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Retinal Physician

Article

Complement Inhibition in Geographic Atrophy

Trial data herald another new era in AMD treatment.

By: William Carrera, MD, MS, Jeffrey S. Heier, MD
Retinal Physician February 1, 2023 Vol 20, Issue Special Edition 2023 Page(s): 9-14

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The early 2000s ushered in the anti-VEGF era for wet age-related macular degeneration (AMD), which completely changed the approach to treating patients with wet AMD. Ophthalmology is on the verge of a similar advance that could provide a therapy for patients with advanced dry AMD. Age-related macular degeneration is the leading cause of irreversible blindness in developed countries and is expected to affect 288 million people globally by 2040.1 Geographic atrophy (GA), characterized by loss of the choriocapillaris, retinal pigment epithelium (RPE), and photoreceptors, represents the most advanced form of dry AMD and has been the target of numerous avenues of therapeutic approach, the most promising thus far proving to be the complement pathway inhibition. With the first 2 drugs in this class being evaluated by the FDA, it is an apt time to review the history of complement inhibition in GA treatment.

THE COMPLEMENT SYSTEM

The complement system forms a core component of the innate immune response and can be classified into 3 pathways that differ by their mode of activation: the classical pathway, the lectin pathway, and the alternative pathway. The classical pathway is activated by antigen-antibody complexes, resulting in activation of C1 by C1q. The C1 complex cleaves C2 and C4, allowing formation of the classical C3 convertase, C4b2a.2,3

The lectin pathway is activated by recognition of bacterial mannose-containing polysaccharides by mannose-binding lectin (MBL).3 Activated MBL binds to MBL serine peptidases (MASPs), cleaving C2 and C4 and again producing C4b2a.

The alternative pathway is initiated by spontaneous C3 hydrolysis into C3a and C3b. C3b binds to complement factor B (CFB) and complement factor D (CFD) to form the alternative C3 convertase, C3bBb. Regulation of this self-amplifying pathway is achieved through inhibitory complement factors H (CFH) and I (CFI). Alternative pathway activation accounts for the majority of complement activity (80%) and is likely the most significant pathway in AMD pathogenesis.2,4

The 3 pathways converge on C3, which cleaves C5 into C5a and C5b, the latter of which initiates the terminal complement pathway. Terminal pathway activation results in phagocytosis, inflammation, and formation of the membrane attack complex.5

RATIONALE FOR COMPLEMENT INHIBITION IN AMD

The role of complement dysfunction in AMD pathogenesis was suggested by genome-wide association studies (GWAS) that identified polymorphisms in complement proteins, including CFH, CFI, C2 and C3, in AMD patients.4,6,7 Particular polymorphisms, such as CFH Y402H, are associated with 2.45 to 5.57-fold increased risk of AMD.4 In vitro, many of these polymorphisms result in either increased complement activation or impaired complement regulation.2,8 Patients with AMD also demonstrate increased serum concentrations of complement activation products, which have also been identified within drusen and in drusen-adjacent RPE and choriocapillaris.3,9,10 Lastly, murine models of complement dysregulation reproduce the clinical features of AMD, including sub-RPE lipofuscin deposition, subretinal drusen-like deposits, and RPE and photoreceptor atrophy.11,12

EARLY TRIALS

Most agents targeting complement in GA have focused on alternative and common pathway proteins, such as C3 and C5. The earliest trials provided largely discouraging results but yielded important lessons that would inform subsequent trials. A summary of previous and ongoing clinical trials in complement inhibition for GA are provided in Table 1.13-29

