Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual
Policy #:	2023037
Category:	Pharmacy
Initiated:	August 2023
Last Review:	August 2025

Pegcetacoplan Intravitreal (e.g., Syfovre)

Description:

Pegcetacoplan (e.g., Syfovre), is an intravitreal therapy for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMO). AMO is a leading cause of severe, irreversible vision impairment. Two types of AMO include: dry (aka atrophic AMO) and wet (aka advanced neovascular AMO). Dry AMO is the more common condition of the two, in which the macula gets thinner with age, specifically because of the loss of photoreceptors and retinal pigment epithelium cells which results in atrophy of the retinal tissue. Dry AMO typically has a slow progression. Late-stage dry AMO is referred to as Geographic Atrophy (GA), which is irreversible. GA is characterized by sharply defined atrophy of the outer retinal tissue, retinal pigment epithelium, and choriocapillaris. Wet AMO typically is seen to progress faster than dry AMO. Late-stage wet AMO can lead to GA. Therefore, GA can occur in both dry and wet AMO.

The complement cascade has been linked to the pathophysiology of dry AMO and GA. Within the innate immune system, there are 3 different pathways: classical, alternative, and lectin. Once a pathway (or multiple pathways) is activated, an inflammatory and cytolytic immune response from proteins within the complement system occurs. All 3 activation pathways converge at C3 convertase. C3 convertase promotes cleavage of C3 into C3a and C3b subunits. Findings of inflammatory cytokines and chemokines in the retina, along with the overactivity of the complement system and the subsequent formation of drusen, supports the hypothesis that the complement system is a key component for the development and progression of GA.

Pegcetacoplan is a pegylated complement C3 inhibitor peptide. It is thought that inhibition at C3 within the complement system can reduce the downstream processes that can lead to continuous retinal atrophy. 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 (RPE) that can lead to impaired vision or blindness.

GA occurs in the intermediate of advanced stages of AMD; the estimated prevalence increases to 3.5% in people 75 years of age and older. More than half of the patients with GA experience significant impairment of everyday vision, and about 20% of patients develop severe vision loss with visual acuity of 20/200 or worse. GA can be considered secondary to other conditions outside of AMO. Those include Stargardt disease, cone rod dystrophy, or toxic maculopathies like plaquenil maculopathy. Pegcetacoplan has only been studied in patients with GA secondary to dry AMO and therefore should not be used to treat GA secondary to any other conditions.

Regulatory Status

Pegcetacoplan (e.g., Syfovre) was approved by the U.S. Food and Drug Administration (FDA) on February 17, 2023, for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD)

Coding

See CPT/HCPCS Code section below.

Policy/
Coverage:

INITIAL AND CONTINUATION APPROVAL will be for duration of treatment course or 12 months (whichever comes first). Approval timeframes may differ for members/participants of Self-Insured plans.

Effective August 06, 2025

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Pegcetacoplan Intravitreal (e.g., Syfovre) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:

INITIAL APPROVAL:

1. Individual has a diagnosis of geographic atrophy of the macula secondary to age-related macular degeneration; AND

2. Diagnosis has been verified as geographic atrophy secondary to age-related macular degeneration; AND

3. Pegcetacoplan intravitreal will not be used for the following situations:

a. Individual has geographic atrophy that is secondary to a condition other than age-related macular degeneration (including but not limited to Stargardt disease, cone rod dystrophy or toxic maculopathies); OR

b. Individual has a history of or active choroidal neovascularization or wet age-related macular degeneration; OR

c. Individual has an ocular or periocular infection or intraocular inflammation; AND

4. Must be administered by or under the supervision of an ophthalmologist.

CONTINUATION OF THERAPY:

1. Individual continues to meet the initial approval criteria; AND

2. Individual experiences objective benefit from continued treatment as defined by vision stabilization or improvement in vision.

Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria

Pegcetacoplan intravitreal (e.g., Syfovre) for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, Pegcetacoplan intravitreal (e.g., Syfovre), for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

POLICY GUIDELINES

There should be an absence of unacceptable toxicity resulting from the treatment (e.g., endophthalmitis and retinal detachments, retinal vasculitis and/or retinal vascular occlusion, neovascular AMD, intraocular inflammation, increased intraocular pressure (IOP).

DOSAGE AND ADMINISTRATION

For FDA labeled indications, Pegcetacoplan intravitreal (e.g., Syfovre) must be dosed in accordance with the indication specific recommended dose per FDA label unless otherwise specified below.

