C5 Inhibitor Slows Geographic Atrophy in Dry Macular Degeneration

SAN ANTONIO — An inhibitor of complement protein C5 significantly slowed geographic atrophy (GA) progression in dry age-related macular degeneration (AMD), a sham injection-controlled trial showed.

Monthly injections of two different doses of avacincaptad pegol (Zimura) reduced GA progression at 1 year by 27% to 28% versus sham. The difference was maintained during an additional 6 months of follow-up.

A post-hoc analysis showed that the C5 inhibitor also substantially reduced the proportion of patients who progressed from drusen to incomplete or complete retinal pigment and outer retinal atrophy (i/cRORA), reported Jason Hsu, MD, of Wills Eye Hospital in Philadelphia, at the American Society of Retina Specialists meeting.

“The primary endpoint was met, showing significant reductions in geographic atrophy growth at 12 months,” said Hsu. “With continuing monthly injections through 18 months, we saw continuous separation occur with about a 28% reduction in the rate of geographic atrophy growth in the avacincaptad pegol 2 mg and 4 mg groups versus sham. There were no avacincaptad pegol-related trial discontinuations or inflammatory events.”

A second pivotal trial of the C5 inhibitor has completed enrollment, and initial results are expected during the second half of 2022, he added.

Complement protein C5 is a key regulator of the complement system. Avacincaptad pegol inhibits cleavage of C5 and formation of the downstream fragments C5a and C5b, which is thought to inhibit retinal inflammation and promote cell survival.

Hsu reported findings from the sham-controlled GATHER 1 trial, which evaluated two doses of avacincaptad pegol. Eligible patients had non-foveal GA secondary to dry AMD. Data analysis included 344 patients: 67 randomized to monthly 2-mg avacincaptad, 110 to the 2-mg sham procedure, 83 to avacincaptad 4 mg, and 84 to the 4-mg sham procedure. The primary endpoint was change in GA from baseline to 12 months.

The primary analysis showed an increase of 0.402 mm with the 2-mg sham versus 0.292 mm with avacincaptad, representing a difference of 27.38% (P=0.0072). In the 4-mg arms, patients in the sham group had an increase of 0.444 in GA as compared with 0.321 with avacincaptad, a difference of 27.81% (P=0.0051).

Follow-up at 18 months showed GA increases of 0.599 and 0.430 mm for the sham and 2-mg avacincaptad groups, respectively, a difference of 28.11% in favor of the active treatment (P=0.0014). The 18-month GA values in the 4-mg groups were 0.559 and 0.391 mm for the sham and avacincaptad groups, a 29.97% difference in favor of the active treatment (P=0.0021).

Hsu also reported preliminary findings from a post-hoc analysis of drusen progression during the trial. The analysis included 44 sham-treated patients and 26 treated with 2-mg avacincaptad. At 18 months, 27.2% of the sham subgroup had progressed to i/cRORA as compared with 7.6% of patients treated with avacincaptad.

“The idea is that if we can prevent drusen progression, the overlying photoreceptors hopefully will better survive and we will see better outcomes for these patients functionally,” Hsu said of the findings from the post-hoc analysis.

The 18-month safety profile included no discontinuations related to the study drug and no inflammation associated with avacincaptad. The most common adverse events involved injection site issues. Additionally, avacincaptad was associated with a higher rate of choroidal neovascularization (CNV) that appeared to be dose dependent (4-9.6% at 12 months and 7.7-15.7% at 18 months vs 2.7% with sham), said Hsu.

During a discussion that followed the presentation, Hsu said investigators have theories about the CNV observed in the study, but no explanations.