Study Raises New Safety Concerns About Geographic Atrophy Drugs Syfovre and Izervay

DENVER — A new analysis of real-world patient data suggests that two recently approved drugs for geographic atrophy (GA), a form of advanced age-related macular degeneration, may come with significant risks.

The study found that patients who took complement inhibitors — either pegcetacoplan (Syfovre) or avacincaptad pegol (Izervay) — had a roughly four times higher chance of developing a type of wet macular degeneration called exudative age-related macular degeneration (eAMD) compared to patients who did not take the drugs. They also had more than twice the risk of the disease progressing to a more severe form known as subfoveal GA.

The findings were presented at the Association for Research in Vision and Ophthalmology meeting by Dr. David Ramsey of the University of Massachusetts Chan Medical School.

“We saw no evidence that these drugs provided any benefit in slowing progression to subfoveal GA over the one-year follow-up period,” Ramsey said.

The study also looked at rates of vision loss. Patients taking either drug faced a higher risk of low vision or blindness, but the risk was only statistically significant for avacincaptad pegol (Izervay). For pegcetacoplan (Syfovre), the increased risk did not reach statistical significance.

Serious eye inflammation was rare, and the data did not suggest any higher risk of problems elsewhere in the body, such as heart-related complications.

Ramsey stressed that more research is needed to fully understand the balance of benefits and risks for these medications.

The research was based on information from the TriNetX clinical database, which collects medical records from many healthcare organizations. The study included 576 patients treated with either Syfovre or Izervay and a matched group of 576 GA patients who did not receive either drug. None of the patients had a history of eAMD at the start of the study.

The treated patients had a median age of about 81, and 66% were women. About 68% of them were on pegcetacoplan. Two-thirds stayed on their original drug, while 3.3% switched medications during the year.

The numbers told a clear story. Compared to the untreated group, those on the drugs had:

– A hazard ratio of 4.05 for developing eAMD — meaning they were about four times more likely to get it.
– A hazard ratio of 2.49 for progression to subfoveal GA.
– A hazard ratio of 1.80 for low vision or blindness.
– A hazard ratio of 3.04 for uveitis and intraocular inflammation.

However, the drugs were not linked to higher rates of glaucoma, high eye pressure, or retinal detachment.

When the researchers looked at each drug separately, the results were similar — except for vision loss. For pegcetacoplan, the hazard ratio for low vision or blindness was 1.63, which was not statistically significant. For avacincaptad pegol, the hazard ratio jumped to 6.89, which was statistically significant.

Ramsey acknowledged several limitations with the study. The data relies on how accurately doctors entered diagnostic codes, and those codes may not always be correct. The GA population in the database may not fully represent all patients with the disease, and treatment choices were likely influenced by factors like access to care and how quickly doctors adopted the new drugs.

Dr. Philip Rosenfeld, a session moderator from the University of Miami Bascom Palmer Eye Institute, questioned whether the data could be trusted. He noted that doctors often struggle to correctly diagnose whether GA is subfoveal or not. He also pointed to a separate ARVO poster showing that pegcetacoplan can cause fluid buildup that might be mistaken for wet AMD if doctors rely only on certain imaging tests.

“The only way you could even attempt to make this relevant to the real world is to see how it compares to clinical trial data,” Rosenfeld said. He added that the study numbers seem to match clinical trial results, but the researchers did not make that comparison directly.

Ramsey agreed that including clinical trial comparisons would have been helpful.

Both drugs were approved in 2023 and have been shown to slow the growth of GA lesions. But Ramsey noted that their ability to slow vision loss in late-stage AMD has not been proven. Results from clinical trials on vision function have been mixed, and there is ongoing debate about whether anatomical improvements always lead to better eyesight.

For doctors counseling patients, Ramsey emphasized the importance of setting realistic expectations. Factors to discuss include the need for repeated injections, long-term follow-up, regular imaging tests, and practical issues like cost, insurance coverage, travel, and time demands on both patients and clinics.

“From the vitreoretinal specialist perspective, there are also concerns about clinic flow,” Ramsey said.

Source: MedPage Today