The recommended dose of pegcetacoplan intravitreal (e.g., Syfovre) is 15 mg (0.1 mL of 150 mg/mL solution) administered by intravitreal injection to each affected eye once every 25 to 60 days.

Pegcetacoplan intravitreal is available as 150 mg/mL in a single-dose vial.

Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Effective September 4, 2024 to August 5, 2025

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

1. Individual has a diagnosis of geographic atrophy of the macula secondary to age-related macular degeneration; AND

2. Diagnosis has been verified as geographic atrophy secondary to age-related macular degeneration; AND

3. Pegcetacoplan intravitreal will not be used for the following situations:

a. Individual has geographic atrophy that is secondary to a condition other than age-related macular degeneration (including but not limited to Stargardt disease, cone rod dystrophy or toxic maculopathies); OR

b. Individual has a history of or active choroidal neovascularization or wet age-related macular degeneration; OR

c. Individual has an ocular or periocular infection or intraocular inflammation; AND

4. Must be administered by or under the supervision of an ophthalmologist; AND

5. Must be dosed in accordance with the FDA label.

Dosage and Administration

Dosing per FDA Guidelines

The recommended dose of pegcetacoplan intravitreal (e.g., Syfovre) is 15 mg (0.1 mL of 150 mg/mL solution) administered by intravitreal injection to each affected eye once every 25 to 60 days.

Pegcetacoplan intravitreal is available as 150 mg/mL in a single-dose vial.

Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Effective August 14, 2023 to September 3, 2024

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Pegcetacoplan (e.g., Syfovre), for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD) or any other indication, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, pegcetacoplan (e.g., Syfovre), for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD) or any other indication, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:

Syfovre was evaluated in the Phase 2 FILLY study (NCT02503332) and two Phase 3 studies, DERBY (NCT03525600) and OAKS (NCT03525613), for the treatment of GA due to AMD. The FDA approval of Syfovre was based on the Phase 3 studies.

In both trials, the discontinuation rates were significant across arms, including sham. In the OAKS trial, 31% of patients in the monthly, 21% of patients in the every-other-month (EOM) and 25% of the patients in the sham group discontinued treatment prior to Month 24. In the DERBY trial, 29% of patients in the monthly, 22% of patients in the EOM, and 21% of the patients assigned to sham discontinued treatment prior to Month 24.

While all primary endpoints were met in the OAKS and FILLY trials, results at 12 months in the DERBY trial were not statistically significant. An extensive review of baseline data has been conducted by the Apellis to explain the disparity in results between the DERBY and OAKS trials. Covariate analyses indicated some baseline imbalances between the groups in study eye focality, lesion location, and presence of intermediate/large drusen, which may partially explain the disparate results.

In subgroup analyses based on pooled results from the DERBY and OAKS trials, it was noted that pegcetacoplan seemed to have a more significant effect on extrafoveal GA lesion growth. This could be related to greater complement activity in extrafoveal areas.

When analyzed in 6-month increments, the change in rate of GA lesion area growth compared to sham seems to increase with increasing time of treatment. Additional details are available in the prescribing information. Of note, previous Apellis publications expressed the difference in growth rate from sham as a positive percentage, while the prescribing information expresses this difference as a negative percentage.

Trial data was analyzed for study eyes versus fellow (untreated) eyes in the study population with bilateral disease. In patients with bilateral disease, GA tends to progress at a similar rate in both eyes. In the analysis, progression of GA in fellow eyes occurred at approximately 2 mm2 per year, which is comparable to the rate of progression seen in natural history studies.

At 24 months, there was no statistically significant difference in measures of visual function, including normal luminance best-corrected visual acuity (BCVA), maximum reading speed, Functional Reading Independence Index, and microperimetry: mean threshold sensitivity (OAKS only), between either treatment group (monthly or EOM) and the sham group. BCVA in the treatment groups continued to decline at a rate similar to the sham group.

The most common adverse reactions (≥5%) reported in Syfovre clinical trials were ocular discomfort, neovascular AMD, vitreous floaters, and conjunctival hemorrhage. At 24 months, Apellis noted 16 cases of intraocular inflammation (IOI) in the pooled data for patients treated monthly in DERBY and OAKS (N = 419), and nine cases of IOI in the pooled EOM group (N = 420). There was one IOI case in the pooled sham group (N = 417). Four of these events occurred in 2018 and were related to a drug impurity. Four cases of infectious endophthalmitis occurred through 24 months: two each in the monthly and EOM groups. Overall, TEAEs were high in Syfovre-treated groups as well as sham groups.

