Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration.

Abstract Objective Geographic atrophy (GA), a late stage of age-related macular degeneration, is a major cause of irreversible blindness. Even while central visual acuity remains relatively well preserved, GA often causes considerable compromise of visual function and quality of life. No treatment currently exists. We evaluated the safety and efficacy of pegcetacoplan (APL-2), a complement C3 inhibitor, for the treatment of GA. Design Prospective, multicenter, randomized, sham-controlled phase 2 study. Subjects 246 subjects with GA. Methods Subjects with GA were randomly assigned in a 2:2:1:1 ratio to receive intravitreal injections of 15 mg pegcetacoplan monthly or every-other-month (EOM) or sham intravitreal injections monthly or EOM, for 12 months with follow-up at months 15 and 18. Area and growth of GA were measured using fundus autofluorescence imaging. Main outcome measures The primary efficacy endpoint was mean change in square root GA lesion area from baseline to month 12. Secondary outcome measures included mean change from baseline in GA lesion area without the square root transformation, distance of GA lesion from the fovea (foveal encroachment), best corrected visual acuity (BCVA), low luminance BCVA (LL-BCVA), and low luminance visual acuity deficit (LL-VD). The primary safety endpoint was the number and severity of treatment emergent adverse events. Results In subjects receiving pegcetacoplan monthly or EOM, the GA growth rate was reduced by 29% (95% CI, 9 to 49; p=0·008) and 20% (95% CI, 0 to 40; p=0.067) compared with sham. Post-hoc analysis showed that the effect was greater in the second 6 months of treatment, with observed reductions of 45% (p=0.0004) and 33% (p=0.009) for pegcetacoplan monthly and EOM, respectively. Two cases of culture-positive endophthalmitis and one case of culture negative endophthalmitis occurred in the pegcetacoplan monthly group. New onset investigator-determined exudative AMD was reported more frequently in pegcetacoplan-treated eyes (18/86 eyes, or 20.9%, and 7/79 eyes, or 8.9%, in monthly and EOM groups, respectively) than in sham-treated eyes (1/81 eyes, or 1.2%). Conclusion Local inhibition of C3 with pegcetacoplan resulted in statistically significant reductions in the growth of GA compared with sham. Phase 3 study will further define the efficacy and safety profile.