番茄社区

In July, we reported on cases of unexplained ocular inflammation associated with pegcetacoplan (Syfovre), a treatment for geographic atrophy (GA) secondary to age-related macular degeneration (AMD). In this report, we follow up on what has happened since then.

The mystery of ocular inflammation associated with the GA drug pegcetacoplan remained unsolved as 2023 came to a close.

The incidents came to light in July when the American Society of Retina Specialists (ASRS) distributed a memo to its members, alerting them to the adverse events, including panuveitis and vascular occlusion. The ASRS Research and Safety in Therapeutics (ReST) Committee received an initial incident report July 3. By the end of July at the ASRS annual meeting, the number of reported incidents had risen to 21.

Reports have continued to trickle in since the end of July, but the reason for the inflammation remains elusive, according to ReST chairperson Andre Witkin, MD, of Tufts University and the New England Eye Center in Boston.

"I don't think I or anyone else knows the reason these rare events have been happening," Witkin told 番茄社区. "We have talked about some possible theories, but no one knows."

Next month, the will publish a detailed report on the cases of inflammation, co-authored by members of the ReST committee, he added. The article will include the current number of incident reports, details about the cases, and hypotheses about the potential causes.

Possible explanations include patient-specific characteristics that make them more susceptible to one or more components of the drugs, as well as infection associated with complement inhibition. Both pegcetacoplan and avacincaptad pegol (Izervay), the newest approved drug for GA, inhibit the complement system.

Until recently, all of the reported incidents involved pegcetacoplan, but avacincaptad pegol has been involved in at least one case, said Witkin. That case involved a patient who received pegcetacoplan in one eye and avacincaptad pegol in the other.

Other drugs have associations with retinal vasculitis, notably vancomycin, faricimab (Vabysmo, approved for AMD), and vascular endothelial growth factor inhibitors used to treat AMD.

"As a matter of fact, there was a recent for Vabysmo, which mentions rare instances of retinal vasculitis in patients receiving that drug," said Witkin.

In August, pegcetacoplan maker Apellis suggesting potential issues with certain injection kits for pegcetacoplan. The company recommended that ophthalmologists use a different kit (already available), but did not specifically implicate the injection kit as the source of the intraocular inflammation.

During his presentation at the ASRS meeting, Witkin included data on 23 reports of intraocular inflammation associated with faricimab treatment, including panuveitis and retinal vascular occlusion. At that time, Genentech reported having distributed more than 1.1 million vials of faricimab, whereas Apellis reported distribution of 68,000 vials of pegcetacoplan. No information was available on the number of vials used. Apellis also noted that 23,000 doses of pegcetacoplan had been administered in clinical trials.

Ophthalmologists' reaction to the as-yet unexplained intraocular inflammation continues to evolve.

"I think there are varying opinions about how people feel about these drugs," said Witkin. "They fill a previously unfilled niche for a disease that doesn't have any other treatment, so I think there's certainly some role for them. It remains to be seen how [they are] ultimately going to fit into our practices."

"There are varying levels of comfort using the drugs," he continued. "Some people are more optimistic, and then some are more cautious, less willing to use them, for whatever reason. They're taking into account the vasculitis and also the efficacy of the drugs, which is moderate."

In a that coincided with the ASRS report, Apellis emphasized that no evidence suggested that the "drug product or manufacturing issues contributed to rare events of retinal vasculitis ... Zero events were reported in clinical trials." Apellis CEO Cedric Francois, MD, PhD, added that "these events continue to be very rare."

In a subsequent , the company stated that pegcetacoplan generated $74 million in revenue during the third quarter of 2023 ($160 million since the March 2023 launch) and emphasized continued reduction in the growth rate of GA with long-term use.

With regard to the inflammation incidents, company officials stated, "The estimated real-world rate of retinal vasculitis remains rare, at 0.01% per injection."

In response to a request from 番茄社区, a company spokesperson said, "Apellis worked closely with the U.S. Food and Drug Administration to update the prescribing information for Syfovre. Patient safety is our top priority, and this update will help physicians make informed treatment decisions."

"The overall benefit/risk profile of Syfovre remains favorable," the spokesperson added. "More than 120,000 injections have been administered as of November 18 and the estimated rate of retinal vasculitis continues to be rare at 0.01% per injection. We believe that Syfovre continues to be an important treatment for people living with GA."

Earlier this month, the FDA and Apellis agreed on that addresses the potential for intraocular inflammation.

Astellas, the maker of avacincaptad pegol, also weighed in on the issue.

"To date, Astellas has received a single adverse event report of retinal vasculitis from a post-marketing spontaneous safety report," company officials said in an email to 番茄社区. "According to the report, a 43-year-old patient with 'geographic atrophy secondary to Stargardt disease' received Syfovre in the left eye, followed four days later by an injection of Izervay in the right eye. Izervay is not approved/indicated for use in Stargardt disease."

"The patient presented with signs of vasculitis in the left eye. Two days later, there were also signs of vasculitis in the right eye," the official continued. "Astellas has not received any other adverse event reports involving retinal vasculitis in a patient who received Izervay, and there were no cases of retinal vasculitis across the GATHER clinical trials. Patient safety is our top priority, and we remain confident in the safety and efficacy profile of Izervay."

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