Pegcetacoplan Orphan Drug Status for Dry AMD
Pegcetacoplan is FDA-approved for the treatment of geographic atrophy (GA) secondary to dry age-related macular degeneration, but the provided evidence does not explicitly state whether it holds orphan drug designation. However, given that GA affects approximately 1.75 million people aged 40+ in the United States with either neovascular AMD or geographic atrophy, and that pegcetacoplan received FDA approval in 2023 specifically for this indication, it likely received orphan drug status during its development pathway 1, 2.
FDA Approval and Clinical Indication
- Pegcetacoplan received FDA approval in 2023 as the first therapeutic agent to treat geographic atrophy secondary to dry AMD 2.
- The drug is a pegylated bicyclic peptide that functions as a complement C3 inhibitor, blocking a key step in the complement cascade implicated in AMD pathogenesis 3.
- Geographic atrophy represents an advanced form of dry AMD characterized by progressive retinal atrophy and is a major cause of blindness, with no prior approved treatments available before 2023 4, 2.
Clinical Efficacy Data
- Pegcetacoplan reduces GA lesion growth rate by 29-45% depending on treatment frequency and duration, with increasing efficacy observed over time 4, 5.
- In the phase 2 FILLY trial, monthly pegcetacoplan reduced GA growth by 29% over 12 months, with post-hoc analysis showing 45% reduction in the second 6 months of treatment 4.
- The phase 3 OAKS and DERBY trials, along with the GALE extension study, demonstrated sustained efficacy up to 30 months, with GA growth rate reductions of 39% (monthly) and 32% (every other month) 5.
- In eyes with nonsubfoveal GA, pegcetacoplan achieved even greater reductions of 45% (monthly) and 33% (every other month) 5.
Critical Safety Considerations
- The most significant safety concern is dose-dependent development of new-onset exudative (wet) AMD, occurring in 20.9% of monthly-treated eyes and 8.9% of every-other-month treated eyes, compared to only 1.2% in sham-treated eyes 4.
- Pegcetacoplan carries higher risks of intraocular inflammation, vasculitis, and nonarteritic ischemic optic neuropathy (NAION) compared to the alternative GA treatment avacincaptad pegol, though real-world data continues to clarify these risks 2.
- Three cases of endophthalmitis (two culture-positive, one culture-negative) occurred in the monthly treatment group during the FILLY trial 4.
- In the first 6 months of the GALE extension study, 3.0% developed exudative AMD, 1.3% developed intraocular inflammation, and 0.1% developed ischemic optic neuropathy 5.
Treatment Algorithm Considerations
- Pegcetacoplan is administered as intravitreal injections either monthly or every other month, with both regimens demonstrating efficacy 4, 5.
- The decision to initiate pegcetacoplan must weigh the 11-45% reduction in GA progression against the substantial 9-21% risk of converting to wet AMD, which itself requires anti-VEGF therapy 4, 3.
- Patients must be counseled that pegcetacoplan slows GA lesion growth but does not improve or restore vision, as demonstrated by unchanged visual acuity outcomes in clinical trials 6, 4.
- Close monitoring for new-onset exudative AMD is mandatory in all treated patients, as this complication requires immediate initiation of anti-VEGF therapy 4, 2.