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Retinal Physician

Article

Treatment of Geographic Atrophy by Anatomic Location

Complement inhibitors could slow progression in lesions with and without subfoveal involvement.

By: Anna Marmalidou, MD, Antonio Yaghy, MD, Nadia K. Waheed, MD, MPH
Retinal Physician February 1, 2023 Vol 20, Issue Special Edition 2023 Page(s): 22-26

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Geographic atrophy (GA) most commonly starts in the perifoveal region sparing the foveal center; the terminology used for this location-based pathology is foveal sparing, extrafoveal, nonfoveal, or noncentral GA (Figure 1).1,2 Over time, GA lesions relentlessly progress both outward toward the periphery and inward toward the fovea (foveal or central GA) at a rate ranging from 0.53 to 2.6 mm2/year (median, 1.78 mm2/year), with a faster growth toward the periphery than the fovea (Figure 2).1,2 Progression of GA lesions toward the fovea leads to central vision loss over time.2 Although visual symptoms are often present prior to foveal involvement, vision can decrease dramatically once the fovea is impacted, leading to a loss of independence, social isolation, depression, and an increased risk of falls and fractures.2-4 In addition, GA location affects GA growth rate, with nonfoveal lesions growing faster than foveal lesions.2 The exact pathogenesis of GA is still unknown.5 Overactivation or dysregulation of the complement system may contribute to the development and progression of GA through inflammation and cell death.5,6 Several genetic variants in complement pathway proteins, including complement factor H (CFH) and C3, have been linked to GA progression.2

Figure 1. Optical coherence tomography scan of a patient with geographic atrophy showing 2 paracentral areas of choroidal hypertransmission >250 µm in diameter corresponding to extrafoveal geographic atrophy.
Figure 1. Optical coherence tomography scan of a patient with geographic atrophy showing 2 paracentral areas of choroidal hypertransmission >250 µm in diameter corresponding to extrafoveal geographic atrophy.
Figure 2. Fundus autofluorescence and optical coherence tomography scan of a patient with geographic atrophy
Figure 2. Fundus autofluorescence and optical coherence tomography scan of a patient with geographic atrophy. An area of central hyperautofluorescence (A, white arrow) and an area of choroidal hypertransmission >250 µm in diameter (B) corresponding to foveal geographic atrophy.

There are currently no US Food and Drug Administration (FDA) or European Medicines Agency (EMA) approved treatment options for patients with GA.2,6 However, clinical trials have investigated complement-inhibiting treatments.6 By targeting complement, these therapies aim to decrease the activity of the complement system and reduce GA lesion progression both outward (periphery) and inward (toward the fovea).2 Slowing growth toward the fovea preserves central vision for a longer period of time.2 Different clinical trials have described nonfoveal or extrafoveal GA differently and have therefore enrolled and analyzed slightly different populations of GA patients.7,8 For example, the GATHER1 and GATHER2 clinical trials enrolled nonfoveal GA lesions within 1,500 μm of the fovea, but not involving the foveal center.7 The OAKS and DERBY clinical trials characterized nonsubfoveal GA as a GA lesion whose border is ≥1 µm from the foveal center point.8 However, the results of these studies suggest that therapeutic complement inhibition seems to have a larger effect on juxtafoveal and extrafoveal lesions than it does on foveal lesions, and this is not simply explained by the faster growth rate of extrafoveal lesions compared to foveal lesions.8 This article will present data (Table 1) on the use of complement inhibitors in GA based on lesion location and summarize some recommendations when considering treatment.

