Pegcetacoplan (Syfovre)

Key Points at a Glance

Pegcetacoplan (brand name: Syfovre) is a first-in-class intravitreal injection targeting complement C3/C3b, approved by the FDA in 2023 for geographic atrophy (GA).
Phase 3 trials (OAKS/DERBY) showed GA lesion growth reduction at 24 months: 22% with monthly dosing and 18% with every-other-month dosing (OAKS).
GA is a progressive disease that impairs daily functions such as reading, driving, and face recognition.
Major side effects include intraocular inflammation (2.1–3.8%), new CNV development, and rare retinal occlusive vasculitis post-marketing.
No visual acuity improvement was observed in OAKS/DERBY trials; due to insufficient evidence of functional benefit, it is not approved in Europe (EMA/MHRA).
As of March 2026, it is not approved in Japan and is not covered by national health insurance.

1. What is Pegcetacoplan (Syfovre)?

Pegcetacoplan (brand name: Syfovre) is a complement C3/C3b inhibitor approved by the U.S. FDA in February 2023 for geographic atrophy (GA). It is the first treatment approved for GA (first-in-class) and is administered as an intravitreal injection of 15 mg/0.1 mL monthly or every other month ³⁾.

Geographic atrophy (GA) is the advanced stage of non-exudative (atrophic) age-related macular degeneration (AMD), characterized by irreversible loss of retinal pigment epithelium (RPE), photoreceptors, and choriocapillaris. As the lesion expands, daily functions such as reading, driving, and face recognition become impaired ⁵⁾.

The preceding Phase 2 FILLY trial (246 patients) showed suppression of GA lesion growth ⁸⁾, and subsequent OAKS/DERBY Phase 3 trials established efficacy and safety ²⁾.

Q For what condition is pegcetacoplan used?

It is used in adult patients with GA associated with age-related macular degeneration, without conversion to exudative AMD. The OAKS/DERBY trials included patients with subfoveal and juxtafoveal GA. As of March 2026, it is not approved in Japan.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

GA progresses slowly, so patients may not notice it for a long period.

Central vision loss: When the lesion extends to the fovea, reading, driving, and face recognition become difficult. With parafoveal lesions, visual acuity may be relatively preserved.
Decreased scotopic sensitivity and contrast sensitivity: Occurs early. It is difficult to detect with visual acuity tests.
Difficulty reading and missing letters: Letters may appear to drop out while reading.
Central scotoma: When the lesion reaches the fovea, the fixation point becomes dark and invisible.

The rate of visual acuity decline varies greatly depending on the location, area, and proximity to the fovea of the lesion⁵⁾.

Clinical Findings

Assessed with multimodal imaging.

Fundus findings: Well-demarcated gray-white atrophic lesions. The medium and large choroidal vessels are visible. Often accompanied by drusen and pigment changes.
Fundus autofluorescence (FAF): Low autofluorescence in atrophic areas. High autofluorescence at the border is a predictor of GA progression. Used as the primary endpoint in the OAKS/DERBY trials²⁾.
Optical coherence tomography (OCT): Evaluates complete RPE and outer retinal atrophy (cRORA) and incomplete RPE and outer retinal atrophy (iRORA). iRORA is important as a precursor lesion of GA⁴⁾.
Fluorescein angiography (FA): Hyperfluorescence (window defect) in areas of RPE loss. If retinal vasculitis is suspected after administration, check for fluorescein leakage into the vessel wall¹⁾.
Microperimetry: Can quantitatively assess retinal sensitivity in the junctional zone around the lesion. In the GALE trial at 36 months, the monthly dosing group showed a significant difference in sensitivity preservation (P=0.0156)⁴⁾.

Q How fast does geographic atrophy progress?

The rate of lesion enlargement varies greatly among individuals. Regular imaging examinations are necessary to monitor proximity to the fovea, lesion area, and bilaterality ⁵⁾.

