Highlights
- •
Pegcetacoplan was linked to more adverse events than avacincaptad pegol based on FAERS.
- •
Pegcetacoplan’s safety profile aligns with early clinical trial findings.
- •
Avacincaptad pegol was linked to fewer events but with higher uncertainty in data.
- •
Study highlights the need for ongoing safety monitoring of both treatments.
Objective
To evaluate the postmarketing ocular adverse events (AEs) reported for avacincaptad pegol and pegcetacoplan, the only Food and Drug Administration (FDA)–approved treatments for geographic atrophy (GA).
Design
Retrospective pharmacovigilance analysis.
Subjects
Ocular AE reports in the FDA Adverse Event Reporting System (FAERS) in which pegcetacoplan or avacincaptad pegol was identified as the primary suspect drug were analyzed.
Methods
Using the OpenVigil 2.1 data mining software, we conducted a retrospective pharmacovigilance analysis of the FAERS database from inception to December 2024. We conducted disproportionality analyses to assess reporting odds ratios (RORs) for specific drug-AE combinations compared with all other drugs in the database.
Main Outcome Measures
Ocular AEs were evaluated.
Results
A total of 752 and 80 patients with AEs secondary to pegcetacoplan and avacincaptad pegol, respectively, were identified. Ocular AEs disproportionately overreported for pegcetacoplan included anterior segment (iris) hemorrhage (ROR 1767, 95% CI 538-5803), iris neovascularization (ROR 1248, 95% CI 502-3099), choroidal neovascularization (ROR 1328, 95% CI 956-1845), intraocular injection complication (ROR 2552, 95% CI 1607-4053), hemorrhagic occlusive retinal vasculitis (ROR 4606, 95% CI 2000-10,611), retinal occlusive vasculitis (ROR 2352, 95% CI 1313-4212), and bacterial endophthalmitis (ROR 1260, 95% CI 613-2589). Ocular AEs disproportionately overreported for avacincaptad pegol included choroidal neovascularization (ROR 1169, 95% CI 426-3205), vitritis (ROR 782, 95% CI 316-1936), dry age-related macular degeneration (ROR 684, 95% CI 316-1936), and cystoid macular edema (ROR 445, 95% CI 140-1412).
Conclusions
Current prescribing patterns indicate that a broader spectrum of ocular AEs were reported for pegcetacoplan than avacincaptad pegol. These findings aim to enhance clinicians’ understanding of the safety profiles of these agents, enabling informed patient care and heightened vigilance of these novel GA treatments.
G eographic atrophy (GA) is an advanced form of dry age-related macular degeneration (AMD) which represents a leading cause of irreversible central vision loss in adults aged ≥50 years. , Characterized by progressive degeneration of the retinal pigment epithelium (RPE), photoreceptors, and choriocapillaris, GA results in the formation and subsequent expansion of atrophic regions in the macula. Unlike neovascular AMD, there are a lack of therapeutic modalities for GA. Indeed, before the approval of the intravitreal agents pegcetacoplan and avacincaptad pegol in 2023, there were no GA therapies approved by the US Food and Drug Administration (FDA). , ,
Pegcetacoplan and avacincaptad pegol target key components of the complement pathway. Pegcetacoplan’s inhibition of C3 and avacincaptad pegol’s targeting of C5 both serve to reduce complement-mediated inflammation and, in turn, prevent the expansion of atrophic lesions. , Despite promising results in early clinical trials, severe ocular adverse events (AEs) have been reported for both agents, including new-onset neovascular AMD, intraocular inflammation, ischemic optic neuropathy, and increased intraocular pressure. , ,
To our knowledge, a comprehensive investigation into the safety profiles of pegcetacoplan and avacincaptad pegol in real-world settings has not yet been conducted. The FDA Adverse Event Reporting System (FAERS) database is a postmarketing drug safety surveillance program that compiles AE information voluntarily submitted to the FDA. This investigation systematically evaluated all reports of ocular AEs attributed to pegcetacoplan and avacincaptad pegol using FAERS data.
METHODS
We conducted a retrospective pharmacovigilance study. Real-world pharmacovigilance data were sourced from the FAERS database, which collects postmarketing reports of AEs voluntarily submitted by consumers, health care professionals, and pharmaceutical companies. This study focused specifically on reports of AEs in which avacincaptad pegol and pegcetacoplan were identified as the primary suspect drugs.
Using OpenVigil 2.1 software (Kiel, Germany), we analyzed FAERS data from the fourth quarter of 2003 to the fourth quarter of 2024. AEs related to each drug were captured following their approval. However, the entire FAERS database time frame was included to establish a stable and robust background reporting rate for comparison.
We evaluated reports of AEs attributed to these drugs compared to the background rates observed across all drugs in the FAERS database. To assess disproportionality, we used reporting odds ratios (RORs), which indicated the odds of a specific AE being reported for the drug of interest compared with all other drugs in the FAERS database.
