Background
Syfovre (pegcetacoplan) was  the first FDA-approved treatment for geographic atrophy (GA) secondary to age-related macular degeneration (AMD). It is administered via intravitreal injection to each affected eye once every 25 to 60 days. Syfovre contains the active ingredient, pegcetacoplan, a complement C3 inhibitor that is the same ingredient in Empaveli™, but the indication, dosage form, dose, and route of administration are different than Empaveli. Both drugs work by blocking C3 and downregulating the complement system. For Syfovre, this is thought to decrease the pathogenesis and progression of GA. Clinical trials found an increased incidence of neovascular AMD in the Syfovre group compared to the sham group, so the FDA labeling suggests monitoring of patients for signs of neovascular AMD. Additionally, patients with ocular history of or active choroidal neovascularization were excluded from the pivotal trials of Syfovre.

AMD is a chronic, multifactorial, progressive central retinal disease that is the leading cause of irreversible blindness in the elderly population. It is divided into two types: exudative or neovascular (“wet”) and nonexudative (“dry”). GA is caused by the gradual breakdown of light-sensitive cells in the macula, resulting in the growth of irreversible lesions in the retinal pigment epithelium that can lead to impaired vision or blindness. It has several potential causes, but can be caused by dry age AMD (intermediate and advanced stages of disease). At this time, there are no other medical therapies for GA.

The December 2024 FDA label update added a Warning for retinal vasculitis and/or retinal vascular occlusion, in addition to existing warnings (endophthalmitis/retinal detachment, intraocular inflammation, neovascular AMD, increased intraocular pressure).

Post‑marketing analyses (ASRS ReST Committee; additional clinicopathology reports) confirm rare but severe events, often occurring after the first injection, including occlusive vasculitis and vision‑threatening outcomes.

Policy
Syfovre (pegcetacoplan) is considered MEDICALLY NECESSARY for the treatment of geographic atrophy (GA) secondary to age‑related macular degeneration (AMD) when ALL of the following criteria are met:

Initial Approval (12 months)

1. Confirmed diagnosis of GA secondary to AMD confirmed by fundus autofluorescence (FAF) and/or OCT; alternative etiologies (e.g., Stargardt disease, cone rod dystrophy, toxic maculopathies) excluded.
2. Prescribed by or in consultation with an ophthalmologist or retina specialist.

Baseline Clinical and Safety Requirements

All of the following must be met in the eye to be treated, consistent with FDA‑labeled contraindications/warnings:

1. No ocular or periocular infection.
2. No active intraocular inflammation.
3. No active choroidal neovascularization (CNV) at initiation of therapy.
   1. Pivotal trials excluded CNV; FDA labeling identifies neovascular AMD as a known risk requiring monitoring.

Dosing Requirements

Syfovre must be administered per FDA labeling:

• 15 mg (0.1 mL of 150 mg/mL) intravitreal injection to each affected eye once every 25 to 60 days.
• No more frequent dosing is permitted.

Limitations and Exclusions

Syfovre is NOT MEDICALLY NECESSARY and NOT COVERED in the following situations:

• History of retinal vasculitis, retinal vascular occlusion, or drug‑induced retinal vasculopathy and choroiditis (DIRVAC) associated with prior pegcetacoplan injection.
• Development of occlusive retinal vasculitis or severe intraocular inflammation after any prior dose of pegcetacoplan (contraindication to further treatment).
• Active choroidal neovascularization (CNV) in the eye to be treated.
• Geographic atrophy not caused by AMD (e.g., Stargardt disease, cone‑rod dystrophy, toxic maculopathy).
• Use in combination with another investigational intravitreal agent for GA or within a clinical trial that conflicts with plan exclusions.
• Dosing more frequently than every 25 days or outside the FDA‑approved labeling.
• Failure to demonstrate clinical benefit or the presence of treatment‑limiting adverse events upon reauthorization.

Continued Therapy (Reauthorization for 12 months)

• Documented clinical benefit or stabilization (e.g., slowing of GA lesion enlargement versus baseline, stabilization of functional measures when appropriate).
• Absence of treatment-limiting adverse events (e.g., retinal vasculitis/vascular occlusion, persistent intraocular inflammation).
• Continued dosing remains within FDA-labeled frequency (every 25 – 60 days).

Evidence Summary

Syfovre (pegcetacoplan) is the first FDA‑approved therapy for geographic atrophy (GA) secondary to age‑related macular degeneration (AMD), supported by outcomes from the pivotal Phase 3 OAKS and DERBY trials. In these studies, Syfovre demonstrated a statistically significant slowing of GA lesion growth compared with sham control, with treatment effects increasing over time. At 24 months in OAKS (n = 637), monthly dosing reduced GA lesion growth by 22%, and every‑other‑month dosing reduced growth by 18%; in DERBY (n = 621), monthly and every‑other‑month dosing slowed lesion expansion by 18% and 17%, respectively. The FDA approval announcement further emphasized that Syfovre produced increasing treatment effects over months 18 – 24, reaching up to a 36% reduction in lesion growth in DERBY with monthly dosing. Safety signals included higher rates of neovascular AMD compared to sham, along with labeled risks of retinal vasculitis, retinal vascular occlusion, intraocular inflammation, and endophthalmitis, necessitating ongoing monitoring. Collectively, these trials established that complement C3 inhibition with pegcetacoplan provides clinically meaningful slowing of GA progression, with a risk‑benefit profile requiring physician vigilance.

References

1. Syfovre [package insert]. Apellis Pharmaceuticals, Inc. Waltham, MA. Updated Feb 2023.
2. Syfovre Drug Evaluation. Express Scripts. Updated March 2023.
3. New Drug Review, Syfovre (pegcetacoplan injection). IPD Analytics. February 2023. Accessed July 20, 2023 Subscription required.
4. Heier, J. S., Lad, E. M., Holz, F. G., Rosenfeld, P. J., Guymer, R. H., Boyer, D., … Wykoff, C. C. (2023). 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. The Lancet, 402(10411), 1434–1448.
5. Wykoff, C. C., Holz, F. G., Chiang, A., et al. (2025). Pegcetacoplan treatment for geographic atrophy in age‑related macular degeneration over 36 months: Data from OAKS, DERBY, and GALE. American Journal of Ophthalmology, 276, 350–364.
6. Apellis Medical Hub. (2024). Pegcetacoplan GA—Visual function outcomes in the OAKS, DERBY, and GALE studies. Apellis Medical Hub
7. Haynes, J., Burch, M., Ribeiro, R., & Tsuboi, M. (2023). Efficacy and safety of pegcetacoplan in patients with geographic atrophy from the Phase 3 OAKS and DERBY Trials. American Academy of Optometry.
8. Mastellos, D. C., & Lambris, J. D. (2024). Pegcetacoplan (Syfovre): Targeting complement C3 in geographic atrophy. Trends in Pharmacological Sciences, 45(12), 1175–1176.
9. Witkin, A. J., Jaffe, G. J., Srivastava, S. K., et al. (2024). Retinal vasculitis after intravitreal pegcetacoplan: Report from the ASRS Research and Safety in Therapeutics (ReST) Committee. Journal of VitreoRetinal Diseases, 8(1), 9–20.
10. Nahar, A., Eliott, D., Avery, R. L., et al. (2025). Retinal vasculopathy and choroiditis after pegcetacoplan injection: Clinicopathologic support for a drug hypersensitivity reaction. Ophthalmology Retina, 9(4), 352–366.
11. Kuriyan, A. E. (2025). A rare, severe hypersensitivity reaction can occur with intravitreal pegcetacoplan. American Academy of Ophthalmology

Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2024 Forward