Pegcetacoplan Comes Out Ahead in Comparison of Drugs for Dry AMD

STOCKHOLM — Atrophic age-related macular degeneration control appeared better with pegcetacoplan (Syfovre) as compared with avacincaptad pegol (Izervay) in a propensity-matched cross-trial comparison.

The comparison, which involved two randomized trials of pegcetacoplan and one of avacincaptad pegol, showed relative differences in geographic atrophy (GA) growth rate ranging from 12-37% in favor of monthly pegcetacoplan at 12 months.

The advantages were also evident at 24 months and with dosing every other month, reported Paul Hahn, MD, PhD, of NJRetina in Teaneck, New Jersey, at the American Society of Retina Specialists meeting.

“Of course, with this type of post-hoc comparative analysis, there are obvious limitations that I don’t need to go through today,” said Hahn. “I would think of this analysis not as definitive proof of any particular conclusion but rather part of a larger pie of data supporting the efficacy of pegcetacoplan for treatment of geographic atrophy.”

Hahn noted that the analysis was supported by Apellis, which markets pegcetacoplan.

During a discussion that followed the presentation, an unidentified member of the audience asked Hahn how he counsels patients, given the results of the analysis.

“We are really in a transition phase with the understanding of geographic atrophy and how to treat geographic atrophy,” said Hahn. “I think we’re lucky to have multiple therapies. The reasons to choose one drug or another are multifactorial: insurance/payer-based, personal experience or preferences, practice accessibility, formulary reasons. I have tried to discuss all the options with my patients.”

Now with 2-year data adding to the similar 1-year analysis presented previously, he said, “because this type of information is out there, it’s hard for me to recommend a drug other than pegcetacoplan. But again, I think the most important thing is that we’re lucky to have multiple options.”

Pegcetacoplan and avacincaptad pegol both target the complement cascade, with the former inhibiting C3/C3b and the latter blocking C5. Subcutaneous pegcetacoplan (Empaveli) received FDA approval for paroxysmal nocturnal hemoglobinuria in 2021, followed by approval of the intravitreal formulation for GA early in 2023. Avacincaptad pegol received FDA approval for GA several months after pegcetacoplan.

Support for the C3 inhibitor’s GA indication came primarily from the OAKS and DERBY randomized, sham-controlled trials. Both trials showed that pegcetacoplan slowed GA progression in both subfoveal and nonsubfoveal lesions. Principal support for avacincaptad pegol’s approval came from the GATHER2 randomized trial, a sham-controlled study that focused on nonsubfoveal lesions.

The two drugs have not been evaluated head to head in a randomized trial, precluding a direct comparison of the drugs’ relative efficacy. Absent true comparative data, Hahn and colleagues performed an anchored matching-adjusted indirect comparison. Limiting the analysis to nonsubfoveal lesions, they used propensity-score weighting to match patients with similar characteristics in OAKS and DERBY with those from GATHER2. The three trials were “anchored” by the common use of a sham-controlled comparator arm.

GATHER2 included 447 patients with nonsubfoveal lesions, randomized between avacincaptad pegol and sham. The more than 1,200 participants in OAKS and DERBY included 446 patients with nonsubfoveal lesions. Investigators compared OAKS and DERBY individually against GATHER2 and combined. They also compared results with monthly and every-other-month administration of pegcetacoplan versus monthly avacincaptad pegol.

The 12-month results with monthly pegcetacoplan showed a 37% relative reduction in GA progression versus avacincaptad pegol in the OAKS trial (P<0.05), a nonsignificant 12.1% lower rate in DERBY, and 30.4% reduction in the two trials combined (P<0.05). The 24-month results showed nonsignificant relative improvement in favor of pegcetacoplan of 24.3% in OAKS and 34.0% in DERBY, which became a significant 26.4% with the two trials combined (P<0.05).

The comparison of pegcetacoplan every other month versus monthly avacincaptad pegol numerically favored the C3 inhibitor at 12 months in OAKS (27.9%), DERBY (6.7%), and the two trials combined (21.4%), although none were statistically significant. The numerical but not statistical advantage for pegcetacoplan persisted at 24 months in OAKS (27.9%), DERBY (38.5%), and both trials (30.3%).

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