Characterizing New-Onset Exudation in the Randomized Phase 2 FILLY Trial of Complement Inhibitor Pegcetacoplan for Geographic Atrophy.

Abstract

OBJECTIVE\nEvaluate clinical characteristics of eyes that developed investigator-determined new-onset exudative age-related macular degeneration (eAMD) during the FILLY trial.\n\n\nDESIGN\nPost-hoc analysis of the phase 2 study of intravitreal pegcetacoplan in geographic atrophy (GA).\n\n\nSUBJECTS\n246 subjects with GA secondary to AMD.\n\n\nINTERVENTION\nEither 15 mg intravitreal pegcetacoplan or sham given monthly or every other month (EOM) for 12 months followed by a 6-month off-treatment period.\n\n\nMAIN OUTCOME MEASURES\nTime of onset of new eAMD in the study eye; history of eAMD in the fellow eye; presence of double layer sign (DLS) on structural optical coherence tomography (OCT) in the study eye; changes in retinal anatomy by structural OCT and fluorescein angiography (FA); and changes in visual acuity.\n\n\nRESULTS\nExudation was reported in 26 study eyes across all treatment groups over 18 months. Mean time to diagnosis of eAMD was 256 days (range: 31 to 555). Overall, a higher proportion of subjects with a history of eAMD in the fellow eye (P=0.016) and a DLS in the study eye at baseline (P=0.0001) developed eAMD. Among study eyes that developed eAMD, 18/26 (69%) had a history of fellow eye eAMD and 19/26 (73.1%) had a DLS at baseline, compared to 72/217 (33%) (P=0.0003) and 70/215 (32.5%) (P<0.0001)respectively, of study eyes that did not develop eAMD. All 21 subjects with structural OCT imaging at the time of eAMD diagnosis had subretinal fluid and/or intraretinal cysts, consistent with exudation. Among 17 subjects who received FA at the time of eAMD diagnosis, 10 had detectable MNV, all occult lesions. Development of eAMD did not appear to have an appreciable impact on visual acuity, and all subjects responded to anti-VEGF therapy.\n\n\nCONCLUSIONS\nIntravitreal injections of pegcetacoplan slowed the rate of GA growth and were associated with an unexpected dose-dependent increased incidence of eAMD with no temporal clustering of onset. eAMD appeared to be associated with the presence of baseline eAMD in the contralateral eye and a DLS, suggestive of nonexudative MNV, in the study eye. The safety profile of pegcetacoplan was acceptable to proceed to phase 3 studies without adjustments to enrollment criteria.