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Combining anti-PDGF with anti-VEGF may improve visual acuity, reduce AMD treatment burden

A phase 2b clinical trial found better results with combination therapy than with anti-VEGF monotherapy.

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Combined therapy to treat a complex disease process — advanced age-related macular degeneration — that is mediated by multiple factors is taking shape now that researchers can modulate two of those factors, VEGF and PDGF, according to an expert.

“Inhibition of PDGF is no longer a theoretical concept,” OSN Retina Medical Editor Carmen A. Puliafito, MD, MBA, told Ocular Surgery News in reaction to the release of phase 2b clinical trial results by Ophthotech that Fovista, its anti-platelet-derived growth factor aptamer, combined with anti-VEGF therapy increased positive visual outcomes compared with anti-VEGF therapy alone.

The clinical trial showed that sequential injection of Fovista on the same day as Lucentis (ranibizumab, Genentech) produced better visual acuity in patients at 6 months, Dr. Puliafito said.

“We have practical clinical results that suggest that, in combination with anti-VEGF therapy, [anti-PDGF] might offer some additional benefit,” he said.

Study design, results

Patients who received a combination of 1.5 mg of Fovista, formerly known as E10030, and 0.5 mg of ranibizumab gained a mean of 10.6 letters at 24 weeks, a 62% improvement over the 6.5-letter gain from ranibizumab monotherapy (P = .019), according to an Ophthotech press release.

“The 62% relative benefit over monotherapy … is a striking finding,” Dr. Puliafito said.

 

Carmen A. Puliafito

The prospective, controlled trial randomized 449 patients with wet AMD into three groups, each receiving one of three treatments every 4 weeks for 24 weeks: Fovista 0.3 mg combined with ranibizumab 0.5 mg; Fovista 1.5 mg combined with ranibizumab 0.5 mg; or sham combined with ranibizumab 0.5 mg.

Fovista 1.5 mg with ranibizumab demonstrated improved visual outcomes at every monthly time point compared with ranibizumab monotherapy, according to the release. The improvement from combination therapy was greater at 6 months than it was at 3 months.

“This is the first randomized prospective trial that demonstrated the combination chemotherapy for wet macular degeneration produced better visual results than monotherapy with anti-VEGF agent,” Dr. Puliafito said.

Overcoming anti-VEGF limitations

The findings account for one limitation of anti-VEGF therapy, which is that there is a refractory component of the neovasculature that resists sustained effects of treatment.

A murine model published by Jo and colleagues in the American Journal of Pathology set the stage for pursuing such combination therapy.

“Vessel endothelium are refractory to VEGF blockade but vessel pericytes are still in an immature state and susceptible to PDGF-B withdrawal,” the study authors wrote. “Consequently, a combination therapy approach, using both VEGF-A and PDGF-B inhibitors, may be a more effective intervention for advanced ocular neovascular disease.”

With anti-VEGF treatment alone, a plateau occurs that requires continued treatments “forever,” according to study investigator Pravin U. Dugel, MD.

“As soon as anti-VEGF monotherapy is stopped, the neovascular complex will grow again,” Dr. Dugel said. Therein lies the scientific basis for anti-VEGF monotherapy resistance.

 

Pravin U. Dugel

A specialized group of tip cells, which are the only naked endothelial cells in the neovascular complex, act as lead cells in expanding the size of the neovascular membrane, Dr. Dugel explained. These cells produce PDGF, which matures and recruits pericytes that cover the neovascular complex like armor, protecting it against anti-VEGF monotherapy.
In the first 2 to 4 months, decreased exudation and improved visual acuity will result, Dr. Dugel said; thereafter, the pericyte armor will prevent penetration of anti-VEGF to the rest of the neovascular complex. Only the tip cells are killed with anti-VEGF therapy, so when anti-VEGF monotherapy stops, the lead cells grow and the complex continues to expand, thus necessitating endless monthly therapy.

PDGF is involved in angiogenesis in the production of both normal and abnormal blood vessels. Blockade of PDGF can reduce neovascularization in the eye, Dr. Puliafito explained, adding that it is believed that PDGF directly attacks the blood vessels, the pericytes.

“In other words, the combo therapy is a one-two punch,” he said. “The anti-VEGF blocks VEGF and reduces vascular permeability and improves retinal architecture; meanwhile, the anti-PDGF molecule is directly, we believe, operating on the neovascularization to actually have the blood vessels regress. This is what we hypothesize.”

“It would make sense that a scientifically logical combination treatment model would consist of anti-PDGF treatment combined with anti-VEGF treatment. The goal would be to have the anti-PDGF treatments chemically strip pericytes from the neovascular complex, rendering it susceptible to the anti-VEGF treatment,” Dr. Dugel said.

Tempered optimism

The added benefit of improved visual acuity with combination therapy is a bonus to reducing the burden of monthly anti-VEGF treatments in advanced cases.

“The possibility of having both better efficacy and an improved and sustainable treatment model is a grand slam,” Dr. Dugel said.

Blockade of VEGF with any of the three available agents — ranibizumab, Avastin (bevacizumab, Genentech) and Eylea (aflibercept, Regeneron) — is “quite effective,” according to Dr. Puliafito.

“When you get down to comparing all three of the anti-VEGF drugs that are used, none of them shows an additional benefit as compared to the other when used in the same way. … This study suggests that if we were to add another agent we might be able to improve the visual result. That’s the hypothesis that needs to be tested,” Dr. Puliafito said.

Dr. Puliafito said that the evidence presented in the phase 2 clinical trial is compelling enough to warrant a phase 3 trial in which the model would be tested in a larger number of eyes over a longer period of time, 12 months or more.

“The results of this trial, as encouraging as they are, need to be vetted by our colleagues in a critical fashion and need to be validated in a peer-review publication,” Dr. Dugel said. – by OSN Staff