The first approved GA treatment leaves room for additional therapies.
The US Food and Drug Administration (FDA) approved pegcetacoplan (Syfovre; Apellis Pharmaceuticals) in February 2023 for the treatment of geographic atrophy (GA) in patients with advanced age-related macular degeneration (AMD), and now, for the first time, the community has a treatment option for dry AMD beyond vitamins. AMD is a degenerative, multifactorial ocular disease that can result in progressive visual loss, and it is the most common cause of permanent blindness in patients older than 50 years in the Western world.1,2 GA is an advanced form of dry AMD that can result in irreversible vision loss, and it affects about 1 million patients in the United States.2,3
In 2021, the FDA originally approved pegcetacoplan for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), a complement-mediated hemolytic disease that can present with thrombosis and bone marrow dysfunction.4,5 Complement refers to serum proteins that participate in the adaptive and innate immune systems to destroy tissue and blood pathogens.6 There are roughly 40 complement system proteins, which interact together in a catalytic cascade as part of immune reactions.6 Pegcetacoplan inhibits C3, the central component in every complement pathway, which has a strong genetic relationship with AMD.7,8
Pegcetacoplan is an intravitreal drug and, unlike anti-VEGF (vascular endothelial growth factor) injections, it is not known yet to restore vision, but rather it slows GA lesion growth and spares retinal tissue from atrophy.9 If dosed monthly, or every other month, it can slow progression by 22% and 16%, on average, respectively.9 However, it seems to be more effective with extrafoveal lesions.9
While at 24 months the phase 3 OAKS (NCT03525613) and DERBY (NCT03525600) study subjects across all study arms did not have statistically significant differences in best-corrected visual acuity, reading speed, functional reading index, or microperimetry, perhaps future data analysis or testing will show some functional benefits.10 After all, Lee et al showed that tissue loss in GA typically precedes visual acuity loss.11 Further, Yehoshua et al demonstrated that baseline low-luminance Early Treatment Diabetic Retinopathy Study visual acuity is significantly associated with GA lesion enlargement between 26 and 52 weeks.12
As more data are evaluated, the long-term visual outcomes of this trial will be essential for determining which patients doctors should advise to take pegcetacoplan. Regardless, all patients with GA should be referred to an eye care provider for consideration for treatment and management.
Additionally, referring patients with GA and/or wet AMD to a dietitian, low vision specialist, mental health specialist, or occupational therapist may be beneficial. Klein et al reported that 42% of GA patients in the Beaver Dam Eye Study saw 20/200 or worse; thus, GA patients may benefit from low-vision services.13 Also, Brody et al reported that 32% of AMD patients meet the vision-specific Sickness Impact Profile for depressive disorder.14 Furthermore, a diet rich in antioxidants may delay or prevent progression of AMD, and a dietitian can help patients navigate an overall healthier diet.15
When educating GA patients, advise them that pegcetacoplan may be costly without insurance and will require regular injection visits. According to the manufacturer, pegcetacoplan is dosed every 25 to 60 days,16 which adds to the cost burden. However, Medicare typically covers 80% of the costs, and there is a chance that supplemental insurance may cover the difference.17 Patients can also undergo intravitreal injections of both pegcetacoplan and an anti-VEGF medication, but if both are performed in the same day, payers may reimburse for only 1 of the injections.18 Even though pegcetacoplan is not subject to the 28-day rule that applies to billing for anti-VEGF medications, payers may initially deny claims for pegcetacoplan if the treatment occurs within 28 days of an anti-VEGF injection in the same eye.18 Thus, patients with both GA and wet AMD may visit a retinal specialist more frequently than patients with wet AMD or GA alone.
Pegcetacoplan use does incur some risks. Like all intravitreal injections, it may be associated with endophthalmitis and retinal detachments.19 It is also associated with increased intraocular pressure, vitritis, iritis, and uveitis.19 Likewise, pegcetacoplan may increase the risk of wet AMD, with an incidence of 12% in patients undergoing monthly injections, 7% in patients undergoing injections every other month, and only 3% in control subjects.19
However, Wykoff et al showed that compared with the natural prevalence, subjects in Apellis’ phase 2 FILLY study (NCT02503332) had a higher prevalence of wet AMD in their fellow eye and that 37% of subjects may have had preexisting subclinical macular neovascularization.20 Wykoff et al postulate that pegcetacoplan may affect the propensity of nonexudative type 1 macular neovascularization to become exudative through multiple mechanisms.20 First, C3 cleavage may slow GA, resulting in adjacent viable choriocapillaris endothelium forming new vessels; second, retinal pigment epithelium pump decompensation could result in fluid accumulation without neovascularization, as some FILLY subjects developed exudate without detectable neovascularization; and, third, that C3 cleavage may result in the presence of proangiogenic macrophages.20 Regardless, at this time, patients treated with pegcetacoplan should be watched closely for complications, such as exudative AMD.
On July 29, 2023, Apellis released a statement regarding 7 reported incidents of retinal vasculitis in patients treated with pegcetacoplan, in which Apellis reported that it does not have indication that the drug or manufacturing process is contributing to these events.19 Further, Apellis reassured the public that it has distributed over 23,000 clinical trial injections and 68,000 commercial vials, and that there are only 7 reported events.19 Anti-VEGF medications have been associated with retinal vasculitis, possibly because of type III or type IV hypersensitivity reaction, infection, or direct cytotoxicity of the vehicle or drug.21,22 Therefore, it is not inconceivable that pegcetacoplan, like other drugs, could result in rare inflammatory events.
If eye care providers are not currently convinced that pegcetacoplan’s benefits outweigh the risks, there are other potential GA drugs in the pipeline. ClinicalTrials.gov lists several active phase 3 studies evaluating drugs for GA.23 These drugs include tinlarebant, an orally administered tablet that inhibits accumulation of bisretinoids, a vitamin A–based toxin, that reportedly slowed or halted lesion growth in a phase 2 trial.24 Alkeus is also conducting a phase 3 trial (NCT03845582) of ALK-001, a modified version of vitamin A that resulted in lower lipofuscin accumulation by substituting deuterium for the traditional hydrogen atom.25 Patel et al. reported that the phase 2 GATHER1 trial (NCT02686658) of avacincaptad pegol, a drug that targets C5 of the complement system, can slow lesion growth by 28.1% to 30%, and that the phase 3 GATHER2 trial (NCT04435366) is currently ongoing.26 In November 2022, the FDA designated avacincaptad pegol as a breakthrough therapy, which may accelerate regulatory review and development.27
ClinicalTrials.gov reported at the time of this report that there have been 19 interventional GA phase 3 trials, and Hwang et al reported that 54% of all phase 3 drugs fail in clinical development.28,29 With FDA approval of pegcetacoplan without evidence of improved or spared vision, the community needs an additional drug that slows structural changes but also assuredly improves visual function.
In the meantime, in addition to diet changes and the antioxidant-rich AREDS 2 vitamins, patients with GA and providers should strongly consider pegcetacoplan, as it is currently the only therapy available. As the standalone prescription therapy for a devastating eye disease, it provides hope that GA might soon see the same magnitude of attention and eventually the therapeutic efficacy seen in current anti-VEGF interventions.