FDA Approval of SYFOVRE (Pegcetacoplan) and IZERVAY (Avacincaptad Pegol) Reshapes Management of GA

Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD) that leads to the gradual loss of central vision due to the degeneration of the retinal pigment epithelium. Until recently, no treatments were approved by the US Food and Drug Administration (FDA) for GA; however, the recent approvals of pegcetacoplan (SYFOVRE; Apellis Pharmaceuticals) and avacincaptad pegol (IZERVAY; IVERIC bio) provide important developments in patient care. These approvals mark a crucial milestone as they are the first treatments indicated for GA.

Understanding GA

AMD manifests in 2 primary forms: “dry,” known as nonexudative or nonneovascular, and “wet,” referred to as exudative or neovascular. Approximately 80% to 85% of patients with AMD have dry AMD; a clinical hallmark of dry AMD is the formation of drusen, defined as pigmentary changes occurring in the macula.¹ GA, an advanced form of dry AMD, causes progressive central vision loss, associated with a gradual, irreversible decline in photoreceptors, retinal pigment epithelium, and the choriocapillaris.^1-3 Initially, patients display minimal symptoms, such as metamorphopsia (vision distortion), near image blurring, reduced contrast sensitivity, and central scotoma (a blurred or blind central vision area).¹ Over time, these lesions progress, eventually involving the fovea, leading to an ongoing, permanent deterioration of vision.¹ Notably, approximately 25% of cases of legal blindness in the United States can be attributed to GA.³

Based on genomewide, histopathologic, in vitro, and animal studies, GA occurs due to activation of the complement system and the resultant chronic inflammation.⁴ The complement system, a component of the innate immune system, consists of more than 30 proteins tasked with fighting infection, liaising between the adaptive and innate immune systems, and disposing of waste from immune complexes and apoptotic cells.⁴

Unlike wet AMD, for which anti–vascular endothelial growth factor drugs have proven effective, no treatments have been approved to prevent onset or prohibit progression of GA until recently, when the FDA approved the use of drugs targeting specific complement proteins.²

FDA Approves New Treatments Targeting GA by Inhibiting Complement Proteins

On February 17, 2023, the FDA approved the use of pegcetacoplan for the treatment of GA secondary to AMD.⁵ Pegcetacoplan is a peptide-based inhibitor of the complement proteins C3 and C3b, proteins involved in promoting inflammation and membrane attack complex (MAC) activity.⁴ Pegcetacoplan is administered by intravitreal injection to each affected eye once every 25 to 60 days.⁵

FDA approval of pegcetacoplan for the treatment of GA was based on the safety and effectiveness as evaluated in 2 randomized, sham-controlled studies involving patients with GA. These multicenter trials, OAKS and DERBY, spanned a duration of 24 months. Combined, a total of 1258 patients were enrolled, with 839 assigned to receive pegcetacoplan and 419 to the sham treatment.⁵ To be enrolled, patients had to be ≥60 years of age and have a GA lesion area between 2.5 and 17.5 mm², including foveal and extrafoveal lesions.⁶ Patients were randomized into 1 of 4 dosing regimens: 2 groups were administered pegcetacoplan either monthly or every other month, and 2 groups were given a sham treatment either monthly or every other month.⁵ The primary efficacy end point for both studies was change in GA lesion size, as measured by fundus autofluorescence, from baseline (Table).^4-6

In both studies, the mean rate of GA lesion growth was reduced. Even though the results of the DERBY study did not reach statistical significance, patients receiving pegcetacoplan monthly did exhibit a reduction in GA lesion growth as compared with those receiving sham treatment (-12%, P=.0528), as did the group receiving treatment every other month (-11%, P=.075).^4,6 The OAKS study results were significant, with patients receiving monthly treatments showing a reduction in GA lesion growth (-21%, P=.0003), and patients in the every-other-month arm also showing a reduction (-16%, P=.0052).⁴ These findings reinforce the results of an earlier phase 2 study indicating that intravitreal pegcetacoplan injections can reduce photoreceptor thinning and loss compared with sham injections.⁷

The most common adverse events reported in ≥5% of patients treated monthly with pegcetacoplan were ocular discomfort (13%), neovascular AMD (12%), vitreous floaters (10%), and conjunctival hemorrhage (8%).⁵ However, the American Society of Retina Specialists (ASRS) Research and Safety in Therapeutics committee released a warning in July 2023 regarding 6 cases of retinal vasculitis associated with pegcetacoplan.⁸ The drug’s manufacturer, Apellis Pharmaceuticals, Inc., issued a statement confirming 7 total events of retinal vasculitis since the February release, but they note the rarity of the events (out of more than 68,000 vials distributed), including no cases of retinal vasculitis reported during clinical trials.⁹