To detect positive safety signals for avacincaptad pegol and pegcetacoplan, we applied the following criteria described by Evans and associates : drug-event combinations with at least 3 reports, a χ 2 value greater than 4, and a proportional reporting ratio greater than 2. To further minimize the risk of false-positive findings, we employed Bayesian confidence propagation neural network (BCPNN) algorithms. Drug-event combinations were considered disproportionately overreported if the lower bound of the 95% CI for the information component (IC) was positive (i.e., IC 025 > 0).
RESULTS
PEGCETACOPLAN
A total of 752 unique patients with AEs secondary to pegcetacoplan were identified over the study period. Of these, 84 patients (11%) were female, 50 (7%) were male, and the sex of the remaining patients was not specified. The mean age across reports was 75.7 ± 15.7, and most reports originated from the United States (n=578, 77%).
The following ocular AEs were significantly overreported for pegcetacoplan: corneal edema (n=10, ROR 126, 95% CI 67.2-235), anterior chamber cell (n=10, ROR 385, 95% CI 205-724), anterior chamber inflammation (n=3, ROR 141, 95% CI 45.3-441), hyphema (n=5, ROR 270, 95% CI 111-655), anterior chamber (iris) hemorrhage (n=3, ROR 1767, 95% CI 538-5803), iritis (n=14, ROR 148, 95% CI 86.8-251), iris neovascularization (n=5, ROR 1248, 95% CI 502-3099), choroidal neovascularization (n=40, ROR 1328, 95% CI 956-1845), intraocular injection complication (n=21, ROR 2552, 95% CI 1607-4053), vitritis (n=19, ROR 308, 95% CI 194-487), vitreous opacities (n=5, ROR 161, 95% CI 66.3-388), vitreous floaters (n=44, ROR 152, 95% CI 112-207), hemorrhagic occlusive retinal vasculitis (n=7, ROR 4607, 95% CI 2000-10611), retinal occlusive vasculitis (n=13, ROR 2352, 95% CI 1313-4212), retinal vasculitis (n=12, ROR 260, 95% CI 147-462), retinal ischemia (n=4, ROR 188, 95% CI 69.9-504), neovascular AMD (n=15, ROR 378, 95% CI 226-634), subretinal fluid (n=4, ROR 105, 95% CI 39.0-280), bacterial endophthalmitis (n=8, ROR 1260, 95% CI 613-2589), and staphylococcal eye infection (n=3, ROR 344, 95% CI 110-1082).
A graphical depiction of the results of our disproportionality analysis of pegcetacoplan can be found in Figure 1 . A comprehensive summary of ocular AEs that were overreported for pegcetacoplan, including those with ROR values less than 100, can be found in Table 1 .
| Ocular AE | n | ROR (95% CI) |
|---|---|---|
| Pegcetacoplan | 552 | |
| Visual impairment | 54 | 13.6 (10.3-17.9) |
| Vitreous floaters | 44 | 152.1 (112-206) |
| Choroidal neovascularization | 40 | 1328 (956-1845) |
| Uveitis | 28 | 67.7 (46.4-98.9) |
| Eye inflammation | 26 | 89.0 (60.2-131.8) |
| Intraocular pressure increased | 22 | 49.4 (32.3-75.6) |
| Intraocular injection complication | 21 | 2552 (1607-4053) |
| Retinal hemorrhage | 19 | 82.177 (52.1-130) |
| Vitritis | 19 | 308 (194-487) |
| Blurred vision | 18 | 4.13 (2.58-6.58) |
| Blindness | 16 | 11.4 (6.94-18.7) |
| Eye pain | 15 | 9.18 (5.51-15.3) |
| Neovascular age-related macular degeneration | 15 | 378 (226-634) |
| Iritis | 14 | 148 (86.8-251) |
| Retinal occlusive vasculitis | 13 | 2352 (1313-4212) |
| Retinal vasculitis | 12 | 260 (146-462) |
| Endophthalmitis | 11 | 50.8 (28.0-92.2) |
| Reduced visual acuity | 10 | 8.94 (4.79-16.7) |
| Iridocyclitis | 10 | 97.6 (52.2-183) |
| Corneal edema | 10 | 126 (67.2-235) |
| Anterior chamber cell | 10 | 385 (205.-724) |
| Ocular hyperemia | 9 | 6.06 (3.14-11.7) |
| Eye hemorrhage | 8 | 18.3 (9.12-36.8) |
| Bacterial endophthalmitis | 8 | 1260 (613-2589) |
| Photophobia | 7 | 12.8 (6.09-27.0) |
| Hemorrhagic occlusive retinal vasculitis | 7 | 4606 (2000-10611) |
| Photopsia | 6 | 30.0 (13.4-67.1) |
| Macular degeneration | 5 | 13.7 (5.70-33.1) |
| Eye infection | 5 | 14.9 (6.18-35.9) |
