Study Clarifies Long-Term Outcomes of Pegcetacoplan for GA, Safety Concerns Prompt Change in Use

Ellen Kurek

August 08, 2023

SEATTLE, Washington — Treatment with pegcetacoplan (Syfovre, Apellis Pharmaceuticals) produced clinically meaningful reductions in the growth of geographic atrophy (GA) lesions through month 30, according to interim results presented at the annual meeting of the American Society of Retina Specialists.

These reductions could delay GA progression into the central fovea and preserve vision in many patients with this form of nonexudative age‑related macular degeneration (AMD), according to study authors.

The study found that by month 30 of the trial, pegcetacoplan resulted in a 24% reduction from baseline in GA lesion growth when used monthly and a 21% reduction when used every other month (EOM) compared with projected sham treatment (both P < .0001). These reductions were greater for those with non-subfoveal lesions: 31% for monthly and 26% for EOM treatment (both P < .0001).

Dr Nathan Steinle

"And if you break that down by 6-month blocks, you can see that increased treatment effect over time," said Nathan Steinle, MD, a co-investigator of the GALE trial and a physician with California Retina Consultants in Santa Barbara, California, during a session presenting the findings. "It's very encouraging to see that pegcetacoplan continues to work better and better the longer a patient is on treatment."

These reductions are about one third greater than those found during the first 6 months of two trials that GALE built upon.

The 3-year, open label study extended the OAKS and DERBY trials, which enrolled more than 1200 patients over age 60 years with a best-corrected visual acuity of at least 24 letters and a GA-affected macular area of 2.5 mm2 to 17.5 mm2 or, if GA was multifocal, at least one focal lesion of at least 1.2 mm2 at baseline. In OAKS and DERBY, GA area was measured by using fundus autofluorescence.

Patients in these trials received either placebo or pegcetacoplan treatment monthly or every other month. Patients entered GALE if they completed the full 24 weeks of the OAKS or DERBY trials, and 83% of those in OAKS or DERBY entered GALE.

Patients who had received the sham treatment in OAKS or DERBY were switched to active treatment during GALE. To determine the growth in GA lesions that would have occurred without treatment during GALE, Steinle and his co-investigators projected lesion progression based on the 6‑month mean rate of change in the OAKS and DERBY sham arms through month 24.

New-Onset Exudative AMD

Regarding safety, the incidence of new-onset exudative AMD (eAMD) after 30 months of treatment was 7.2 per 100 patient-years in the group treated monthly and 3.6 per 100 patient-years in the group treated EOM.

"Numerous studies now have shown that treatments targeting the complement system show a dose-dependent relationship with exudative AMD development," said Roger Goldberg, MD, MBA, a vitreoretinal surgeon at Bay Area Retina Associates in Pleasanton, California, in a separate presentation on eAMD events in OAKS and DERBY during the meeting's third Wet AMD Symposium.

Dr Roger Goldberg

Although rates of eAMD were greater in the pegcetacoplan arms than in the sham arms of OAKS and DERBY, no serious adverse events or study discontinuation occurred in pegcetacoplan-treated patients, Goldberg said. Patients also could continue to receive pegcetacoplan injections safely while anti-VEGF injections were initiated.

"When does exudation develop? Well, there was really no rhyme or reason," Goldberg said. "So this is something you need to be paying attention to throughout the course of therapy."

He noted that cases of exudation occurred at the edge of the GA lesion.

"The initial signs may be subtle, and OCT [optical coherence tomography] retinal thickness maps can be helpful to detect those subtle changes as we follow our patients with GA," Goldberg said.

During the first 6 months of GALE, no cases of infectious endophthalmitis were reported. One patient with an at-risk optic disc on monthly treatment developed ischemic optic neuropathy after six injections.

Intraocular Inflammation Rate

After more than 15,000 injections were given during the 24 months of OAKS and DERBY and 6 months of GALE combined, the rate of intraocular inflammation was 0.26% per injection, and no cases of retinitis or vasculitis occurred.

"To date, the sponsor and a panel of expert reviewers have confirmed seven cases of intraocular inflammation with retinal vasculitis," Steinle said. "We went back and looked at the review of manufacturing and the drug product and saw no indications that either the drug product or the manufacturing contributed to any issues going forward."

A show-of-hands poll of the audience revealed that many of those who had pegcetacoplan available and had used it eventually changed their clinical application.

"My only treatment paradigm shift is that I used to do bilateral same-day injections the first time, and I've shifted now to doing one eye injection the first time," Steinle said. "And I'll choose the eye with poorer vision."

The study was funded by Apellis Pharmaceuticals. Steinle reported consulting and working as a principal investigator for Apellis. Goldberg reported working as a consultant and investigator for Apellis and receiving institutional funding from the company.

American Society of Retina Specialists (ASRS) 2023 Annual Meeting. Presented July 28-31, 2023.

A former staff reporter for Cardio magazine and contributor to MD Magazine's vision disease coverage, Ellen Kurek earned her nonfiction writing certificate from the University of Washington.

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