Table 1: Randomized Clinical Trials Investigating Geographic Atrophy Therapies Based on Anatomic Location
Treatment RCT Name NCT Number RCT Phase RCT Status Patients (N) Treatment Duration GA Growth as a Primary Efficacy Endpoint
Nonfoveal and foveal GA
Pegcetacoplan FILLY NCT02503332 2 Completed 246 12 months Monthly dosing: ↓ 29%; every-other-month dosing: ↓ 20%
Pegcetacoplan OAKS NCT03525600 3 Active, not recruiting 637 12 months Monthly dosing: ↓ 21%; every-other-month dosing: ↓ 16%
24 months Monthly dosing: ↓ 22%; every-other-month dosing: ↓ 18%
Pegcetacoplan DERBY NCT03525613 3 Active, not recruiting 621 12 months No statistically significant reduction
24 months Monthly dosing: ↓ 19%; every-other-month dosing: ↓ 16%
Pegcetacoplan OAKS/DERBY combined OAKS: NCT03525600, Derby: NCT03525613 3 Active, not recruiting 1,258 24 months Overall: monthly dosing ↓ 20%; every-other-month dosing ↓ 17%. Extrafoveal GA: monthly dosing ↓ 26%; every-other-month dosing ↓ 22%. Foveal GA: monthly dosing ↓ 19%; every-other-month dosing↓ 16%.
GT005 HORIZON NCT0456645 2 Recruiting 250 48 weeks Unpublished
NGM621 CATALINA NCT04465955 2 Active, not recruiting 320 52 weeks No statistically significant reduction
ANX007 ARCHER NCT04656561 2 Active, not recruiting 270 12 months Unpublished
Nonfoveal GA
Avacincaptad pegol GATHER1 NCT02686658 2/3 Completed 286 12 months 2 mg: ↓ 27.4%4 mg: ↓ 27.8%
Avacincaptad pegol GATHER2 NCT04435366 3 Active, not recruiting 448 12 months 2 mg: ↓ 14.3%
RCT, randomized clinical trial; GA, geographic atrophy.

CLINICAL TRIALS OF TREATMENTS FOR LESIONS WITH AND WITHOUT SUBFOVEAL INVOLVEMENT

Pegcetacoplan (Apellis Pharmaceuticals) is a novel complement C3 protein inhibitor.8 FILLY is a phase 2 randomized, single-masked, sham-controlled, multicenter clinical trial investigating pegcetacoplan.9 Both OAKS and DERBY are phase 3 randomized, double-masked, sham-controlled, multicenter clinical trials investigating pegcetacoplan.8,9 These clinical trials evaluated the efficacy and safety of monthly and every-other-month intravitreal injections of pegcetacoplan in a broad GA population involving patients with both nonsubfoveal/extrafoveal (GA lesion border ≥1 µm from foveal center point) and subfoveal (GA lesion present at the center point of fovea) GA secondary to age-related macular degeneration (AMD).8,9 In all of these clinical trials, patients were randomized to receive either pegcetacoplan or sham monthly or every other month for 12 months.8,9 In OAKS and DERBY, patients continued to receive masked injections for 24 months.8 There were 246 participants in FILLY, 637 in OAKS, and 621 in DERBY.9,10 FILLY and OAKS met the 12-month primary endpoint for both monthly and every-other-month treatment, demonstrating a significant reduction in GA lesion growth compared with sham therapy; FILLY showed a 29% (P=.008) and 20% (P=.067) reduction, respectively, and OAKS showed a 21% (P=.0004) and 16% (P=.0055) reduction, respectively.8,9 DERBY did not meet the 12-month primary endpoint of GA lesion growth, showing a reduction of 12% (P=.0609) and 11% (P=.0853) with monthly and every-other-month treatment, respectively, compared with sham therapy.8 OAKS and DERBY, however, both achieved their prespecified secondary endpoint of GA lesion growth at 24 months: monthly and every-other-month treatment was found to reduce GA lesion growth by 22% (P<.0001) and 18% (P=.0002), respectively, in OAKS, and by 19% (P=.0004) and 16% (P=.0030), respectively, in DERBY.8

Combined OAKS and DERBY data showed that pegcetacoplan decreased GA lesion growth by 20% (P<.0001) and 17% (P<.0001) with monthly and every-other-month treatment, respectively, over 24 months.8 Between 18 and 24 months, treatment effect accelerated compared to the prior 6-month periods, with 30% (P<.0001) and 24% (P<.0001) reductions in growth of GA lesions with monthly and every-other-month pegcetacoplan, respectively.11 At 24 months, there was a signal of functional preservation with pegcetacoplan treatment on microperimetry junctional zone analysis in the OAKS trial.8 However, no significant differences in the secondary endpoints of visual function, including best-corrected visual acuity (BCVA), maximum reading speed, functional reading independence index, and mean threshold sensitivity were found with monthly and every-other-month treatment compared with sham therapy.8 Notably, in the combined studies over 24 months, pegcetacoplan reduced nonsubfoveal GA lesion growth by 26% (P<.0001) and 22% (P<.0001) with monthly and every-other-month treatment, respectively, and reduced subfoveal GA lesion growth by 19% (P<.0001) and 16% (P=.0003), respectively.8