A second drug, avacincaptad pegol, was approved by the FDA on August 4, 2023, to treat GA secondary to AMD. Avacincaptad pegol is an RNA aptamer that inhibits the complement protein C5 to ultimately reduce MAC formation.¹⁰ Avacincaptad pegol is administered by intravitreal injection to each affected eye monthly for up to 1 year.^5,10

The FDA approval of avacincaptad pegol was based on data obtained from the GATHER1 and GATHER2 randomized, double-masked, phase 3 clinical trials.¹⁰ Combined, these 2 studies evaluated 624 patients,¹¹ aged ≥50 years, having a GA lesion area between 2.5 and 17.5 mm².¹¹ In GATHER1, the GA lesion area was measured at baseline and every 6 months for the duration of the trial.^11,12 Patients were randomized between groups receiving 1 to 4 mg of avacincaptad pegol monthly and a control group receiving a monthly sham treatment.^11,12 The studies lasted up to 18 months, and the primary efficacy end point was the mean change in GA lesion area, as measured by fundus autofluorescence (Table).^10-12

Within the first 12 months of treatment, the avacincaptad pegol–treated patients showed a statistically significant reduction in the mean rate of change in GA area compared with the patients in the sham group (0.292 mm vs 0.402 mm, P=.0072).¹¹ This trend was still evident after 18 months of treatment. Moreover, patients receiving avacincaptad pegol had a lower decline in visual acuity than patients in the sham group.¹²

Across both GATHER1 and GATHER2 clinical trials, the most common ocular adverse reactions reported were conjunctival hemorrhage (13%), increased intraocular pressure (9%), blurred vision (8%), and choroidal neovascularization (7%).¹⁰

GA Disease Progression Increases Healthcare Costs and Resource Utilization

As the landscape of GA-associated healthcare evolves, the anticipated costs of care and its corresponding utilization are important. Several recent studies present pivotal insights that shed light on the prevalence and progression of GA, its economic ramifications, and the anticipated patterns of care use.

On a global scale, GA is emblematic of the broader AMD issue, contributing to 8.7% of blindness and emerging as the foremost cause of blindness in developed nations.¹³ A study published in 2021 reports the prevalence of GA as 2.88 cases per 10,000 individuals with an incidence rate of 1.75 new cases per 10,000 individuals annually.² Projections point to a surge in the global AMD population, which is estimated to reach 288 million individuals by 2040; thus, the imperative for efficient and cost-effective care becomes increasingly evident.¹³

Within this context, the association between GA severity and escalating patient-related costs within outpatient settings becomes particularly relevant. Notably, patients with advanced GA exhibit higher healthcare resource use and associated costs compared with their counterparts with less advanced AMD.² Although outpatient visits for early to intermediate GA average 1.98 per year, advanced GA cases average 2.63 visits annually.² This trend is further underscored by the fact that 83% of patients with GA seek care in outpatient settings, whereas inpatient settings account for only 9% of patient visits.²

Unveiling the financial impact of GA, even after accounting for baseline characteristics and comorbidities, the mean patient-related outpatient costs for advanced GA are significantly higher than those for early GA. This difference is quantified as $30 (95% confidence interval [CI], $4-$56; P=.024) for unilateral GA and is even more pronounced at $44 (95% CI, $19-$69; P=.001) for bilateral GA.² Alongside these figures, an estimate places the first-year healthcare system cost per patient after diagnosis at $11,672, underscoring the need for efficient management and cost-effective interventions.¹⁴

GA does progress in severity, a factor to take into account when considering treatment strategies. One study observed a 4.8% progression rate in patients with GA over a 1-year period.² It should be noted that this study occurred prior to the availability of FDA-approved treatments to help decrease the rate of progression.

Furthermore, disease progression can increase healthcare expenditures. Patients with GA face higher risks for additional illnesses and injuries. For example, a Medicare study highlighted an 11% increased risk for incident hip fractures among patients with GA.^14,15 With an aging population, the surge in Medicare claims under Current Procedural Terminology code 67028, which codes for intravitreal injection of a pharmacologic agent, such as avacincaptad pegol and pegcetacoplan, has more than tripled between 2008 and 2022, surpassing 3.5 million claims annually.¹⁶

The American Academy of Ophthalmology recommends follow-up for 6 to 24 months for patients with asymptomatic GA, but they recommend prompt examination for individuals presenting new symptoms suggestive of choroidal neovascularization.¹⁷ This guidance aims to facilitate proactive care and early interventions, crucial elements in the overall management of GA.

