C3 Complement Inhibition
Dysregulation of the complement system is well-documented in GA, with C3 overactivation playing a crucial role in driving downstream processes that contribute to the development and progression of GA.1 Pegcetacoplan specifically targets C3 and C3b, effectively inhibiting the damaging downstream effects of the complement pathway.
OAKS, DERBY, and GALE clinical trials
The OAKS and DERBY studies were two 24-month pivotal phase III trials that led to the approval of pegcetacoplan.2 The GALE study, an open-label extension, provided additional data over the subsequent year.
Combined data from the OAKS and DERBY trials demonstrated a significant reduction in GA lesion growth over two years, with a notable increase in efficacy over time. The most substantial reduction occurred between months 18 and 24.* This improvement continued in the open-label extension study, with even greater reduction between months 24 and 36.# Importantly, reductions were apparent as early as six months. Furthermore, after three years, reductions were observed in both non-subfoveal and subfoveal GA lesions.
Based on learnings about GA from other trials (CHROMA and SPECTRI), microperimetry showed the strongest correlation with GA area, while other measures including best-corrected visual acuity, low-luminance visual acuity, NEI-VFQ–25, Functional Reading Independence Index, and reading speed showed poor correlation.3,4 Pegcetacoplan demonstrated significant benefits in microperimetry, especially in reducing the risk of progression to absolute scotoma in both central 4 and 16 macular loci over 2 years.** Additionally, pegcetacoplan delayed progression to severe and sustained visual impairment in the study eye, with severe vision loss defined as a loss of 35 letters, in line with the World Health Organization criteria.
Safety Profile
In the combined OAKS and DERBY studies at 24 months, the most common adverse effects (incidence ≥5%) included ocular discomfort, new-onset exudative AMD, vitreous floaters, and conjunctival hemorrhage. Rare adverse events (incidence <5%) included intraocular inflammation, ischemic optic neuropathy, and endophthalmitis.##
The safety profile from the first 12 months of the GALE study remained consistent with findings from OAKS and DERBY. Longitudinal data from the OAKS, DERBY, and GALE trials (months 0 to 36) showed approximately one case of infectious endophthalmitis per 3,600 injections (0.03%), one case of ischemic optic neuropathy per 2,000 injections (0.05%), and intraocular inflammation at a rate of 0.26% per injection. No cases of occlusive or non-occlusive retinitis or vasculitis were reported across these studies.!
As of November 2024, over 420,000 injections of pegcetacoplan have been given in the real world and in clinical trials. Rare cases of intraocular inflammation with vasculitis have been observed post marketing. This appears to be primarily a first-injection phenomenon, with an incidence of approximately one case per 4,000 first injections. Importantly, no increased incidence has been observed with subsequent injections or in fellow eyes after the first eye has been treated.
Introduction of Pegcetacoplan Into Real-World Settings
Managing GA in Real-World Settings
When introducing new treatments into clinical practice, multiple factors impact the decision to treat and which eye to treat (Figure 1). These factors include the patient’s age, comorbidities, access to care, and the feasibility of treatment adherence. Unlike wet AMD where treatment intervals may be extended based on assessment of fluid, treatment for GA is not tapered based on biomarkers such as OCT. Once initiated, the treatment must continue consistently.
Key considerations include the status of the fellow eye (e.g., if one eye has already lost vision due to CNV, advanced GA or another cause), GA lesion characteristics, tempo of GA progression, family history, and patient symptoms. A comprehensive discussion of the risks and benefits is essential. Other considerations involve whether to inject the poorer or better seeing eye first, the injection technique, and the development of a strategy for monitoring treatment effectiveness. The injection dose volume of complement inhibitors is 100-microliter which may elevate IOP: gentle ocular decompression with a Q-Tip was done in the clinical trial. Additionally, it is important to consider whether discontinuing treatment might ever be appropriate. These factors require ongoing discussion and careful monitoring throughout the treatment process. Moreover, managing realistic expectations is critical.
*Ferrone, P. et al. Presented at Macula Society 2023.
#Steinle, N. et al. Presented at Retina Society 2024.
**Lad, N. et al. Presented at Retina Society 2024; Steinle, N. et al. Presented at Retina Society 2024.
##Wykoff C. et al. Presented at AAO 2022.
!Steinle, N. et al. Presented at Retina Society 2024.
1. Bakri, S. J. et al. Geographic atrophy: Mechanism of disease, pathophysiology, and role of the complement system. J Manag Care Spec Pharm 29, S2–S11 (2023).
2. Heier, J. S. et al. Pegcetacoplan for the treatment of geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY): two multicentre, randomised, double-masked, sham-controlled, phase 3 trials. Lancet 402, 1434–1448 (2023).
3. Heier, J. S. et al. Visual Function Decline Resulting from Geographic Atrophy: Results from the Chroma and Spectri Phase 3 Trials. Ophthalmol Retina 4, 673–688 (2020).
4. Chang, D. S. et al. Macular Sensitivity Endpoints in Geographic Atrophy: Exploratory Analysis of Chroma and Spectri Clinical Trials. Ophthalmology Science 4, 100351 (2024).
