In this episode of Evidence Based Retina, Rishi P. Singh, MD, FASRS, is joined by Mathew MacCumber, MD, PhD, FASRS, to discuss phase 1 results for APL-3007—a systemic complement C3 small interfering RNA (siRNA) being developed alongside intravitreal pegcetacoplan for geographic atrophy (GA) secondary to age-related macular degeneration (AMD).
Dr. MacCumber is a retina specialist at Illinois Retina Associates, a professor of ophthalmology at Rush University Medical Center, and an investigator on the ongoing phase 2 GALLOP study evaluating this combination approach.
APL-3007 with pegcetacoplan for GA fast facts
- Geographic atrophy affects an estimated 1 million people in the US and is responsible for roughly 20% of legal blindness in the country, with no way to restore vision already lost to the disease.1
- Two intravitreal complement inhibitors are FDA approved for GA: pegcetacoplan, a C3/C3b inhibitor approved in February 2023, and avacincaptad pegol, a C5 inhibitor approved 6 months later.2
- In an anchored matching-adjusted indirect comparison across the OAKS, DERBY, and GATHER2 phase 3 trials, monthly pegcetacoplan produced a 30.4% greater reduction in GA lesion growth than monthly avacincaptad pegol at month 12.3
- Through 30 months of continuous treatment in the GALE long-term extension study, pegcetacoplan reduced GA growth rate by up to 45% in nonsubfoveal lesions, with the treatment effect increasing over time.4
- The ASRS ReST Committee's post-marketing review confirmed retinal vasculitis in 14 eyes of 13 patients following intravitreal pegcetacoplan; all cases occurred after the first injection, presenting a median of 10.5 days later.5
- APL-3007, a systemic siRNA that silences hepatic C3 production, showed significant systemic C3 reduction through 3 months and a favorable safety profile in its phase 1 trial, presented at the 2026 ASRS Annual Meeting; it is now being tested in combination with pegcetacoplan in the phase 2 GALLOP study.6
APL-3007 mechanism and delivery
APL-3007 is a systemic C3 siRNA tested with intravitreal pegcetacoplan, aiming for a broad C3/C3b blockade in the retina and choroid. Once inside the hepatocyte, the siRNA is incorporated into the RNA-induced silencing complex (RISC) and pairs with C3 mRNA. AGO2 then cleaves the transcript, preventing translation into C3 protein and reducing systemic C3 levels.6
“What's really great about this approach is that the drug itself only stays in the body for 24 to 48 hours. But the fact that it's taken up by endosomes in the liver [means], it has effects that last up to 180 days.”
Phase 1 trial outcomes
APL 3007-HV-001 is a phase 1, randomized, double-blind, placebo-controlled study testing the safety and tolerability of a single subcutaneous dose of APL-3007 in healthy adults. Participants received ascending doses in cohorts (Dose 1, Dose 2, Dose 3, Dose 4, or placebo) and were monitored for 6 months to assess efficacy and safety.
The highest doses showed significant systemic C3 reduction through 3 months, with lasting effects up to 6 months.6 In addition, APL3007-HV-001 showed a good safety profile, with no serious adverse events (AEs) or reasons for study discontinuation.6
“The most common treatment-emergent AEs were injection site reactions and liver enzyme increases that were transient. They were mild and dose-dependent. There were no serious adverse events and no AEs leading to study discontinuation.”
Phase 2 GALLOP Study
The phase 2 GALLOP study (NCT07215390) has three arms: two dosing schedules testing different combinations of intravitreal pegcetacoplan and APL 3007, and one control arm using subcutaneous pegcetacoplan with placebo.6,7 The study objective is to evaluate the efficacy, safety, tolerability, and pharmacodynamics.6
The primary outcome measurement is the change from baseline (CFB) in the area of AI-based SD-OCT assessment of RPE lesions in the study eye. Estimated completion date is late 2027.7
Complement inhibitors in practice
Dr. MacCumber reports that Retina Consultants of America (RCA) practices are seeing steady growth in complement inhibitor use.
Initially, there were safety concerns about occlusive retinal vasculitis associated with intravitreal pegcetacoplan, as reported by the American Society of Retina Specialists (ASRS) Research and Safety in Therapeutics (ReST) Committee,5 but these concerns have decreased due to improved administration protocols and lower event rates. Additionally, in the phase 1 trial, no participants developed a positive anti-drug antibody response.6
As Dr. MacCumber explained: "There was a short pause because there was the ReST report that gave some concern about occlusive retinal vasculitis with pegcetacoplan, but since that time we've learned how to use the drug safely. You can only treat one eye. You can even use a half dose. The events themselves are also becoming less and less frequent. There have only been two events this past year with pegcetacoplan, and none at RCA."
