Complement 5 Inhibition for GA

Cheryl Guttman Krader reports

Post-hoc analyses of data from a phase 2/3 study investigating avacincaptad pegol (“ACP”, Zimura, IVERIC bio) as a treatment for geographic atrophy (GA)—a chronic progressive degeneration of the macula and form of late-stage, age-related macular degeneration—should provide insights about the complement 5 inhibitor’s effect on earlier stages of GA and disease progression.

Carl J Danzig MD presented the findings from the primary endpoint and post-hoc analyses in the GATHER1 study. The international trial enrolled patients with non-centre pointinvolving GA and excluded those with evidence of choroidal neovascularisation in either eye or any sign of diabetic retinopathy.

GATHER1 consisted of two parts, each with a duration of 18 months. Part 1 randomised 77 patients 1:1:1 to monthly injections with sham, ACP 1 mg, or ACP 2 mg. Part 2 started after part 1 was completed and randomised 209 patients 2:1:2 to sham, ACP 2 mg, or ACP 4 mg.

Describing results from the primary endpoint of the trial, Dr Danzig reported the mean rate of GA area growth—as measured by square root transformation—was significantly reduced in the ACP 2 mg and 4 mg groups compared with sham (27% and 28%, respectively). Extrapolation to 18 months showed reductions in GA growth rate of 28% and 30%, respectively.

Results of a post-hoc analysis of patient subgroups defined by baseline characteristics showed the mean rate of GA growth from baseline was consistently lower in the ACP groups than in the sham group for subgroups stratified by baseline GA area (<4 DA and ≥4 DA) and by part 1 and part 2 of the study.

“There were too few patients to allow for proper analysis and meaningful conclusions of the treatment effect for subgroups of patients categorised by baseline VA or pattern of fundus autofluorescence at the junctional zone of GA,” Dr Danzig noted.

Another post-hoc analysis examined how ACP might affect the evolving atrophic process. Masked readers at the Doheny Image Reading and Research Lab received OCT images to grade for the presence of drusen, incomplete RPE and outer retinal atrophy (iRORA), and complete retinal pigment epithelium and outer retinal atrophy (cRORA) by applying Classification of Atrophy Meeting criteria.

Characteristics of the patients with drusen at baseline and the patients with iRORA at baseline were well balanced between the ACP and sham groups. At 18 months, ACP 2 mg was associated with a reduction compared to sham in the rate of progression from drusen to iRORA or cRORA and progression from iRORA to cRORA. The treatment effect was evident by 6 months and increased over time. By month 18, investigators observed a reduction in the progression rate of approximately 50% with avacincaptad pegol compared with sham in the progression from iRORA to cRORA.

Dr Danzig noted GATHER2, a phase 3 trial investigating ACP for treating GA, was fully enrolled in July 2021. GATHER2 randomised 448 patients to monthly treatment for 12 months with ACP 2 mg or sham. At 12 months, the patients in the ACP group will be re-randomised to receive the treatment monthly or every other month. Primary efficacy endpoint 12-month assessment results are expected in the third quarter of 2022.

Dr Danzig presented these findings at ARVO 2022 in Denver, Colorado, US.

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