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

Abstract

Objectives: To evaluate clinical characteristics of eyes in which investigator-determined new-onset exudative age-related macular degeneration (eAMD) developed during the FILLY trial.Design: Post hoc analysis of the phase 2 study of intravitreal pegcetacoplan in geographic atrophy (GA). Subjects: Patients with GA secondary to age-related macular degeneration (AMD), n ¼ 246. Intervention: Either 15 mg intravitreal pegcetacoplan or sham given monthly or every other month for 12 months followed by a 6-month off-treatment period.Main Outcome Measures: Time of new eAMD onset in the study eye, history of eAMD in the fellow eye, presence of double-layer sign (DLS) on structural OCT in the study eye, changes in retinal anatomic features by structural OCT and fluorescein angiography (FA), and changes in visual acuity.Results: Exudation was reported in 26 study eyes across treatment groups over 18 months. Mean time to eAMD diagnosis was 256 days (range, 31e555 days). Overall, a higher proportion of patients with a baseline history of eAMD in the fellow eye (P ¼ 0.016) and a DLS in the study eye (P ¼ 0.0001) demonstrated eAMD. Among study eyes in which eAMD developed, 18 of 26 (69%) had history of fellow-eye eAMD and 19 of 26 (73.1%) had DLS at baseline, compared with 76 of 217 study eyes (35%; P ¼ 0.0007) and 70 of 215 study eyes (32.5%; P < 0.0001), respectively, in which eAMD did not develop. All 21 patients with structural OCT imaging at the time of eAMD diagnosis demonstrated subretinal fluid, intraretinal cysts, or both consistent with exudation. Among 17 patients who underwent FA at eAMD diagnosis, 10 showed detectable macular neovascularization (MNV), all occult lesions. Development of eAMD did not have an appreciable impact on visual acuity, and all patients responded to antievascular endothelial growth factor (VEGF) therapy.Conclusions: Intravitreal pegcetacoplan slowed the rate of GA growth and was associated with an unexpected dose-dependent increased incidence of eAMD with no temporal clustering of onset. Exudative AMD seemed to be associated with 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. Ophthalmology 2021;-:1e12

Pegcetacoplan: First Approval

“…Newonset investigator-determined exudative AMD occurred in 20.9% of 86 monthly pegcetacoplan-treated eyes, 8.9% of 79 EOM pegcetacoplan-treated eyes and 1.2% of 84 shamtreated eyes in FILLY [19]. It was not associated with any substantial changes in visual acuity [19] and according to a post-hoc analysis appears to be associated with baseline history of exudative AMD in the contralateral eye and the presence of the double-layer sign in the study eye [24]. The risk of exudative AMD with intravitreal pegcetacoplan therapy may be mitigated by the use of a pegcetacoplan formulation that does not require reconstitution [19].…”

Targeting the Complement Cascade for Treatment of Dry Age-Related Macular Degeneration

“…An additional post hoc analysis of the FILLY trial determined 20.9% (18 of 86), 8.9% (7 of 79), and 1.2% (1 of 81) of study eyes developed wet AMD in the pegcetacoplan monthly, pegcetacoplan EOM, and sham groups, respectively, throughout the 18-month study course. Importantly, eyes that eventually developed wet AMD demonstrated increased baseline prevalence of both the double-layer sign (DLS), a finding suggestive of type I macular neovascularization (MNV), and wet AMD in the fellow eye [ 67 ]. Irrespective of the inclusion or exclusion of data for patients with new onset wet AMD, the study’s primary endpoint of reducing GA growth rate was still attained in the FILLY trial.…”

“…Irrespective of the inclusion or exclusion of data for patients with new onset wet AMD, the study’s primary endpoint of reducing GA growth rate was still attained in the FILLY trial. Furthermore, an independent safety monitoring committee permitted completion of the study, as the exudations did not appreciably impact visual acuity [ 67 ].…”

A Review of Completed and Ongoing Complement Inhibitor Trials for Geographic Atrophy Secondary to Age-Related Macular Degeneration

“…Additionally, 20.9% (95% CI: 12.9-31%) of participants in the monthly group converted to eAMD, compared to 8.9% (95% CI: 3.6-17.4%) in the EOM group and 1.2% (95% CI: 0-6.7%) in the sham groups (Figure 3). While a post hoc analysis of FILLY data outlined some risk factors for conversion to eAMD, including baseline eAMD in the contralateral eye and a double-layer sign on ocular coherence tomography (OCT) in the study eye, there was a persistent dose-related association between complement inhibition and the development of eAMD, regardless of the presence of these risk factors [13]. Despite the limitations of the FILLY study, two phase 3 trials have been approved and are currently under way to evaluate the efficacy of pegcetacoplan in patients with GA (NCT03525613 and NCT03525600).…”