Pegcetacoplan was found to have a favorable safety profile, especially with every-other-month treatment. In the combined trials, the most common adverse events reported at 24 months were intraocular inflammation, with rates of 3.8% in the monthly cohort, 2.1% in the every-other-month cohort, and 0.2% in the sham group; infectious endophthalmitis, with rates of 0.5% in both monthly and every-other-month cohorts; and ischemic optic neuropathy/papilledema, with a rate of 0.95% in the monthly cohort.12 Further, combined data showed that pegcetacoplan was associated with increased incidence of conversion to new-onset neovascular (wet) AMD, with rates of 12.2% in the monthly cohort, 6.7% in the every-other-month cohort, and 3.1% in the sham group.11 Given the positive phase 3 efficacy data from DERBY and OAKS, the company announced submission of part of its New Drug Application (NDA) and acceptance of NDA Amendment by the FDA.10,13

CLINICAL TRIALS OF TREATMENTS IN NONSUBFOVEAL GEOGRAPHIC ATROPHY

Avacincaptad pegol (Zimura; Iveric Bio) is an investigational complement C5 protein inhibitor that has been investigated primarily in patients with nonsubfoveal GA.7 This therapy met its prespecified primary endpoint of reduction of mean rate of growth in GA area at 12 months in 2 pivotal clinical trials.7 The completed GATHER1 (n=286) and ongoing GATHER2 (n=448) are phase 2/3 and phase 3, respectively, randomized, double-masked, sham-controlled, multicenter clinical trials comparing the efficacy and safety of avacincaptad pegol with sham therapy in patients with nonfoveal GA (GA lesions within 1,500 μm, but not involving the foveal center) secondary to AMD.7,14,15 In GATHER1, the reduction in nonfoveal GA growth over 12 months was 27.4% (P=.0072) with 2 mg avacincaptad pegol and 27.8% (P=.0051) with 4 mg avacincaptad pegol compared with sham therapy.14 In GATHER2, the effect on size was more modest but still statistically significant, with 2 mg avacincaptad pegol decreasing the GA growth by 14.3% (P=.0064) at 12 months.15 Avacincaptad pegol was well tolerated with no drug-related adverse events and no cases of endophthalmitis, intraocular inflammation, or ischemic optic neuropathy after 12 months of treatment in GATHER1 and GATHER2.14,16 However, there was an increased risk of choroidal neovascularization (CNV) or wet AMD in treated eyes, with rates of 9.0% in the 2 mg cohort and 9.6% in the 4 mg cohort compared with 2.7% in the sham group in GATHER1 and a rate of 6.7% in the 2 mg cohort compared with 4.1% in the sham group in GATHER2.14,16 Given the positive phase 3 efficacy results, the company submitted the first part of its NDA to the FDA for rolling review of avacincaptad pegol for the treatment of GA.16

OTHER STUDIES ENROLLING SUBGROUPS BY LESION LOCATION

Given that complement inhibition appears to work on both foveal and nonsubfoveal GA, albeit better in nonsubfoveal GA, some trials have taken the strategy of enrolling separate subgroups of foveal and nonsubfoveal GA to conduct prespecified analysis of treatment efficacy on these 2 groups. One such study is the HORIZON study, which evaluates GT005.17 GT005 (Gyroscope Therapeutics) is an investigational AAV2-based gene therapy designed to increase the expression of complement factor I (CFI) protein, a protein that downregulates complement system activity.18 The ongoing phase 2, randomized, multicenter HORIZON clinical trial is actively enrolling 250 patients with both foveal and nonfoveal GA secondary to AMD, with a prespecified stratified analysis of the foveal and nonsubfoveal lesions.17 The trial is evaluating the efficacy and safety of 2 doses of GT005 administered as a single subretinal injection, with the primary efficacy endpoint of GA lesion growth at 48 weeks.17

NGM621 (NGM Pharmaceuticals) is a novel complement protein C3 inhibitor.19 The randomized, double-masked, sham-controlled CATALINA phase 2 trial enrolled 320 patients with nonfoveal and foveal GA secondary to AMD.19 The primary objectives of this trial were to explore the efficacy and safety of NGM621 administered every 4 or 8 weeks via intravitreal injections compared with sham therapy for a total of 52 weeks.19 The trial did not meet its primary efficacy endpoint of reduction of GA lesion growth rate, showing reductions of 6.3% (P=.435) and 6.5% (P=.422) with 4-week and 8-week therapy respectively, compared with sham therapy at 52 weeks.19 NGM621 seemed to have a good safety profile with no cases of endophthalmitis, retinal vasculitis, or retinal vein occlusion; a low rate of intraocular inflammation; and no evidence of CNV conversions, with fewer cases of CNV in treated eyes compared with sham.19

