With Approval Pending, Pegcetacoplan Shows Mixed Results for Treating Geographic Atrophy

Richard Mark Kirkner

October 03, 2022

CHICAGO — Pegcetacoplan, an investigative complement factor inhibitor that has the potential to be the first US Food and Drug Administration (FDA)–approved treatment for geographic atrophy (GA) in dry, age-related macular degeneration (AMD), has shown an ability to reduce growth in geographic lesions in the retina after 2 years of treatment. The results, from two phase 3 clinical trials, were presented at the annual meeting of the American Academy of Ophthalmology.

However, the studies, known as OAKS and DERBY, also showed that up to 12.2% of treated eyes converted to exudative, or wet, AMD, nearly four times the rate of sham eyes, and went on to lose visual acuity despite treatment for wet AMD. Treated eyes also lost best-corrected visual acuity (BCVA) over 24 months at the same rate as sham eyes.

Dr Charles Wykoff

"Pegcetacoplan slowed geographic atrophy lesion growth with an increasing treatment effect over time," Charles Wykoff, MD, PhD, said while presenting the results. Wykoff is a retina specialist at Retina Consultants of Texas in Houston and deputy chair of ophthalmology at Blanton Eye Institute, Houston Methodist Hospital.

Pegcetacoplan inhibits the C3 complement pathway, which has been implicated in GA lesion growth, an advanced stage of dry, or nonexudative, AMD. Wet AMD is a form of the disease for which FDA-approved anti–vascular endothelial growth factor (anti-VEGF) agents are indicated. However, no approved treatment exists for the dry form of the disease. The FDA has accepted Apellis Pharmaceuticals's new drug application for pegcetacoplan and has set a Prescription Drug User Fee Act target date of November 26 for action on the application.

Prevent Blindness estimates that around 3 million Americans aged 55 years or older have some form of intermediate or advanced AMD, 85%-90% of whom have the untreatable dry form.  

Trial Details, Findings

The Phase 3 DERBY and OAKS trials included 1256 patients randomly assigned to monthly or every-other-month treatment with pegcetacoplan or sham. The primary endpoint was change in GA lesion size measured with fundus autofluorescence after 1 year. The 24-month study evaluated BCVA, reading speed, and lesion growth, among other outcomes.

Wykoff noted that 30% and 24% of patients on monthly and every-other-month treatment, respectively, demonstrated reduction in lesion growth in months 18-24 (P < .0001). Those rates ranged from 13% to 20% for monthly treatment (P = .0141 to .0004) and 12% to 17% for every-other-month dosing (P = .0058 to < .001) at previous 6-month intervals.

BCVA declined about seven Early Treatment Diabetic Retinopathy Study (ETDRS) letters in sham eyes, about eight letters in the monthly pegcetacoplan group, and about nine letters in the every-other-month group (P = .3558 and .069 vs sham, respectively), changes that weren't statistically different. A loss of five ETDRS letters represents the loss of the ability to read one line on the Snellen visual acuity chart. "From a functional perspective there were no significant differences across study arms on the key study endpoints in BCVA, reading speed, and Functional Reading Independence Index," Wykoff said.

He also said that microperimetry testing of the area around the GA lesions showed a signal of functional vision preservation in treated eyes in the last 6 months of the study.

Adverse Events

In terms of adverse events (AEs), rates of intraocular inflammation were 3.8%, 2.1% and 0.2% in the monthly, every-other-month, and sham groups, with no reports of occlusive vasculitis, retinitis, or retinal involvement. "Sixty-six [percent] and 21% were mild and severe," he said of the AEs, "and 77% of patients continued or resumed treatment without intraocular inflammation recurrence," he said.

However, rates of conversion to wet AMD were 12.2%, 6.7%, and 3.1% in the monthly, every-other-month, and sham groups, Wykoff said. Twenty-one additional cases of choroidal neovascularization were confirmed at month 24 by the study reading centers — nine, four, and eight cases in the three treatment groups. "All of them continued with treatment," he said. "There were no severe events and the patients received anti-VEGF therapy at the investigators' discretion."

Dr Demetrios Vavvas

Wykoff called the AEs "manageable," but Demetrios Vavvas, MD, PhD, associate retina service director at Massachusetts Eye and Ear in Boston, questioned the study findings on GA growth reduction. "Basically, we have a 20% reduction of the predicted GA growth, not the actual, observed GA growth, with a 20% discontinuation rate and a 10 to 20% higher rate of inflammation and four times the neovascularization rate," he said in an interview with Medscape Medical News. He also noted that in the Phase 2 FILLY trial of pegcetacoplan, patients who had new onset exudation and anti-VEGF treatment lost BCVA.

"So this idea that the wet AMD is no problem because we can treat it is not supported by the data," Vavvas said in an interview. "Once you convert to wet AMD in these trials you're actually losing more vision than if you didn't convert. So it's still better not to convert to wet AMD.

"So here we're taking patients that we're going to give them a drug to tell them that your GA and scotoma will grow slower; it will still grow but it will grow slower, but we guarantee you a 10% risk per year of conversion to worse visual acuity."

Vavvas also called into question the use of projected GA growth as a measure of progression rather than observed lesion change. "These are not observed data; these are calculated data based on a mixed model," he said.

Wykoff said that the research into pegcetacoplan will continue with the GALE 3-year open-label extension study.

Apellis Pharmaceuticals funded the study. Wykoff disclosed he serves on a steering committee for Apellis. Vavvas has no relevant disclosures.

American Academy of Ophthalmology Annual Meeting 2022. Presented September 30, 2022. Study

Richard Mark Kirkner is a medical journalist based in the Philadelphia area.

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