3. Causes and Risk Factors

GA is a multifactorial disease, and chronic dysregulation of the complement system is one of the main pathogenic factors.

Aging: The greatest risk factor. With aging, the metabolic function of the RPE declines, leading to accumulation of drusen.
Complement system genetic polymorphisms: Complement-related gene polymorphisms such as CFH (complement factor H), C3, and C2/BF are associated with GA risk. In patients with age-related macular degeneration, C3a and C3b accumulate within drusen, causing chronic complement-mediated damage to the RPE.
Smoking: A common risk factor for both exudative and atrophic age-related macular degeneration. Smoking cessation is important for prevention.
Drusen accumulation: Large drusen and reticular pseudodrusen (SDD) are considered precursor lesions of GA.
Genetic background: A family history increases the risk.

4. Diagnosis and Examination Methods

Multiple imaging modalities are combined for the diagnosis of GA and for monitoring treatment efficacy and side effects.

The main examination methods are shown below.

Examination	Main purpose	Features
FAF	Quantification of GA area	Measures atrophic area by low autofluorescence
OCT	cRORA/iRORA assessment	Confirms RPE and photoreceptors in tomographic structure
FA/ICGA	Detection of CNV and vasculitis	Confirms leakage and vessel wall staining

Fundus autofluorescence (FAF): A standard imaging test for quantitative assessment of GA area and shape. Changes in lesion area were adopted as the primary endpoint in OAKS/DERBY ²⁾.
Spectral-domain OCT (SD-OCT): Essential for differentiating and monitoring cRORA (complete RPE and outer retinal atrophy) and iRORA (incomplete RPE and outer retinal atrophy) ⁴⁾.
Microperimetry: Quantifies parafoveal sensitivity loss that cannot be detected by visual acuity testing. It is expected to be used as a functional endpoint in future clinical trials⁴⁾.
Fluorescein angiography (FA): Performed to check for fluorescein leakage from vessel walls when intraocular inflammation or retinal vasculitis is suspected after pegcetacoplan administration¹⁾.

Q Which is more important: fundus autofluorescence or OCT?

Both tests are complementary. FAF is suitable for assessing the overall area and shape of GA, while OCT can evaluate the layered structure of the RPE and photoreceptors in detail. OCT is essential for distinguishing between cRORA and iRORA⁴⁾.

5. Standard Treatment

Results of the OAKS/DERBY Phase 3 Trials

The efficacy of pegcetacoplan was evaluated in two Phase 3 RCTs: the OAKS trial (n=637) and the DERBY trial (n=621)²⁾.

At 24 months, the reduction in GA lesion growth (compared to sham) was as follows^{2, 3)}:

Trial	Monthly	Every other month
OAKS	22% reduction	18% reduction
DERBY	19% reduction	16% reduction

Heier et al. (Lancet 2023) reported statistically significant GA suppression in a pooled analysis of OAKS/DERBY at both monthly and every-other-month dosing intervals ²⁾. No significant improvement in BCVA (best-corrected visual acuity) was observed in either study ²⁾.

GALE Long-Term Extension Study (36 Months)

The GALE study is an extension study evaluating long-term data at 36 months. In the monthly dosing group, a statistically significant difference (P=0.0156) was observed in the preservation of junctional zone sensitivity assessed by microperimetry ⁴⁾.

Dosage and Administration

Inject 15 mg/0.1 mL intravitreally. The dosing interval can be chosen as monthly or every other month ³⁾.

Comparison with Avacincaptad Pegol

Compared to avacincaptad pegol (Izervay; complement C5 inhibitor), another GA treatment, pegcetacoplan targets C3, providing more upstream complement inhibition ³⁾.

Pegcetacoplan

Target: Complement C3/C3b

Mechanism: Central complement cascade (upstream of C3 convertase)

Dosing Interval: Monthly or every other month

FDA Approval: February 2023

Avacincaptad Pegol

Target: Complement C5

Mechanism: Downstream complement cascade (inhibits MAC formation)

Dosing interval: Once a month or every other month

FDA approval: August 2023

Side Effects

The frequency of side effects is as follows³⁾.

Side Effect	Frequency
Intraocular inflammation (IOI)	2.1–3.8%
New CNV development	Monthly 11%/bimonthly 8% (OAKS)
Endophthalmitis	0.03% per injection
Retinal vasculitis	0.01% per injection (post-marketing)

Intraocular inflammation (IOI): A side effect reported in 2.1–3.8% of cases³⁾. Symptoms include redness, blurred vision, and floaters, and are often managed with steroid eye drops.

New choroidal neovascularization (CNV) development: In the OAKS trial, new CNV developed in 11% of the monthly dosing group and 8% of the every-other-month dosing group ³⁾. This represents a transition to neovascular age-related macular degeneration, requiring additional anti-VEGF therapy.

Retinal occlusive vasculitis: In post-marketing surveillance (ASRS REST Committee), it was reported at a rate of 0.01% per injection ⁷⁾. Although rare, it is a serious side effect that can significantly impact visual prognosis (see Pathophysiology section). Cases have occurred with the first injection, with an estimated frequency of about 1 in 4000 ⁷⁾.

Q Does pegcetacoplan improve vision?

In the OAKS/DERBY trials, no significant improvement in BCVA was observed ^{2, 3)}. The effect is to suppress the enlargement of GA lesions, with the main goal being to slow progression. Data from the GALE trial at 36 months suggest functional preservation ⁴⁾.

6. Pathophysiology and detailed pathogenesis

Complement system and GA relationship

One of the major etiologies of GA is chronic, dysregulated activation of the complement system. With normal aging, drusen accumulate under the RPE, and their components include C3, C3a, C3b, and C5b-9 (membrane attack complex; MAC). These complement components sustain chronic inflammation, leading to irreversible damage to RPE and photoreceptors (geographic atrophy).

Mechanism of action of pegcetacoplan

Pegcetacoplan is a PEGylated peptide that binds with high affinity to complement C3 and its activated fragment C3b. By inhibiting the cleavage of C3, it blocks the formation of C3 convertase, suppressing activation of the classical, alternative, and lectin pathways at the C3 stage. This inhibits downstream production of C3a, C5a (anaphylatoxins), and MAC formation.

Mechanisms of intraocular inflammation and retinal vasculitis

Intraocular inflammation (IOI) is a non-specific inflammatory reaction after injection and is considered part of the immune response within the vitreous cavity.

Retinal occlusive vasculitis is a more severe adverse reaction and is thought to involve a type IV (delayed-type, cell-mediated) hypersensitivity reaction^{1, 9, 10)}. In a case report by Douros et al., a 78-year-old woman developed occlusive retinal vasculitis 11 days after the first injection¹⁾. Scattered retinal hemorrhages, vascular sheathing, hyphema, and vitreous hemorrhage were observed; cultures and HSV-PCR were negative. She was treated with systemic steroids (high-dose prednisolone) and intravitreal aflibercept, and stabilized with a final VA of 20/400¹⁾.

Baumal et al. (Ophthalmology 2020), in a comparative study with brolucizumab-associated vasculitis, suggested that retinal vasculitis after anti-VEGF drug administration may be a type II or type IV drug-induced hypersensitivity reaction⁹⁾. The mechanism of vasculitis may differ between drugs, and the detailed mechanism of pegcetacoplan-associated vasculitis is still under investigation.

Witkin et al. (Ophthalmology 2017) suggested the involvement of a type IV hypersensitivity reaction in the analysis of hemorrhagic occlusive retinal vasculitis (HORV) after vancomycin administration¹⁰⁾, and mechanistic similarities with pegcetacoplan-associated vasculitis are being discussed.