Table 1: Clinical Trials of Complement Inhibitors for Geographic Atrophy
Year Trial Phase Drug Target Design   N Primary Outcome Result
2014 COMPLETE (NCT00935883) 2 Eculizumab (intravenous) (Soliris; Alexion) C5 2:1:1 randomization to low-dose, high-dose, sham weekly for 4 weeks, then Q2W until week 24   30 Growth of geographic atrophy (GA); decrease in drusen volume at 26 weeks No significant reduction in GA growth rate at 26 weeks (P=.96) or 52 weeks (P=.93)
2017 MAHALO (NCT01229215) 2 Lampalizumab (intravitreal) (Genentech) CFD 1:1:1 randomization to monthly or every other month (EOM) vs sham   123 Growth rate of GA area from baseline at 18 months 20% reduction in GA growth rate vs sham (P=.117). CFI risk-allele carriers showed 44% reduction (P=.0037)
2018 NCT01527500 2 LFG316 (intravitreal) (Novartis) C5 2:1 randomization to monthly dosing vs sham   158 GA growth from baseline at 505 days; safety Well tolerated. No significant difference in GA growth vs sham
2018 CHROMA (NCT02247479) 3 Lampalizumab (intravitreal) (Genentech) CFD 2:1:2:1 randomization to Q4W or Q6W vs sham   906 Change in GA area from baseline at 48 weeks No significant reduction in GA growth with Q4W (P=.80) or Q6W dosing (P=.59)
2018 SPECTRI (NCT02247531) 3 Lampalizumab (intravitreal) (Genentech) CFD 2:1:2:1 randomization to Q4W or Q6W vs sham   975 Change in GA area from baseline at 48 weeks No significant reduction in GA growth with Q4W (P=.048, favoring sham) or Q6W dosing (P=.27)
2020 FILLY (NCT02503332) 2 Pegcetacoplan (intravitreal) (Apellis Pharmaceuticals) C3 2:2:1:1 randomization to monthly or EOM vs sham   246 Change in GA area from baseline at 12 months ; Safety Well tolerated. Reduction in GA growth of 29% (P=.008) with monthly and 20% (P=.067) with EOM vs sham
2020 GATHER1 (NCT02686658) 2/3 Avacincaptad pegol (Zimura; Iveric Bio) C5 Part 1: 1:1:1 randomization to 1 mg, 2 mg, sham dosed monthly. Part 2: 1:1:1 randomization to 2 mg, 4 mg, sham dosed monthly   286 Mean rate of change in GA area at 12 months 27.4% reduction in GA growth rate over 12 months with 2 mg dosed monthly (P=.0072) and 27.8% with 4 mg dosed monthly (P=.0051) vs sham
2021 DERBY (NCT03525600) 3 Pegcetacoplan (intravitreal) (Apellis Pharmaceuticals) C3 2:2:1:1 randomization to monthly, EOM or sham   621 Change in GA area from baseline at 12 months Nonsignificant reduction in GA growth of 12% with monthly dosing (P=.0528) and 11% with EOM dosing (P=.0750) vs sham
2021 OAKS (NCT03525613) 3 Pegcetacoplan (intravitreal) (Apellis Pharmaceuticals) C3 2:2:1:1 randomization to monthly, EOM or sham   637 Change in GA area from baseline at 12 months Reduction in GA growth of 22% over 12 months with monthly dosing (P=.0003) and 16% with EOM dosing (P=.0052) vs sham
2022 GATHER2 (NCT04435366) 3 Avacincaptad pegol (Zimura; Iveric Bio) C5 Part 1 (12 months): 1:1 randomization to 2 mg vs sham monthly. Part 2 (12 months): 2 mg monthly arm re-randomized to 2 mg monthly or EOM, sham continues monthly.   448 Mean rate of change in GA over 12 months Reduction in GA growth rate of 14.3% over 12 months (P=.0064) using square root transformation, or of 17.7% using observed GA area
2022 NCT03144999 1 JNJ-81201887 (Janssen) (intravitreal gene therapy) CD59 Dose escalation study   17 Safety No SAEs or systemic SAEs over 24 months
2022 ReGAtta (NCT04643886) 2a GEM103 (Gemini) CFH Open-label, multiple dose study   62 Safety over 18 months Study terminated by sponsor
Ongoing GALE (NCT04770545) 3 Pegcetacoplan (intravitreal) (Apellis Pharmaceuticals) C3 Open label extension   ~1,200 Safety over 36 months Pending
Ongoing ARCHER (NCT04656561) 2 ANX007 (intravitreal) (Annexon) C1q 1:1:1 randomization to monthly or EOM vs sham   270 GA lesion growth rate at 12 months Pending
Ongoing GOLDEN (NCT03815825) 2 IONIS-FB-LRx (subcutaneous) (Ionis) CFB Randomization to 3 dose levels vs placebo   ~330 Change in GA area at week 49 Pending
Ongoing NCT05019521 2 Danicopan (oral) (Alexion) CFD Randomization to 100 mg BID, 200 mg BID, 400 mg QD, or placebo   ~332 Change in GA area at week 52 Pending
Ongoing FOCUS (NCT03846193) 1/2 GT011 (subretinal gene therapy) (Gyroscope) CFI Nonrandomized dose escalation study via transvitreal subretinal injection or suprachoroidal cannulation approach   56 Safety Pending
Ongoing EXPLORE (NCT04437368) 2 GT011 (subretinal gene therapy) (Gyroscope) CFI 1:1:1 randomization to low-dose or high-dose vs untreated control in patients with rare CFI allele   ~75 Change in GA area at week 48 Pending
Ongoing HORIZON (NCT04566445) 2 GT011 (subretinal gene therapy) (Gyroscope) CFI 1:1:1 randomization to medium-dose or high-dose vs untreated control   ~250 Change in GA area at week 48 Pending