Conclusion

As the US population ages, the number of age-related diseases, such as GA, increases along with an increased burden on the healthcare system. The arrival of FDA-approved therapies, pegcetacoplan and avacincaptad pegol, signifies a transformative chapter in GA management. Addressing the unmet need for GA-specific interventions, these breakthroughs hold the potential to slow disease progression and alleviate the burden of care. With GA’s prevalence and associated costs due to untreated disease progression, these treatments not only enhance patient outcomes but also offer the possibility of optimizing healthcare resources. As the healthcare landscape evolves, these approvals pave the way for a future where GA’s impact may be mitigated, reshaping the course of care for those affected.

References

1. Thomas CJ, Mirza RG, Gill MK. Age-related macular degeneration. Med Clin North Am. 2021;105(3):473-491.
2. Kim A, Devine B, Campbell J, Shirneshan E, Zhao C, Bansal A. Healthcare resource utilization and costs in patients with geographic atrophy secondary to age-related macular degeneration. Clin Ophthalmol Auckl NZ. 2021;15:2643-2651.
3. Chakravarthy U, Bailey CC, Johnston RL, et al. Characterizing disease burden and progression of geographic atrophy secondary to age-related macular degeneration. Ophthalmology. 2018;125(6):842-849.
4. Cruz-Pimentel M, Wu L. Complement inhibitors for advanced dry age-related macular degeneration (geographic atrophy): some light at the end of the tunnel? J Clin Med. 2023;12(15):5131.
5. SYFOVRETM (Pegcetacoplan Injection), for Intravitreal Use [Prescribing Information]. Apellis Pharmaceuticals; February 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217171s000lbl.pdf. Accessed August 20, 2023.
6. Goldberg R, Heier JS, Wykoff CC, et al. Efficacy of intravitreal pegcetacoplan in patients with geographic atrophy (GA): 12-month results from the phase 3 OAKS and DERBY studies. Invest Ophthalmol Vis Sci. 2022;63(7):1500.
7. Riedl S, Vogl WD, Mai J, et al. The effect of pegcetacoplan treatment on photoreceptor maintenance in geographic atrophy monitored by artificial intelligence-based OCT analysis. Ophthalmol Retina. 2022;6(11):1009-1018.
8. Wehrwein P. Amid favorable results, questions about Syfovre’s safety | ASRS 2023. Managed Healthcare Executive. Published July 31, 2023. https://www.managedhealthcareexecutive.com/view/amid-favorable-results-questions-about-syfovre-s-safety-asrs-2023. Accessed August 20, 2023.
9. Apellis provides update on review of rare safety events with SYFOVRE® (pegcetacoplan injection) for geographic atrophy. Apellis Pharmaceuticals. Published July 29, 2023. https://investors.apellis.com/news-releases/news-release-details/apellis-provides-update-review-rare-safety-events-syfovrer. Accessed August 20, 2023.
10. IZERVAYTM (Avacincaptad Pegol Intravitreal Solution) [Prescribing Information]. Iveric Bio; August 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217225s000lbl.pdf. Accessed August 20, 2023.
11. Jaffe GJ, Westby K, Csaky KG, et al. C5 inhibitor avacincaptad pegol for geographic atrophy due to age-related macular degeneration: a randomized pivotal phase 2/3 trial. Ophthalmology. 2021;128(4):576-586.
12. Patel SS, Lally DR, Hsu J, et al. Avacincaptad pegol for geographic atrophy secondary to age-related macular degeneration: 18-month findings from the GATHER1 trial. Eye. Published online March 24, 2023:1-7.
13. Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2(2):e106-e116.
14. Sarda SP, Heyes A, Bektas M, et al. Humanistic and economic burden of geographic atrophy: a systematic literature review. Clin Ophthalmol Auckl NZ. 2021;15:4629-4644.
15. 15. Anastasopoulos E, Yu F, Coleman AL. Age-related macular degeneration is associated with an increased risk of hip fractures in the Medicare database. Am J Ophthalmol. 2006;142(6):1081-1083.
16. Find-A-Code. CPT® Code 67028. https://www.findacode.com/cpt/67028-cpt-code.html. Accessed August 21, 2023.
17. Flaxel CJ, Adelman RA, Bailey ST, et al. Age-Related Macular Degeneration Preferred Practice Pattern®. Ophthalmology. 2020;127(1):P1-P65.