Association of Pegcetacoplan With Progression of Incomplete Retinal Pigment Epithelium and Outer Retinal Atrophy in Age-Related Macular Degeneration

Abstract

IMPORTANCE Change in areas of incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA) within eyes with geographic atrophy (GA) might reflect similar changes among eyes with drusen but no GA.OBJECTIVE To evaluate the potential association of pegcetacoplan with progression of iRORA in eyes with GA secondary to AMD. DESIGN, SETTING, AND PARTICIPANTSThis post hoc analysis of the phase 2 multicenter, randomized, single-masked, sham-controlled FILLY trial of intravitreal pegcetacoplan for 12 months took place from February 2 to July 7, 2020. Participants comprised 167 patients with GA secondary to AMD who received pegcetacoplan monthly (n = 41) or every other month (n = 56) or a sham injection (n = 70) in the FILLY trial, completed the month 12 study visit, and did not develop exudative AMD.INTERVENTIONS Intravitreal pegcetacoplan, 15 mg, or sham injection, monthly or every other month for 12 months.MAIN OUTCOMES AND MEASURES Masked readers analyzed spectral-domain optical coherence tomography scans in regions beyond a perimeter of 500 μm from the GA border according to the Classification of Atrophy Meetings criteria. Primary outcome measures were progression from iRORA to complete RPE and outer retina atrophy (cRORA) from baseline to 6 and 12 months. RESULTS Among the 167 patients in the study, at baseline, iRORA was present in 45.0% of study eyes (18 of 40) in the pegcetacoplan monthly group, 61.8% of study eyes (34 of 55) in the pegcetacoplan every other month group, and 50.7% of study eyes (34 of 67) in the sham group. At 12 months, progression from iRORA to cRORA occurred in 50.0% of study eyes (9 of 18) in the pegcetacoplan monthly group (P = .02 vs sham), 60.6% of study eyes (20 of 33) in the pegcetacoplan every other month group (P = .06 vs sham), and 81.8% of study eyes (27 of 33) in the sham group. Compared with sham treatment, the relative risk of progression at 12 months from iRORA to cRORA was 0.61 (95% CI, 0.37-1.00) for eyes in the pegcetacoplan monthly group and 0.74 (95% CI, 0.54-1.02) for eyes in the pegcetacoplan every other month group.CONCLUSIONS AND RELEVANCE Eyes receiving intravitreal pegcetacoplan had lower rates of progression from iRORA to cRORA compared with controls, suggesting a potential role for pegcetacoplan therapy earlier in the progression of AMD prior to the development of GA.

Association of Complement C3 Inhibitor Pegcetacoplan with Photoreceptor Degeneration Beyond Areas of Geographic Atrophy

“…47,48 Besides incident iRORA (or nGA) as an endpoint, the rate of iRORA to RPE-atrophy transition distant to the junctional zone has been proposed as an endpoint. 49 In another post-hoc study of the FILLY trial, a reduced iRORA to RPE-atrophy transition rate in eyes treated with pegcetacoplan was reported. 50 Further studies are warranted to examine whether the observed lesser thinning at the level of the ONL along contour-lines reflects the sum of decreased focal thinning primarily, 50 or reduced thinning in a 'macula-wide' manner.…”

Association of complement C3 inhibitor pegcetacoplan with reduced photoreceptor degeneration beyond areas of geographic atrophy

“…This concept was more recently incorporated by the Classification of Atrophy Meeting (CAM) consortium as a part of incomplete RPE and outer retinal atrophy (iRORA) 57 , 58 . Besides incident iRORA (or nGA) as an endpoint, the rate of iRORA to RPE-atrophy transition distant to the junctional zone has been proposed as an endpoint 59 . In another post-hoc study of the FILLY trial, a reduced iRORA to RPE-atrophy transition rate in eyes treated with pegcetacoplan was reported 60 .…”

“…Besides incident iRORA (or nGA) as an endpoint, the rate of iRORA to RPE-atrophy transition distant to the junctional zone has been proposed as an endpoint 59 . In another post-hoc study of the FILLY trial, a reduced iRORA to RPE-atrophy transition rate in eyes treated with pegcetacoplan was reported 60 . Further studies are warranted to examine whether the observed reduced thinning at the level of the ONL along contour-lines reflects the sum of decreased focal thinning primarily 60 , or reduced thinning in a ‘macula-wide’ manner.…”

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

“…Post hoc analysis suggested pegcetacoplan may be useful in AMD prior to the development of GA [ 66 ]. Incomplete RPE and outer retinal atrophy (iRORA) without neovascularization are considered precursor lesions to GA, while progression to complete RPE and outer retinal atrophy (cRORA) without neovascularization are synonymous with GA.…”

“…In the trial, patient eyes receiving pegcetacoplan possessed lower rates of progression from iRORA to cRORA. As such, although findings did not achieve statistical significance, pegcetacoplan may prevent the incidence of GA [ 66 ]. However, in the FILLY study, new-onset wet AMD was more prevalent in the pegcetacoplan groups compared with the sham arm.…”