Perhaps more concerning than the rate of TEAEs is the potential for accelerated development of nAMD in the clinical trials; nAMD occurred in 12% of patients in the pegcetacoplan monthly arms of the DERBY and OAKS trials (pooled), 7% of patients in the pegcetacoplan EOM arms, and 3% of patients in the sham groups.

Previous results from the FILLY trial indicated that patients with CNV in the fellow (untreated) eye were more likely to develop nAMD in the study eye. In pooled results from the DERBY and OAKS trials, this correlation was not as pronounced.

Patients who developed nAMD during a clinical trial continued treatment with Syfovre and received VEGF inhibitor therapy at the discretion of the investigator.

2024 Update

Annual policy review completed with a literature search using the MEDLINE database through August 2024. No new literature was identified that would prompt a change in the coverage statement.

2025 Update

GALE is a prospective open-label extension study following the 24-month, sham-controlled, phase 3 OAKS (NCT03525613) and DERBY (NCT03525600) studies of pegcetacoplan.

Patients with nonsubfoveal or subfoveal GA who completed OAKS, DERBY, or phase 1b APL2-103 (NCT03777332) studies.

Pegcetacoplan was administered monthly (PM) or every other month (PEOM) to all study eyes in GALE. Eyes receiving pegcetacoplan in OAKS and DERBY continued the same regimen (PM-PM and PEOM-PEOM), while eyes observed with sham in OAKS and DERBY crossed over to receive pegcetacoplan at the same dosing interval in GALE (SM-PM and SEOM-PEOM). Safety and efficacy through the first 12 months of GALE were assessed, reflecting up to 36 months of continuous pegcetacoplan treatment.

Mean rate of change in GA area, total number of microperimetry scotomatous points, and adverse events.

Through the first 12 months of GALE, 92.0% (727/790) patient retention was observed. Across all eyes, including eyes with nonsubfoveal and subfoveal GA, pegcetacoplan reduced the mean rate of change in GA area up to 32% versus projected sham. Year after year, the reductions in the mean rate of change in GA area increased, with up to a 42% reduction observed in eyes with nonsubfoveal GA in the PM-PM group compared with projected sham in the first year of GALE. An 18% reduction in new scotomatous points (P = .0156) was observed with PM-PM at 36 months, highlighting a significant impact in a prespecified microperimetry analysis. Adverse events included 33 (4.5%) eyes with exudative AMD, 15 (1.9%) intraocular inflammation (classified as mild or moderate in severity), 1 (0.1%) ischemic optic neuropathy, and 1 (0.1%) infectious endophthalmitis. No events of vasculitis were reported.

Over 36 months, pegcetacoplan continued to reduce GA growth with increasing efficacy over time and reduced formation of new scotomatous points. The safety profile of pegcetacoplan in the first 12 months of GALE was consistent with the prior 24-month OAKS and DERBY studies. (Wykoff, 2025)

CPT/HCPCS:

References:

Apellis Pharmaceuticals.(2024) Study to Compare the Efficacy and Safety of Intravitreal APL-2 Therapy With Sham Injections in Patients With Geographic Atrophy (GA) Secondary to Age-Related Macular Degeneration. NCT03525600. Clinicaltrials.gov. Available at: https://clinicaltrials.gov/study/NCT03525600?term=NCT03525600&rank=1

Apellis Pharmaceuticals.(2024) Study to Compare the Efficacy and Safety of Intravitreal APL-2 Therapy With Sham Injections in Patients With Geographic Atrophy (GA) Secondary to Age-Related Macular Degeneration. NCT03525600. Clinicaltrials.gov. Available at: https://clinicaltrials.gov/study/NCT03525613?term=NCT03525613&rank=1

New Drug Review, Syfovre (pegcetacoplan injection). IPD Analytics. February 2023. Accessed July 20, 2023 Subscription required.

Syfovre [package insert] Waltham, MA: Apellis Pharmaceuticals, Inc.; 2024

Syfovre [package insert]. Waltham, MA: Apellis Pharmaceuticals, Inc.; 2023

Syfovre(2023) Package Insert Waltham, MA: Apellis Pharmaceuticals, Inc.; Revised November 2023.

Wykoff CC, Holz FG, Chiang A, et.al.,(2025) Pegcetacoplan Treatment for Geographic Atrophy in Age-Related Macular Degeneration Over 36 Months: Data From OAKS, DERBY, and GALE. Am J Ophthalmol. 2025 Aug;276:350-364. doi: 10.1016/j.ajo.2025.04.016. Epub 2025 Apr 23. PMID: 40280279.

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants.