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Review
. 2023 Jun 14;6(6):CD009300.
doi: 10.1002/14651858.CD009300.pub3.

Complement inhibitors for age-related macular degeneration

Nikolaos Tzoumas  1   2 , George Riding  1   3 , Michael A Williams  4 , David Hw Steel  1   2
Affiliations
Review

Complement inhibitors for age-related macular degeneration

Nikolaos Tzoumas et al. Cochrane Database Syst Rev. .

Abstract

Background: Age-related macular degeneration (AMD) is a common eye disease and leading cause of sight loss worldwide. Despite its high prevalence and increasing incidence as populations age, AMD remains incurable and there are no treatments for most patients. Mounting genetic and molecular evidence implicates complement system overactivity as a key driver of AMD development and progression. The last decade has seen the development of several novel therapeutics targeting complement in the eye for the treatment of AMD. This review update encompasses the results of the first randomised controlled trials in this field.

Objectives: To assess the effects and safety of complement inhibitors in the prevention or treatment of AMD.

Search methods: We searched CENTRAL on the Cochrane Library, MEDLINE, Embase, LILACS, Web of Science, ISRCTN registry, ClinicalTrials.gov, and the WHO ICTRP to 29 June 2022 with no language restrictions. We also contacted companies running clinical trials for unpublished data.

Selection criteria: We included randomised controlled trials (RCTs) with parallel groups and comparator arms that studied complement inhibition for advanced AMD prevention/treatment.

Data collection and analysis: Two authors independently assessed search results and resolved discrepancies through discussion. Outcome measures evaluated at one year included change in best-corrected visual acuity (BCVA), untransformed and square root-transformed geographic atrophy (GA) lesion size progression, development of macular neovascularisation (MNV) or exudative AMD, development of endophthalmitis, loss of ≥ 15 letters of BCVA, change in low luminance visual acuity, and change in quality of life. We assessed risk of bias and evidence certainty using Cochrane risk of bias and GRADE tools.

Main results: Ten RCTs with 4052 participants and eyes with GA were included. Nine evaluated intravitreal (IVT) administrations against sham, and one investigated an intravenous agent against placebo. Seven studies excluded patients with prior MNV in the non-study eye, whereas the three pegcetacoplan studies did not. The risk of bias in the included studies was low overall. We also synthesised results of two intravitreal agents (lampalizumab, pegcetacoplan) at monthly and every-other-month (EOM) dosing intervals. Efficacy and safety of IVT lampalizumab versus sham for GA For 1932 participants in three studies, lampalizumab did not meaningfully change BCVA given monthly (+1.03 letters, 95% confidence interval (CI) -0.19 to 2.25) or EOM (+0.22 letters, 95% CI -1.00 to 1.44) (high-certainty evidence). For 1920 participants, lampalizumab did not meaningfully change GA lesion growth given monthly (+0.07 mm², 95% CI -0.09 to 0.23; moderate-certainty due to imprecision) or EOM (+0.07 mm², 95% CI -0.05 to 0.19; high-certainty). For 2000 participants, lampalizumab may have also increased MNV risk given monthly (RR 1.77, 95% CI 0.73 to 4.30) and EOM (RR 1.70, 95% CI 0.67 to 4.28), based on low-certainty evidence. The incidence of endophthalmitis in patients treated with monthly and EOM lampalizumab was 4 per 1000 (0 to 87) and 3 per 1000 (0 to 62), respectively, based on moderate-certainty evidence. Efficacy and safety of IVT pegcetacoplan versus sham for GA For 242 participants in one study, pegcetacoplan probably did not meaningfully change BCVA given monthly (+1.05 letters, 95% CI -2.71 to 4.81) or EOM (-1.42 letters, 95% CI -5.25 to 2.41), as supported by moderate-certainty evidence. In contrast, for 1208 participants across three studies, pegcetacoplan meaningfully reduced GA lesion growth when given monthly (-0.38 mm², 95% CI -0.57 to -0.19) and EOM (-0.29 mm², 95% CI -0.44 to -0.13), with high certainty. These reductions correspond to 19.2% and 14.8% versus sham, respectively. A post hoc analysis showed possibly greater benefits in 446 participants with extrafoveal GA given monthly (-0.67 mm², 95% CI -0.98 to -0.36) and EOM (-0.60 mm², 95% CI -0.91 to -0.30), representing 26.1% and 23.3% reductions, respectively. However, we did not have data on subfoveal GA growth to undertake a formal subgroup analysis. In 1502 participants, there is low-certainty evidence that pegcetacoplan may have increased MNV risk when given monthly (RR 4.47, 95% CI 0.41 to 48.98) or EOM (RR 2.29, 95% CI 0.46 to 11.35). The incidence of endophthalmitis in patients treated with monthly and EOM pegcetacoplan was 6 per 1000 (1 to 53) and 8 per 1000 (1 to 70) respectively, based on moderate-certainty evidence. Efficacy and safety of IVT avacincaptad pegol versus sham for GA In a study of 260 participants with extrafoveal or juxtafoveal GA, monthly avacincaptad pegol probably did not result in a clinically meaningful change in BCVA at 2 mg (+1.39 letters, 95% CI -5.89 to 8.67) or 4 mg (-0.28 letters, 95% CI -8.74 to 8.18), based on moderate-certainty evidence. Despite this, the drug was still found to have probably reduced GA lesion growth, with estimates of 30.5% reduction at 2 mg (-0.70 mm², 95% CI -1.99 to 0.59) and 25.6% reduction at 4 mg (-0.71 mm², 95% CI -1.92 to 0.51), based on moderate-certainty evidence. Avacincaptad pegol may have also increased the risk of developing MNV (RR 3.13, 95% CI 0.93 to 10.55), although this evidence is of low certainty. There were no cases of endophthalmitis reported in this study.