ANX007 (Annexon Biosciences) is an investigational inhibitor of C1q and the classical complement pathway.20 The ongoing randomized, double-masked, sham-controlled, multicenter phase 2 ARCHER clinical trial has completed enrollment of 270 patients with nonfoveal and foveal GA secondary to AMD.20 Patients are randomly assigned to receive monthly or every-other-month intravitreal injections of 5 mg ANX007 or sham therapy over 12 months, followed by a 6-month off-treatment period. The primary efficacy endpoint is the change in GA lesion area.20

DISCUSSION

Geographic atrophy is an age-related progressive degenerative disease associated with irreversible vision loss. Although the pathogenesis of GA remains a topic of debate, the complement system plays a role in GA onset and progression. Investigational treatments rely on decreasing complement system activity and slowing GA progression. Although NGM621 failed to show efficacy, and gene therapy and ANX007 are still developing, avacincaptad pegol and pegcetacoplan showed good efficacy, safety, and tolerability but had increased risk for CNV conversion for patients with nonsubfoveal and subfoveal GA.

If any of these therapies achieve regulatory approval, it will change the paradigm of how retina specialists manage patients with GA. On the one hand, these therapies represent a significant treatment burden (monthly or every-other-month injections) on patients who have a chronic disease. Patients may not notice any immediate improvement or indeed any improvement at all from the therapy. On the other hand, like any treatment for chronic disease, the effects of these therapies are apparent over the long term and seem to compound over time. Therefore, careful thought must be given to which patients are likely to benefit the most from these therapies. The benefits are potentially greater for patients with extrafoveal disease who therefore still have preserved BCVA and the potential to retain good visual function for longer. Because this patient population is older, treatment benefit could last a lifetime with regular therapy.

In patients with foveal lesions, the question of clinically meaningful benefit is more difficult to answer. However, microperimetry data from the OAKS trial demonstrates better preservation of perilesional retinal sensitivity at 24 months in these patients, pointing to the potential for reducing scotoma progression and preserving visual function if not acuity over the long term. In any case, if these medications do get approved, decision making for patients with GA should involve a careful discussion with each patient about expected progression of the disease, how it may be modified with regular therapy, and what patients may expect to experience, as well as the importance of compliance with a regular injection schedule. The decision to treat or not must be made by careful collaboration between the patient and their retina specialist to ensure compliance to optimal treatment schedules.

Retina specialists may also consider classifying patients with GA into those with subfoveal and those without subfoveal involvement, because the course of progression, prognosis, and therapeutic options available may be different between these groups. The ability to allocate a GA patient to 1 of these 2 classes on EMR allows for appropriate discussions with patients around the risks and benefits of the therapeutic options and enables retina specialists to monitor treatment outcomes and analyze costs in each of these patient groups. RP

Editor’s note: This article is part of a special edition of Retinal Physician that was supported by Apellis Pharmaceuticals. Authors and editors maintained editorial control for all articles in this special edition.

Anna Marmalidou, MD, and Antonio Yaghy, MD, are research fellows, and Nadia K. Waheed, MD, MPH, is a retina specialist with the department of ophthalmology at the New England Eye Center of Tufts Medical Center and Tufts University School of Medicine, in Boston, Massachusetts. Dr. Marmalidou and Dr. Yaghy report no relevant disclosures. Dr. Waheed reports research for Zeiss, Topcon, and Nidek; speaker fees from Nidek and Zeiss; consultancy to Topcon, Complement Therapeutics, OliX Pharmaceuticals, lolyx Pharmaceuticals, Hubble, Saliogen, and Syncona; equity interest in Ocudyne and Gyroscope; and employment with AGTC. Reach Dr. Waheed at nadiakwaheed@gmail.com. Editor’s note: Hear discussion of this article on the Retina Podcast at www.retinapodcast.com .

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  20. Annexon, Inc. Annexon Biosciences completes enrollment in ARCHER phase 2 trial of novel C1q inhibitor, ANX007, in patients with geographic atrophy. News release. April 7, 2022. Accessed January 3, 2023. https://ir.annexonbio.com/news-releases/news-release-details/annexon-biosciences-completes-enrollment-archer-phase-2-trial/

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