COMPLETE (NCT00935883) was a small, phase 2 trial evaluating intravenous eculizumab, an anti-C5 monoclonal antibody (Soliris; Alexion Pharmaceuticals) that failed to demonstrate reduction in mean GA growth rate at 26 weeks.13

MAHALO (NCT01229215) was a small, phase 2 trial evaluating lampalizumab, an anti-CFD monoclonal antibody fragment (Genentech). MAHALO met a prespecified alpha of 0.20 for reduction of GA growth at 18 months (P=.117). However, it provided intriguing results in a subset of patients with high-risk CFI alleles, in whom a more substantial GA growth reduction of 44% was observed.14 Based on these results, lampalizumab was evaluated in the larger CHROMA (NCT02247479) and SPECTRI (NCT02247531) trials. These identical phase 3 trials were the largest studies not only of complement inhibition in AMD but also of GA more generally, at the time they were conducted (n=1,881).16 Both failed to show a benefit of lampalizumab in reducing GA growth rate, including in the high-risk CFI allele subgroup. Around the same time, a phase 2 trial (NCT01527500) of LFG316 (Novartis), an anti-C5 monoclonal antibody, also failed to demonstrate a significant reduction in GA growth compared to sham.15,30

The failure of COMPLETE raised fundamental questions about the promise of the complement system as a therapeutic target, about the association between the complement polymorphisms identified in GWAS and GA progression, and whether an optimal therapeutic target within the complement cascade may exist.13 These concerns were only amplified following the failure of CHROMA and SPECTRI. However, these trials made important contributions. They established GA area growth rate assessed by fundus autofluorescence (FAF) as a standard endpoint and demonstrated good tolerability of a 0.1 mL injection volume. CHROMA and SPECTRI also provided useful information about GA natural history by identifying an average annual lesion growth rate of ~2 mm2 and by identifying baseline lesion size, multifocality, and nonfoveal location as risk factors for rapid enlargement, consistent with AREDS2 findings also released in 2018.16,31 They also highlighted problems with post hoc subset analyses.

FIRST SIGNS OF SUCCESS

Initial success came in 2020 with the phase 2 FILLY trial (NCT02503332) evaluating intravitreal pegcetacoplan, a pegylated anti-C3 and C3b peptide (APL-2; Apellis Pharmaceuticals).17 FILLY demonstrated a significant reduction of 29% in GA growth rate at 12 months with monthly dosing. Twelve-month efficacy data from the DERBY (NCT03525600) and OAKS (NCT03525613) phase 3 trials evaluating pegcetacoplan was released the following year. Pegcetacoplan significantly reduced GA growth at 12 months in OAKS, but narrowly missed this endpoint in DERBY.19

Also in 2020, the GATHER1 trial (NCT02686658) evaluating intravitreal avacincaptad pegol (Zimura; Iveric Bio), a pegylated RNA aptamer targeting C5, demonstrated significant reductions of 27.4% and 27.8% in GA growth at 12 months with 2 mg and 4 mg dosed monthly.18 The phase 3 GATHER2 trial (NCT04435366) (n=448) met its primary endpoint and demonstrated a 14.3% to 17.7% reduction in GA growth rate over 12 months vs sham.20 Post hoc analysis of GATHER1 data found a strong correlation between GA as measured by FAF and as measured by OCT, and identified OCT ellipsoid zone integrity as a possible biomarker for GA. This has important implications for clinical practice, as OCT-based assessment of GA is likely to be more widely utilized by practicing retina specialists compared to FAF.32 Iveric Bio completed its NDA submission in December 2022.20

RECENT DEVELOPMENTS

Pegcetacoplan continues to show promise with 24-month data from DERBY and OAKS. At 24 months, pegcetacoplan reduced GA growth by 19% when dosed monthly (P=.0004) and by 16% when dosed every other month (EOM) (P=.0030) in DERBY, and by 22% (monthly) (P<.0001) and 18% (EOM) (P=.0002) in OAKS.33 Notably, DERBY met its primary endpoint at 24 months after narrowly missing its 12-month primary endpoint. Pegcetacoplan also showed positive trends toward preventing perilesional photoreceptor functional loss as assessed by microperimetry, which met significance in the EOM dosing group in OAKS. This represents some of the first human functional data demonstrating a benefit to complement inhibition in GA. An open-label extension study of pegcetacoplan (GALE; NCT04770545) is ongoing with approximately 1,200 patients.23 Pegcetacoplan will be the first drug for GA to be evaluated by the FDA, with a PDUFA date of February 26, 2023.34

An interesting trend to emerge from DERBY and OAKS is an acceleration of treatment effect over time. In DERBY and OAKS, the effect of pegcetacoplan treatment increased over months 18 to 24, with a reduction of GA growth of 36% with monthly dosing (P<.0001) and 29% with EOM dosing (P=.0002) in DERBY and 24% (P=.0080) and 25% (P=.0007), respectively, in OAKS.33 Earlier data from FILLY also demonstrated reductions of 45% and 33% in GA growth rate with monthly and EOM dosing during the second 6 months of the trial, compared to 29% and 20% overall.17 The reason for this treatment acceleration remains unclear. The concept of “dead retina walking” has been proposed as a possible explanation, in which terminally damaged perilesional retina leads to an inevitable, initial progression of GA with or without treatment, followed by stabilization of GA growth once complement inhibition arrests further retinal damage.35

A concerning theme also emerged from these studies: increased rates of choroidal neovascularization (CNV) in the setting of complement inhibition. Both FILLY treatment arms demonstrated increased rates of CNV vs sham, accounting in part for the high rate of treatment dropout.17 DERBY and OAKS demonstrated rates of new CNV of 6.0%, 4.1%, and 2.4% at 12 months and 12.2%, 6.7%, and 3.1% at 24 months in the monthly, EOM, and sham arms, respectively.36,37 Retrospective analysis of FILLY found OCT double-layer sign and contralateral eye CNV to correlate with new CNV, suggesting the possible role of complement inhibition in unmasking pre-existing subclinical CNV.38 While pre-existing anatomic features may influence risk of CNV with complement inhibition, more research is needed to fully elucidate the role of complement in vascular homeostasis and CNV in the context of AMD.

NEW AGENTS ON THE HORIZON

Numerous promising agents are in early development for complement inhibition in patients with GA. Ongoing phase 2 trials include ARCHER (NCT04656561) (n=270) evaluating intravitreal ANX007 anti-C1q monoclonal antibody fragment (Annexon); GOLDEN (NCT03815825) (n=~330) evaluating IONIS-FB-LRx antisense oligonucleotide targeting CFB (Ionis Pharmaceuticals); and NCT05019521 (n=~332) evaluating danicopan small-molecule inhibitor of CFD (ALXN2040; Alexion Pharmaceuticals).24,25,26,39-43 Other agents, such as CB2782-PEG (Catalyst Biosciences, Inc.) a C3-inactivating protease, are in preclinical development.44,45

Recent results were less encouraging for other agents. The phase 2a ReGAtta trial (NCT04643886) (n=62) evaluating GEM103 recombinant human CFH (Gemini Therapeutics) demonstrated good tolerability and positive CFH biomarkers, but was not designed to detect statistically significant treatment effect and was terminated in Q1 2022.22 The phase 2 CATALINA trial (NCT04465955) (n=320) evaluating NGM621 anti-C3 monoclonal antibody (NGM Bio) failed to yield a significant reduction in GA growth compared to sham after showing positive phase 1 results.46,47 However, CATALINA post hoc analyses have highlighted a variety of challenges related to grading methodology and FAF assessment of GA lesions, particularly large or complex lesions.48 These challenges may have complicated the interpretation of CATALINA results, and also provide useful lessons for future trials.