Authors' conclusions: Despite confirmation of the negative findings of intravitreal lampalizumab across all endpoints, local complement inhibition with intravitreal pegcetacoplan meaningfully reduces GA lesion growth relative to sham at one year. Inhibition of complement C5 with intravitreal avacincaptad pegol is also an emerging therapy with probable benefits on anatomical endpoints in the extrafoveal or juxtafoveal GA population. However, there is currently no evidence that complement inhibition with any agent improves functional endpoints in advanced AMD; further results from the phase 3 studies of pegcetacoplan and avacincaptad pegol are eagerly awaited. Progression to MNV or exudative AMD is a possible emergent adverse event of complement inhibition, requiring careful consideration should these agents be used clinically. Intravitreal administration of complement inhibitors is probably associated with a small risk of endophthalmitis, which may be higher than that of other intravitreal therapies. Further research is likely to have an important impact on our confidence in the estimates of adverse effects and may change these. The optimal dosing regimens, treatment duration, and cost-effectiveness of such therapies are yet to be established.

Trial registration: ClinicalTrials.gov NCT02686658 NCT02515942 NCT00935883 NCT01229215 NCT02247479 NCT02247531 NCT01527500 NCT02503332 NCT03525600 NCT03525613 NCT03815825 NCT04435366 NCT04437368 NCT04465955 NCT04566445 NCT04643886 NCT04656561 NCT05019521 NCT05230537.

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Conflict of interest statement

This research did not receive any specific grant from funding agencies in the public, commercial or not‐for‐profit sectors. Nikolaos Tzoumas: no disclosures. George Riding: no disclosures. Michael A Williams: support to attend meetings from Novartis and Bayer Pharmaceuticals, ad hoc speaker for AbbVie, Novartis and Bayer Pharmaceuticals, education grant received from Bayer Pharmaceuticals. David HW Steel: Alcon (C, F), Bayer Pharmaceuticals (F), Boehringer Ingelheim (F), BVI Medical (C), Dutch Ophthalmic Research Centre [DORC] (C, F), Gyroscope Therapeutics (C), Roche (C). The financial relationships of the authors did not influence the collection, analysis or interpretation of data, the writing of the report, or the decision to submit the article for publication.

