| Richard Mark Kirkner, Editor |
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Geographic atrophy secondary to age-related macular degeneration is a well-known unmet need, and the stakes have been raised as potential treatments for GA move through the pipeline. One of the most advanced candidates is pegcetacoplan, once known as APL-2 (Apellis Pharmaceuticals), a complement inhibitor now in two Phase III clinical trials, DERBY and OAKS.
But a post-hoc analysis of data from the Phase II FILLY trial has gained recent attention. SriniVas Sadda, MD, lead investigator of the post-hoc analysis, recently reported that pegcetacoplan reduced the rate of progression from early stage, or nascent, GA to full-blown GA by about 40 percent compared to sham.1
Pegcetacoplan is a synthetic cyclic peptide conjugated to a polyethylene glycol polymer. It targets C3, a complement factor that has been implicated in AMD. The Food and Drug Administration in 2018 granted it fast-track designation for GA.
Here, Dr. Sadda, president and chief scientific officer of the Doheny Eye Institute in Los Angeles, answers questions about the post-hoc analysis of the FILLY trial. The study was supported in part by Apellis.
Q: What role does the complement pathway play in geographic atrophy?
A: The complement proteins C3, C5 and the membrane attack complex (MAC) have been found in the eyes of AMD patients, and particularly in drusen.
Genetic evidence also supports the role of complement proteins in AMD. Complement factor H (CFH) is a regulator of the complement system, and different polymorphisms of the CFH gene are clearly associated with increased risk of AMD. Others, such as C3 and C2, also have variants that increase the risk for AMD and advanced AMD. Some AMD patients have higher serum levels of complement activation products as well. C3 is of particular interest because preclinical studies have shown it may be associated with deposits below the retinal pigment epithelium and even RPE atrophy.
Q: What was the rationale for the post-hoc analysis?
A: The goal was to see if pegcetacoplan could have any impact on the progression of macular degeneration outside the GA lesion. It focused on nascent GA, but it also evaluated progression from drusen to nascent GA, also termed incomplete retinal pigment epithelium and outer retinal atrophy (iRORA), or complete atrophy.
Few patients progress from drusen to atrophy in 18 months, but the study population showed a hint of progression events after six months. The sham group seemed to continue to progress after six months, whereas the pegcetacoplan patients stabilized, but the numbers were small.
It was important to determine if the treatment had any positive impact in areas outside the atrophy, which could suggest that the possibility of earlier intervention warrants further exploration.
Q: How does pegcetacoplan target the C3 pathway?
A: It specifically inhibits cleavage of C3 into its subproducts, C3a and C3b. It’s an attractive target because, regardless of how complement is activated, pegcetacoplan in essence shuts down the downstream pathway. Three of the pathways of complement activation converge at C3: the classical; the lectin; and the alternative pathway.
The complement cascade has been divided into three major events known as the three A’s: activation followed by amplification, which is a feedback loop that amplifies complement, and then the attack that destroys tissue. Disrupting C3 cleavage blocks all downstream activity regardless of the pathway.
Q: What’s the most significant finding of the post-hoc analysis?
A: This was a small study cohort: 42 patients from the monthly pegcetacoplan group and 69 sham patients who completed 12 months of the study receiving all injections and didn’t develop exudative AMD. It should be emphasized that the findings are for hypothesis generation and need to be confirmed in an appropriately powered randomized prospective study.
Fifty percent of the pegcetacoplan-treated group demonstrated nascent or full GA vs. 81.8 percent of the sham group (p=0.02). Also, progression from large drusen to nascent GA or GA at 12 months occurred in 22.6 percent of the treatment group vs. 33.3 percent of sham (p=0.31).
Overall, paralleling the primary results of the study that showed that pegcetacoplan slowed the progression of GA, this analysis suggested that it also slowed progression from nascent GA to complete atrophy.
Q: How might the findings inform the DERBY and OAKS trials?
A: The primary outcome of FILLY was based on measuring atrophy with fundus autofluorescence. The good news is that DERBY and OAKS are collecting optical coherence tomography scans as well. This may provide an opportunity to determine if the post-hoc FILLY findings can be confirmed in a larger study. RS
REFERENCE
1. Sadda S, Nittala M, Metlapally R, Ribeiro R. Impact of pegcetacoplan on progression of nascent atrophy in AMD. Free paper presented at the European Society of Retina Specialists 2020 Virtual. October 2, 2020.