GENE THERAPY

One of the biggest concerns with respect to current phase 3 agents under investigation is the significant treatment burden incurred by monthly or EOM injections. Long-term, durable treatment for GA may be on the horizon with gene therapy finally approaching late-stage clinical development.

Interim safety results of the phase 1/2 FOCUS trial (NCT03846193) evaluating GT005 AAV2-based gene therapy for CFI (Gyroscope Therapeutics) demonstrated good tolerability of subretinal, transvitreal delivery of GT005 (n=31).27,49 Results of GT005 delivered by the Orbit subretinal delivery system are pending. Two concurrent phase 2 trials evaluating GT005, EXPLORE (NCT04437368) and HORIZON (NCT04566445), are ongoing and will assess patients with (EXPLORE) or without (HORIZON) a rare CFI allele.28,29

JNJ-81201887 (also JNJ-1887, formerly AAVCAGsCD59 or HMR59) (Janssen Research & Development, LLC), is a gene therapy expressing CD59, thereby inhibiting C9 insertion and membrane attack complex formation. Phase 1 results (NCT03144999) demonstrated that JNJ-81201887 was well tolerated at 3 escalating doses given by intravitreal injection (n=17).21,50,51

CONCLUSIONS

Complement inhibition has shown remarkable and rapid progress as a viable treatment for GA following the uncertain beginnings and trial failures that marked its inception. Several drugs are in late-stage development and many more are in early phases of development. Complement inhibition may soon begin to address one of the largest unmet needs currently facing the practicing retinal physician. 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.

William Carrera, MD, MS, is a retina fellow with Ophthalmic Consultants of Boston. He reports no relevant disclosures. Jeffrey S. Heier, MD, is co-president and medical director, director of the vitreoretinal service, and director of retina research at Ophthalmic Consultants of Boston. He reports consultancy to 4DMT, Abpro, Adverum, Affamed, AGTC, Akouos, Allegro, Annexon, Apellis, Asclepix, Bausch + Lomb, Biovisics, Clearside Biomedical, Curacle, DTx Pharma, Genentech/Roche, Glaukos, Gyroscope, Immunogen, Iveric Bio, Janssen R&D, jCyte, Kriya, Nanoscope, NGM Bio, Notal Vision, Novartis, Ocular Therapeutix, Ocuphire, OcuTerrra, Olix, ONL Therapeutics, Palatin, Perceive, Ray Therapeutics, Regeneron, Regenxbio, RetinAI, RevOpsis, Stealth, Thea, and Vanotech; research for Annexon, Apellis, AsclepiX, Bayer, Genentech/Roche, Gyroscope, Iveric Bio, Kodiak, NGM Bio, Notal Vision, Regeneron, and Regenxbio; equity in Adverum, Aldeyra, Allegro, Aviceda, DTx Pharma, jCyte, Ocuphire, Ocular Therapeutix, RevOpsis, Vinci, and Vitranu; and that he is on the board of directors for Ocular Therapeutix. Reach Dr. Carrera at wcarrera@eyeboston.com.

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  44. Catalyst Biosciences & Mosaic Biosciences Present Preclinical Data on Pegylated CB 2782 for the Treatment of Dry Age-Related Macular Degeneration. April 29, 2019. Accessed November 1, 2022. Available at: https://ir.catalystbiosciences.com/news-releases/news-release-details/catalyst-biosciences-mosaic-biosciences-present-preclinical-data
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  50. Cohen, MN. Phase 1 study of JNJ-81201887 gene therapy in geographic atrophy (GA) due to age-related macular degeneration (AMD). Presented at: AAO Annual Meeting 2022, Chicago, IL.
  51. Janssen announces late-breaking data from two gene therapy programs at the American Academy of Ophthalmology annual meeting 2022. News release. October 1, 2022. Accessed November 1, 2022. Available at: https://www.jnj.com/janssen-announces-late-breaking-data-from-two-gene-therapy-programs-at-the-american-academy-of-ophthalmology-2022-annual-meeting

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