Figures

1
1
2
2
Review authors' judgements about each risk of bias domain across included studies.
3
3
Review authors' judgements about each risk of bias domain for each included study.
1.1
1.1. Analysis
Comparison 1: Efficacy and safety of IVT lampalizumab 4‐weekly versus sham for geographic atrophy (GA), Outcome 1: BCVA change at 1 year
1.2
1.2. Analysis
Comparison 1: Efficacy and safety of IVT lampalizumab 4‐weekly versus sham for geographic atrophy (GA), Outcome 2: GA lesion size change at 1 year (mm2)
1.3
1.3. Analysis
Comparison 1: Efficacy and safety of IVT lampalizumab 4‐weekly versus sham for geographic atrophy (GA), Outcome 3: Safety: Development of MNV or exudative AMD at 1 year
1.4
1.4. Analysis
Comparison 1: Efficacy and safety of IVT lampalizumab 4‐weekly versus sham for geographic atrophy (GA), Outcome 4: Safety: Development of endophthalmitis at 1 year
2.1
2.1. Analysis
Comparison 2: Efficacy and safety of IVT lampalizumab 6‐ to 8‐weekly versus sham for geographic atrophy (GA), Outcome 1: BCVA change at 1 year
2.2
2.2. Analysis
Comparison 2: Efficacy and safety of IVT lampalizumab 6‐ to 8‐weekly versus sham for geographic atrophy (GA), Outcome 2: GA lesion size change at 1 year (mm2)
2.3
2.3. Analysis
Comparison 2: Efficacy and safety of IVT lampalizumab 6‐ to 8‐weekly versus sham for geographic atrophy (GA), Outcome 3: Safety: Development of MNV or exudative AMD at 1 year
2.4
2.4. Analysis
Comparison 2: Efficacy and safety of IVT lampalizumab 6‐ to 8‐weekly versus sham for geographic atrophy (GA), Outcome 4: Safety: Development of endophthalmitis at 1 year
3.1
3.1. Analysis
Comparison 3: Efficacy and safety of IVT pegcetacoplan 4‐weekly versus sham for geographic atrophy (GA), Outcome 1: GA lesion size change at 1 year (mm2)
3.2
3.2. Analysis
Comparison 3: Efficacy and safety of IVT pegcetacoplan 4‐weekly versus sham for geographic atrophy (GA), Outcome 2: Extrafoveal GA lesion size change at 1 year (mm2)
3.3
3.3. Analysis
Comparison 3: Efficacy and safety of IVT pegcetacoplan 4‐weekly versus sham for geographic atrophy (GA), Outcome 3: Safety: Development of MNV or exudative AMD at 1 year
3.4
3.4. Analysis
Comparison 3: Efficacy and safety of IVT pegcetacoplan 4‐weekly versus sham for geographic atrophy (GA), Outcome 4: Development of endophthalmitis at 1 year
4.1
4.1. Analysis
Comparison 4: Efficacy and safety of IVT pegcetacoplan 8‐weekly versus sham for geographic atrophy (GA), Outcome 1: GA lesion size change at 1 year (mm2)
4.2
4.2. Analysis
Comparison 4: Efficacy and safety of IVT pegcetacoplan 8‐weekly versus sham for geographic atrophy (GA), Outcome 2: Extrafoveal GA lesion size change at 1 year (mm2)
4.3
4.3. Analysis
Comparison 4: Efficacy and safety of IVT pegcetacoplan 8‐weekly versus sham for geographic atrophy (GA), Outcome 3: Safety: Development of MNV or exudative AMD at 1 year
4.4
4.4. Analysis
Comparison 4: Efficacy and safety of IVT pegcetacoplan 8‐weekly versus sham for geographic atrophy (GA), Outcome 4: Development of endophthalmitis at 1 year
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References