| Visual field defect | 5 | 19.3 (8.03-46.6) |
| Vitreous opacities | 5 | 161 (66.3-388) |
| Hyphema | 5 | 270 (111-655) |
| Iris neovascularization | 5 | 1248 (502-3099) |
| Papilledema | 4 | 25.5 (9.54-68.2) |
| Conjunctival hemorrhage | 4 | 30.5 (11.4-81.4) |
| Retinal tear | 4 | 52.1 (19.5-139) |
| Subretinal fluid | 4 | 105 (39.0-280) |
| Retinal ischemia | 4 | 188 (69.9-504) |
| Blindness unilateral | 3 | 6.11 (1.97-19.0) |
| Optic neuritis | 3 | 9.47 (3.05-29.4) |
| Ocular discomfort | 3 | 10.0 (3.22-31.1) |
| Retinal detachment | 3 | 10.0 (3.22-31.1) |
| Blindness transient | 3 | 12.0 (3.87-37.4) |
| Swelling of eyelid | 3 | 16.7 (5.39-52.1) |
| Ocular hypertension | 3 | 45.9 (14.7-143) |
| Anterior chamber inflammation | 3 | 141 (45.3-441) |
| Eye infection staphylococcal | 3 | 344 (110-1082) |
| Iris hemorrhage | 3 | 1767 (538-5803) |
| Avacincaptad pegol | 53 | |
| Visual impairment | 8 | 19.5 (9.37-40.4) |
| Vitreous floaters | 6 | 197 (85.7-453) |
| Endophthalmitis | 5 | 228 (92.1-564) |
| Eye pain | 5 | 30.1 (12.2-74.3) |
| Vitritis | 5 | 782 (316-1936) |
| Choroidal neovascularization | 4 | 1169 (426-3205) |
| Eye inflammation | 4 | 130 (47.7-356) |
| Blurred vision | 4 | 8.85 (3.24-24.2) |
| Cystoid macular edema | 3 | 445 (140-1412) |
| Dry age-related macular degeneration | 3 | 684 (215-2172) |
| Optic ischemic neuropathy | 3 | 304 (95.7-963) |
| Reduced visual acuity | 3 | 25.8 (8.15-81.9) |
AVACINCAPTAD PEGOL
A total of 80 unique patients with AEs secondary to avacincaptad pegol were identified over the study period. Of these, 46 (58%) patients were female, 19 (24%) were male, and the sex of the remaining patients was not specified. The mean age across reports was 83.7 ± 10.0 years. All reports originated from the United States.
The following ocular AEs were disproportionately overreported for avacincaptad pegol: choroidal neovascularization (n=4, ROR 1169, 95% CI 426-3205), vitritis (n=5, ROR 782, 95% CI 316-1936), vitreous floaters (n=6, ROR 197, 95% CI 85.7-453), optic ischemic neuropathy (n=3, ROR 304, 95% CI 95.7-963), dry AMD (n=3, ROR 684, 95% CI 215-2172), cystoid macular edema (n=3, ROR 445, 95% CI 140-1412), endophthalmitis (n=5, ROR 228, 95% CI 92.1-564), and eye inflammation (n=4, ROR 130, 95% CI 47.7-356).
A graphical depiction of the results of our disproportionality analysis of avacincaptad pegol can be found in Figure 2 . A comprehensive summary of ocular AEs that were overreported for avacincaptad pegol, including those with ROR values less than 100, can be found in Table 1 .
Our disproportionality analysis identified 9 ocular AEs that were overreported for both pegcetacoplan and avacincaptad pegol, including choroidal neovascularization (pegcetacoplan: n=40, ROR 1328, 95% CI 956-1845; avacincaptad pegol: n=4, ROR 1169, 95% CI 426-3205), vitritis (pegcetacoplan: n=19, ROR 308, 95% CI 194-487; avacincaptad pegol: n=5, ROR 782, 95% CI 316-1936), vitreous floaters (pegcetacoplan: n=44, ROR 152, 95% CI 112-207; avacincaptad pegol: n=6, ROR 197, 95% CI 85.7-453), endophthalmitis (pegcetacoplan: n=11, ROR 50.8, 95% CI 28.0-92.2; avacincaptad pegol: n=5, ROR 228, 95% CI 92.1-564), eye inflammation (pegcetacoplan: n=26, ROR 89.0, 95% CI 60.2-132; avacincaptad pegol: n=4, ROR 130, 95% CI 47.7-356), eye pain (pegcetacoplan: n=15, ROR 9.18, 95% CI 5.51-15.3; avacincaptad pegol: n=5, ROR 30.1, 95% CI 12.2-74.4), blurred vision (pegcetacoplan: n=18, ROR 4.13, 95% CI 2.58-6.58; avacincaptad pegol: n=4, ROR 8.85, 95% CI 3.24-24.2), reduced visual acuity (pegcetacoplan: n=10, ROR 8.94, 95% CI 4.79-16.7; avacincaptad pegol: n=3, ROR 25.8, 95% CI 8.15-81.9), and visual impairment (pegcetacoplan: n=54, ROR 8.94, 95% CI 4.79-16.7; avacincaptad pegol: n=8, ROR 19.5, 95% CI 9.37-40.4).
A graphical depiction of ocular AEs that were overreported for both drugs can be found in Figure 3 .