7. Latest Research and Future Perspectives (Investigational Reports)

Establishment of Functional Endpoints

In the GALE trial (36 months), functional endpoints assessed by microperimetry were evaluated in addition to GA area measured by FAF. A significant difference (P=0.0156) in junctional zone sensitivity preservation was observed in the monthly dosing group⁴⁾, and the adoption of functional endpoints in addition to structural endpoints (GA area) is being discussed for future clinical trials. Differential assessment of cRORA/iRORA is also being incorporated into trial designs⁴⁾.

Non-approval by EMA/MHRA and Future Challenges

The European Medicines Agency (EMA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA) have not approved pegcetacoplan⁴⁾. The main reason is that although a reduction in GA area was demonstrated, evidence of visual improvement was insufficient. How to evaluate the dissociation between structural and functional endpoints is the biggest challenge moving forward.

Positioning of the FILLY Phase 2 Trial

The FILLY trial (n=246; Liao et al. 2020) was a Phase 2 trial of pegcetacoplan (then APL-2), which first demonstrated GA suppression at 12 months⁸⁾. It served as the foundation for subsequent development leading to OAKS/DERBY.

Development Status in Japan and Future Prospects

As of March 2026, pegcetacoplan is not approved in Japan, and insurance-covered treatment is not available ⁶⁾. The current standard treatment for atrophic GA in the Japanese age-related macular degeneration clinical guidelines has not been established, and the progress of domestic approval review is of interest.

OAKS/DERBY

Trial size: 637/621 patients (Phase 3 RCT)

Primary endpoint: Change in GA area at 24 months

Results: Monthly 22%/19%, every other month 18%/16% reduction

GALE Extension Trial

Trial size: OAKS/DERBY extension (36 months)

New endpoint: Microperimetry

Results: Monthly group showed sensitivity preservation P=0.0156

Q When will pegcetacoplan become available in Japan?

As of March 2026, no information on a new drug application has been disclosed in Japan. It has also not been approved in Europe, and accumulation of functional endpoint data is expected to be key for future approval review ^{4, 6)}.

8. References

Douros S, et al. Occlusive retinal vasculitis following intravitreal pegcetacoplan injection. Am J Ophthalmol Case Rep. 2024;33:101999.
Heier JS, 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. 2023;402:1434-1448.
American Academy of Ophthalmology. Age-Related Macular Degeneration Preferred Practice Pattern. AAO; 2024.
Dinah C, Esmaeelpour M, Rachitskaya AV, De Salvo G, Munk MR. Functional endpoints in patients with geographic atrophy: what to consider when designing a clinical trial. Prog Retin Eye Res. 2026;110:101421. doi:10.1016/j.preteyeres.2025.101421.
Fleckenstein M, Mitchell P, Freund KB, et al. The progression of geographic atrophy secondary to age-related macular degeneration. Ophthalmology. 2018;125(3):369-390. doi:10.1016/j.ophtha.2017.08.038.
日本眼科学会. 加齢黄斑変性診療ガイドライン. 2023年版.
Witkin AJ, Jaffe GJ, Srivastava SK, Davis JL, Kim JE. Retinal vasculitis after intravitreal pegcetacoplan: report from the ASRS Research and Safety in Therapeutics (ReST) Committee. J Vitreoretin Dis. 2024;8(1):9-20. doi:10.1177/24741264231220224. PMID: 38223782.
Liao DS, et al. Complement C3 inhibitor pegcetacoplan for geographic atrophy secondary to age-related macular degeneration: a randomized phase 2 trial. Ophthalmology. 2020;127:186-195.
Baumal CR, et al. Retinal vasculitis and intraocular inflammation after intravitreal injection of brolucizumab. Ophthalmology. 2020;127:1345-1359.
Witkin AJ, et al. Hemorrhagic occlusive retinal vasculitis: expanding the spectrum of disease. Ophthalmology. 2017;124:583-595.

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