References to studies included in this review

Avacincaptad pegol Phase 2/3 (GATHER1) {published data only (unpublished sought but not used)}
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CLG561 ± LFG316 Phase 2 {unpublished data only}
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Eculizumab Phase 2 (COMPLETE) {published data only}
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Lampalizumab Phase 2 (MAHALO) {published data only (unpublished sought but not used)}
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Lampalizumab Phase 3 (CHROMA) {published data only (unpublished sought but not used)}
    1. Heier JS, Pieramici D, Chakravarthy U, Patel SS, Gupta S, Lotery A, et al. Visual function decline resulting from geographic atrophy: results from the Chroma and Spectri phase 3 trials. Ophthalmology Retina 2020;4(7):673-88. - PubMed
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    1. NCT02745119. Long-term safety of lampalizumab intravitreal (ITV) injections in participants with geographic atrophy (GA) secondary to age-related macular degeneration (OMASPECT). clinicaltrials.gov/ct2/show/NCT02745119 (first received 20 April 2016).
    1. Pieramici D, Holz F, Heier JS, Sadda SR, Busbee BG, Chew EY, et al. Lampalizumab for geographic atrophy (GA) in age-related macular degeneration (AMD): pooled results of the Chroma and Spectri phase 3 randomized clinical trials (RCTs). Investigative Ophthalmology and Visual Science 2018;59(9):ARVO E-abstract 4948.
Lampalizumab Phase 3 (SPECTRI) {published data only}
    1. Heier JS, Pieramici D, Chakravarthy U, Patel SS, Gupta S, Lotery A, et al. Visual function decline resulting from geographic atrophy: results from the Chroma and Spectri phase 3 trials. Ophthalmology Retina 2020;4(7):673-88. - PubMed
    1. Holz FG, Sadda SR, Busbee B, Chew EY, Mitchell P, Tufail A, et al. Efficacy and safety of lampalizumab for geographic atrophy due to age-related macular degeneration: Chroma and Spectri phase 3 randomized clinical trials. JAMA Ophthalmology 2018;136(6):666-77. - PMC - PubMed
    1. NCT02745119. Long-term safety of lampalizumab intravitreal (ITV) injections in participants with geographic atrophy (GA) secondary to age-related macular degeneration (OMASPECT) . clinicaltrials.gov/ct2/show/NCT02745119 (first received 20 April 2016).
    1. Pieramici D, Holz F, Heier JS, Sadda SR, Busbee BG, Chew EY, et al. Lampalizumab for geographic atrophy (GA) in age-related macular degeneration (AMD): pooled results of the Chroma and Spectri phase 3 randomized clinical trials (RCTs). Investigative Ophthalmology and Visual Science 2018;59(9):ARVO E-abstract 4948.
LFG316 Phase 2 {unpublished data only}
    1. NCT01527500. Intravitreal LFG316 in patients with age-related macular degeneration (AMD). clinicaltrials.gov/ct2/show/record/NCT01527500 (first received 27 July 2018).
Pegcetacoplan Phase 2 (FILLY) {published and unpublished data}10.1016/j.ophtha.2019.07.011
    1. Bogunovic H, Lachinov D, Mai J, Reiter GS, Riedl S, Vogl WD, et al. Predictive identification of the fastest progressing geographic atrophy lesions based on deep learning in the phase 2 FILLY clinical trial of pegcetacoplan. Investigative Ophthalmology and Visual Science 2021;62(8):ARVO E-abstract 129.
    1. Chakravarthy U, Ip M, Nittala M, Metlapally R, Ribiero R, Sadda S. Impact of pegcetacoplan on progression of nascent atrophy in age-related macular degeneration (AMD). Investigative Ophthalmology and Visual Science 2021;62(8):ARVO E-abstract 1213.
    1. Liao DS, Grossi FV, El Mehdi D, Gerber MR, Brown DM, Heier JS, et al. Complement C3 inhibitor pegcetacoplan for geographic atrophy secondary to age-related macular degeneration: a randomized phase 2 trial. Ophthalmology 2020;127(2):186-95. - PubMed
    1. Liao DS, Metapally R, Joshi P. Pegcetacoplan treatment for geographic atrophy due to age-related macular degeneration: a plain language summary of the FILLY study. Immunotherapy 2022;14(13):995-1006. - PubMed
    1. Nittala MG, Metlapally R, Ip M, Chakravarthy U, Holz FG, Staurenghi G, et al. Association of pegcetacoplan with progression of incomplete retinal pigment epithelium and outer retinal atrophy in age-related macular degeneration: a post hoc analysis of the FILLY randomized clinical trial. JAMA Ophthalmology 2022;140(3):243-9. - PMC - PubMed
Pegcetacoplan Phase 3 (DERBY) {published and unpublished data}
    1. Goldberg R, Heier JS, Wykoff CC, Staurenghi G, Singh RP, Steinle N, et al. Efficacy of intravitreal pegcetacoplan in patients with geographic atrophy (GA): 12-month results from the phase 3 OAKS and DERBY studies. Investigative Ophthalmology and Visual Science 2022;63(7):ARVO E-abstract 1500.
    1. Wykoff CC. Treatment of geographic atrophy secondary to age-related macular degeneration with pegcetacoplan: updates on the randomized phase 3 DERBY and OAKS trials. American Academy of Ophthalmology Annual Meeting, New Orleans, LA, United States 2021.
Pegcetacoplan Phase 3 (OAKS) {published and unpublished data}
    1. Goldberg R, Heier JS, Wykoff CC, Staurenghi G, Singh RP, Steinle N, et al. Efficacy of intravitreal pegcetacoplan in patients with geographic atrophy (GA): 12-month results from the phase 3 OAKS and DERBY studies. Investigative Ophthalmology and Visual Science 2022;63(7):ARVO E-abstract 1500.
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References to studies excluded from this review

