Avacincaptad Pegol, A Novel C5 Inhibitor, Significantly Reduces the Mean Rate of Geographic Atrophy Growth in a Pivotal Clinical Trial

Abstract

Purpose : The role of complement in age related macular degeneration (AMD) is under investigation. Cleavage of complement C5 leads to the generation of C5a and C5b. C5a is involved in priming and activation of inflammasomes while the generation of C5b leads to the formation of membrane attack complex (MAC), both resulting in RPE cell death.

Methods : Pivotal, randomized, double masked, sham controlled clinical trial evaluating the efficacy and safety of avacincaptad pegol (1, 2 and 4 mg) (Zimura®), a novel complement C5 inhibitor, for the treatment of patients with geographic atrophy secondary to dry AMD. Patients who received monthly treatments of either sham, 2mg or 4 mg avacincaptad pegol were analyzed for statistical analysis. The inclusion criteria included: non-foveal GA; a total GA area ≥ 2.5 and ≤ 17.5 mm²; GA in part within 1500 microns from the foveal center; the atrophic lesion able to be imaged in its entirety; and best corrected visual acuity in the study eye between 20/25 – 20/320, inclusive. The primary efficacy endpoint was the mean rate of change in GA over 12 months measured by fundus autofluorescence (FAF) at three time points: Baseline, Month 6, and Month 12.

Results : 286 patients were enrolled in this trial. The reduction in the mean rate of GA growth over 12 months was 27.38% (p-value = 0.0072) for the avacincaptad pegol 2 mg group as compared to the corresponding sham group and 27.81% (p-value = 0.0051) for the avacincaptad pegol 4 mg group as compared to the corresponding sham group. Although efficacy data from patients receiving the 1 mg dose was not part of the prespecified statistical analysis, preliminary descriptive analysis indicated that, on average, the percent growth from baseline to month 12 for the 1 mg group was less than for the corresponding sham group. The overall data suggested a dose response relationship between 1 mg and the 2 and 4 mg groups. Avacincaptad pegol was well tolerated after 12 months of administration. There was no avacincaptad pegol-related inflammation or adverse events, no ocular serious adverse events, and no cases of endophthalmitis.

Conclusions : Complement C5 is a viable target for inhibition to potentially prevent or slow RPE cell death in patients with geographic atrophy secondary to dry AMD. A second pivotal clinical trial is initiating to confirm the efficacy and safety of avacincaptad pegol in GA.

This is a 2020 ARVO Annual Meeting abstract.