I wouldn't hang my hat on them. Let's see what the future holds in the phase 3 trials."

Dr. Dugel reports being a consultant to and minor shareholder in Ophthotech Corporation, which funded the study. Dr. Bhavsar has disclosed no relevant financial relationships.

American Academy of Ophthalmology (AAO) 2012 Annual Meeting. Presented November 11, 2012.