Pegcetacoplan Carries Risk of New Exudation
Ophthalmology, September 2021
The pathogenesis of geographic atrophy (GA) is known to involve the complement pathway, but effective treatments for GA have been elusive. In the phase 2 FILLY trial, investigators found that intravitreal pegcetacoplan, which inhibits cleavage of complement component C3, slowed progression of GA lesions but raised the risk of new exudative age-related macular degeneration (AMD). In a post hoc analysis of that study, Wykoff et al. aimed to identify clinical factors that may signal the onset of exudative AMD during treatment with pegcetacoplan. They found that double-layer sign (DLS) in the study eye and a history of exudative AMD in the fellow eye were indicators of new exudative disease.
For this analysis, the researchers evaluated 246 patients with GA secondary to AMD who received intravitreal pegcetacoplan (15 mg) or placebo monthly or every other month for 12 months or until new exudative AMD was found in the study eye. This was followed by six months without treatment. Primary outcome measures were time to new AMD onset, changes in visual acuity (VA), and findings on OCT and fluorescein angiography (FA).
During treatment, exudative AMD occurred in 26 (10.6%) of the 246 eyes, including 18 (21%) of 86 eyes that received pegcetacoplan monthly, 7 (9%) of 79 eyes that received pegcetacoplan every other month, and 1 (1%) of 81 eyes in the placebo group. The time to detection of new exudative AMD varied widely (mean, 256 days), and strong indicators of new disease were exudative AMD in the contralateral eye at baseline and DLS in the study eye on OCT. All 21 patients who had OCT when the new AMD was detected were found to have subretinal fluid or intraretinal cysts. Ten of the 17 patients with FA at exudative AMD diagnosis also had occult macular neovascularization. Onset of AMD was not linked to loss of VA, and all new cases of exudative disease responded to anti-VEGF therapy.
This research indicates that intravitreal pegcetacoplan slows GA growth but carries an unexpected risk of new-onset AMD, which seems to be dose dependent. However, the risk-benefit profile of pegcetacoplan was deemed sufficiently favorable to retain the current enrollment criteria for subsequent studies. The conversion of nonexudative macular neovascularization may have an immunologic basis, said the authors. They are exploring this possibility and other hypotheses in a global phase 3 program.
The original article can be found here.