Complications From Geographic Atrophy Drug Fuel Questions About Incidence, Conflicts of Interest

Richard Mark Kirkner

August 07, 2023

SEATTLE — "Falsely reassuring" is how one retina specialist characterized an extension study of pegcetacoplan that found no cases of occlusive retinal vasculitis after 23,000 injections into eyes. A panel of the American Society of Retina Specialists (ASRS) was charged with investigating at least eight reports of the side effect and dealt with questions regarding conflicts of interest.

The fallout from a July 15 e-mail from the ASRS committee, known as the Research and Safety in Therapeutics (ReST) committee, that was sent to members and that reported six cases of occlusive retina vasculitis after pegcetacoplan injection became the focus of a session of the American Society of Retina Specialists (ASRS) 2023 Annual Meeting. The US Food and Drug Administration (FDA) approved the drug, which is marketed by Apellis as Syfovre, in February as the first intravitreal injection for the treatment of geographic atrophy (GA), an advanced form of dry age-related macular degeneration (AMD).

Dr Nathan Steinle

Nathan Steinle, MD, a vitreoretinal specialist with California Retina Associates in San Luis Obispo, said the 36-month results from the GALE open-label extension study failed to find any reports of occlusive or nonocclusive retinitis or vasculitis. GALE included 782 patients from the pivotal OAKS and DERBY trials.

Although the rate of infectious endophthalmitis across the trials was 1:3700 injections, Steinle said no cases were reported in the first 6 months of GALE. The rate of intraocular inflammation in the studies was 0.26%. He said the rate of retinal vasculitis, as estimated from 60,000 total injections, is "on the order of 1:10,000, or 0.1%."

Push Back

Soraya Rofagha, MD, a retina specialist with East Bay Retina Consultants in Oakland, California, challenged Steinle's estimates.

Rofagha noted that a previous presentation showed that vasculitis cases occurred largely after the first injection and that there was only one case after a second shot. "While it's impossible to know the total number of patients treated, it is falsely reassuring in my opinion to quote a total vasculitis rate based on the total number of injections," said Rofagha, who declined an interview with Medscape Medical News.

Steinle said information on first or second injections is unavailable. "We'll definitely investigate that over time," he said.

In an interview, Steinle told Medscape, "rare things happen rarely.... The denominator becomes larger and larger as the community starts to use the drug."

So far, the investigation has failed to find evidence implicating the manufacturing process or specific product lots, Steinle said. "Nor did all these cases happen at the same time," he said. "They happened sporadically — two cases here, a case here, two cases there."

He noted that the injection technique for pegcetacoplan differs significantly from that for intravitreal antivascular endothelial growth factor (anti-VEGF) agents used in the treatment of wet AMD. Pegcetacoplan is administered as a 100-μL dose, vs a 50-μL dose for anti-VEGF agents, so the injection itself takes longer. The procedure also requires a larger-bore needle, 29-gauge vs 30- or 32-gauge for anti-VEGF injections. And it requires the use of a lid speculum to hold the eye open during the procedure.

"There's probably an increased risk of becoming unsterile if you don't use a lid speculum and if you don't have really good injection technique," he said.

ReST Committee Findings

In presenting findings from the ReST committee, Andre Witkin, MD, a retina specialist at the New England Eye Center and an assistant professor at Tufts University School of Medicine, both in Boston, said the panel had now received reports of eight patients and 10 eyes with suspected RV, up from six patients on July 15. After review, the committee confirmed that seven of the patients had occlusive vasculitis. In all, the committee has received reports of 22 cases of intraocular inflammation, Witkin said.

Dr Andre Witkin

Witkin, a committee member, reviewed nine patient cases in all, including one that was added at the last minute that wasn't included in the panel's review. The committee determined that all eight patients in the summary had panuveitis ― one without retinal vasculitis, one with nonocclusive retinal vasculitis, and the rest with the occlusive form of the condition.

"Some features that are interesting: the presentations are 8 to 15 days after the injections," Witkin said. "There are some patients who had not-too-bad outcomes, and then there's some who had very bad outcomes." Last best-corrected visual acuity ranged from 20/80 to light perception, hand motions, and no light perception, he said.

The ReST committee does not have an accurate number as to how many vials have been injected or the true incidence of retinal vasculitis per injection, Witkin said.

Dr Peter Kaiser

ReST chair Peter Kaiser, MD, said the committee is exploring possible links with previous SARS-CoV-2 infection and vaccination status as well as systemic inflammatory disease but that it has not had enough time to investigate those potential associations.

Conflict of Interest Concerns

Kaiser himself was the target of criticism at the meeting after news broke that he had not disclosed a potential conflict of interest as a consultant and stock owner in Iveric Bio, a company developing the drug Izervay for GA. That drug will compete with pegcetacoplan. The FDA approved the drug earlier this month.

In disclosures made available later, the ASRS reported that Kaiser had listed his relationship with Iveric Bio, along with Apellis. Witkin also disclosed a relationship with Apellis, as did four other members of the ReST committee. Two others besides Kaiser also have relationships with Iveric Bio.

Kaiser told Medscape that he had disclosed his relationship with Iveric Bio to ASRS but that it hadn't updated its website. "My disclosures were 100% known by ASRS, and they haven't changed," he said.

Jill Blim, the vice president of ASRS, said the group has an automated system for members' disclosure information. "The system does not provide real-time updates to the static listing on the website, which we update annually," she told Medscape.

Apellis is sponsoring the GALE study. Steinle is a consultant and principal investigator for Apellis and has relationships with Genentech/Roche, Novartis, and Regeneron Pharmaceuticals. Kaiser has relationships with Genentech/Roche, Novartis and Regeneron. Witkin has a relationship with Genentech/Roche. Rofagha has disclosed no relevant financial relationships.

American Society of Retina Specialists (ASRS) 2023 Annual Meeting: Presented July 30, 2023.

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

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