NCT01157065 {published data only}
    1. NCT01157065. Evaluation of AL-78898A in exudative age-related macular degeneration (RACE). clinicaltrials.gov/ct2/show/NCT01157065 (first received 5 July 2010).
NCT01624636 {published data only}
    1. NCT01624636. Safety and tolerability of intravenous LFG316 in wet age-related macular degeneration (AMD). clinicaltrials.gov/ct2/show/NCT01624636 (first received 21 June 2012).
NCT03362190 {published data only}
    1. NCT03362190. ZIMURA in combination with LUCENTIS in patients with neovascular age related macular degeneration (NVAMD). clinicaltrials.gov/ct2/show/NCT03362190 (first received 5 December 2017).
NCT03446144 {published data only}
    1. NCT03446144. Safety and efficacy of IONIS-FB-Lrx in up to 120 patients 55 and older with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). clinicaltrials.gov/ct2/show/NCT03446144 (first received 26 February 2018).

References to ongoing studies

NCT03815825 {published data only}
    1. NCT03815825. GOLDEN STUDY: a study to assess safety and efficacy of multiple doses of IONIS-FB-LRx in participants with geographic atrophy secondary to age-related macular degeneration (AMD). clinicaltrials.gov/ct2/show/NCT03815825 (first received 24 January 2019).
NCT04435366 {published data only}
    1. NCT04435366. A phase 3 safety and efficacy study of intravitreal administration of zimura (complement C5 inhibitor). clinicaltrials.gov/ct2/show/NCT04435366 (first received 17 June 2020).
NCT04437368 {published data only}
    1. NCT04437368. EXPLORE: a phase II study to evaluate the safety and efficacy of two doses of GT005 (EXPLORE). clinicaltrials.gov/ct2/show/NCT04437368 (first received 18 June 2020).
NCT04465955 {published data only}
    1. NCT04465955. A study of NGM621 in participants with geographic atrophy (CATALINA). clinicaltrials.gov/ct2/show/NCT04465955 (first received 10 July 2020).
NCT04566445 {published data only}
    1. NCT04566445. HORIZON: a phase II study to evaluate the safety and efficacy of two doses of GT005. clinicaltrials.gov/ct2/show/NCT04566445 (first received 28 September 2020).
NCT04643886 {published data only}
    1. NCT04643886. A multiple dose study of repeat intravitreal injections of GEM103 in dry age-related macular degeneration. clinicaltrials.gov/ct2/show/NCT04643886 (first received 25 November 2020).
NCT04656561 {published data only}
    1. NCT04656561. A study investigating the efficacy and safety of intravitreal injections of ANX007 in patients with geographic atrophy (ARCHER). clinicaltrials.gov/ct2/show/NCT04656561 (first received 7 December 2020).
NCT04820452 {published data only}
    1. NCT04820452. A study of IBI302 in patients with nAMD. clinicaltrials.gov/ct2/show/NCT04820452 (first received 29 March 2021).
NCT05019521 {published data only}
    1. NCT05019521. A study of danicopan in participants with geographic atrophy secondary to age-related macular degeneration. clinicaltrials.gov/ct2/show/NCT05019521 (first received 25 August 2021).
NCT05230537 {published data only}
    1. NCT05230537. A masked, placebo-controlled study to assess iptacopan in age-related macular degeneration. clinicaltrials.gov/ct2/show/NCT05230537 (first received 9 February 2022).

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