First Comprehensive Post-marketing Comparison Conducted for Recent GA Meds

AEs noted on the FDA drug’s label for avacincaptad pegol like increased intraocular pressure, retinal detachment and neovascular AMD did not emerge as significant safety signals in the FAERS database. Photo: Anna Bedwell, OD. Click image to enlarge. Adverse events (AEs) associated with the newer drugs for geographic atrophy (GA) are known, but not yet well described in literature outside of those reported in the FDA clinical trials. In a recent paper appearing in American Journal of Ophthalmology, researchers used data from the FDA Adverse Event Reporting System (FAERS) to identify AEs with pegcetacoplan and avacincaptad pegol.Identified were 752 and 80 patients, respectively, with secondary AEs from pegcetacoplan and avacincaptad.Ocular adverse events for pegcetacoplan included anterior segment (iris) hemorrhage, iris neovascularization, choroidal neovascularization, intraocular injection complication, hemorrhagic occlusive retinal vasculitis, retinal occlusive vasculitis and bacterial endophthalmitis. For avacincaptad, AEs included choroidal neovascularization, vitritis, dry age-related macular degeneration (AMD) and cystoid macular edema.In the discussion section of their paper, the authors highlight how the FDA clinical trials have documented some important presentations. The Phase III OAKS and DERBY trials (n=1,258) revealed that 61.6% of patients receiving monthly pegcetacoplan injections had treatment-emergent AEs in the study eye by 24 months, compared with only 55% in the bimonthly group and 46.3% in the placebo. For this drug, AEs reported were vitreous floaters, new-onset exudative AMD, retinal hemorrhage and decreased visual acuity, along with three serious cases of ischemic optic neuropathy.In avacincaptad pegol’s GATHER1 Phase II/III trial (n=286), treatment-emergent AEs were seen in 58.2% of patients receiving 2mg of the agent (the FDA-approved dosage), while this rose to 73.5% in the 4mg group and was just 40.9% in the sham group. AEs occurring at a rate of ≥2% in the cohorts (n=150) at 18 months included conjunctival hyperemia, conjunctival edema, punctate keratitis, cataracts, vitreous detachment, choroidal neovascularization, eye pain and reduced visual acuity. In the GATHER2 Phase III trial, ocular AEs occurring in ≥2% (n=225) at month 12 also included dry eye, increased ocular pressure and macular neovascularization.The study authors also reflect that clinical trial data suggest comparable rates of ocular adverse events between both agents, but the current study identified a broader range of adverse events with pegcetacoplan and a relatively narrower risk profile for avacincaptad with fewer reported AEs. However, avacincaptad had a higher uncertainty level in data, prompting the authors to caution that “our findings are also subject to the real-world utilization of these agents, but that they emphasize the necessity of a proactive, risk-based approach to patient management.”The investigators also speculated about the difference in absolute numbers of AEs in the FAERS database, offering three possibilities: pegcetacoplan may pose a greater intrinsic risk, may provoke more noticeable adverse reactions or may just be prescribed more frequently than avacincaptad. Also worth noting is that FDA approval of avacincaptad happened six months after pegcetacoplan, which may partially explain the discrepancy in number of reported AEs between the two agents. As well, clinicians’ expertise with pegcetacoplan may have improved their ability in detecting and reporting AEs. Based on the temporal differences in availability of the two, the authors write that this underscores “the need for ongoing surveillance of AEs for both agents to better elucidate the long-term implications of their mechanisms of action and inform their safe use in clinical practice.” Click here for the journal source.  Kailani Z, Mihalache A, Popovic MM, Kertes PJ, Muni RH. Ocular adverse events associated with pegcetacoplan and avacincaptad pegol for geographic atrophy: a population-based pharmacovigilance study. Am J Ophthalmol. April 25, 2025. [Epub ahead of print].