The complement system is a central component of the immune system, predominantly functioning as a frontline defense against foreign pathogens. Beyond its role in the innate immune response, complement system byproducts also enhance activity of the adaptive (cellular) immune system while stimulating tissue repair and fibrosis (Figure 1).^1,2 A growing body of evidence has implicated complement system dysregulation in the pathogenesis of geographic atrophy (GA) secondary to age-related macular degeneration (AMD).³ Complement inhibition has therefore emerged as a promising therapeutic strategy to slow GA progression.⁴ In 2023, the US Food and Drug Administration (FDA) approved 2 novel intravitreal complement inhibitors for the treatment of GA — pegcetacoplan (Syfovre; Apellis Pharmaceuticals) and avacincaptad pegol (Izervay; Astellas Pharma) — marking the beginning of a new era of GA therapy.

The Complement System

The complement system consists of an intricate network of more than 30 proteins that collaborate to target and destroy foreign pathogens in human tissues (Figure 2).⁵ This
complex system includes plasma proteins circulating in inactive forms (“complement components,” eg C1-C9) along with regulatory proteins that modulate activity to prevent host tissue damage (“complement factors,” eg CFB, CFD, CFH, CFI, and CD59). Activation of the complement cascade occurs via 1 of 3 pathways: the classical pathway, triggered by antibody-antigen complexes; the lectin pathway, activated by microbial sugars; and the alternative pathway, spontaneously activated and amplified on microbial surfaces via a feedback loop. 

All 3 complement pathways converge upon the cleavage (activation) of complement component C3, resulting in downstream cleavage of C5 and ultimate formation of the membrane attack complex (MAC) on target cell membranes to induce cell lysis. Byproducts of this enzymatic process also recruit adaptive immune cells and mark pathogens for elimination. Due to its potency, the complement cascade must be tightly regulated to avoid damage to host tissues.

The Complement System in AMD

Chronic low-grade inflammation has been identified as a key driver of AMD pathogenesis and progression.⁶ In particular, molecular genetic studies have consistently shown that certain mutations in complement-regulating genes correlate with higher risk of AMD.⁷ Complement factor H (CFH) mutations, for example, have been implicated in more than half of AMD cases.⁸ Additionally, drusen — the hallmark of AMD — have been found to harbor high concentrations of complement byproducts, suggesting they may be biomarkers of localized complement-driven inflammation at the RPE-Bruch’s membrane junction.⁹ Finally, elevated levels of complement byproducts have been detected within the retinal pigment epithelium (RPE) and photoreceptor outer segments of GA-affected areas in patients with AMD.¹⁰

Inhibition of the complement system is therefore a promising strategy to slow AMD and GA progression, potentially improving visual outcomes and quality of life. In addition to 2 complement inhibitors currently on the market, several complement inhibitor therapies are under investigation (Figure 3).

Targets and Treatments: Common Pathway 

Pegcetacoplan is an intravitreal C3 inhibitor that prevents the cleavage of C3 by C3-convertase, blocking downstream complement activity across all 3 pathways to slow the growth of GA. The phase 3 trials OAKS and DERBY evaluated monthly and every-other-month (EOM) treatment regimens in patients aged ≥60 years with baseline best-corrected visual acuity (BCVA) of at least 24 ETDRS letters (approximately 20/320 Snellen equivalent) and GA areas ranging from 2.5 mm² to 17.5 mm². Pegcetacoplan was found to slow GA growth by 19% to 22% with monthly therapy and 16% to 18% with EOM therapy over 24 months, compared to sham.¹¹ Preliminary data from the ongoing phase 3 extension study GALE suggest that continued treatment may limit GA growth up to 36 months.¹² However, despite promising anatomic benefits, the OAKS and DERBY trials did not demonstrate significant differences in secondary visual function endpoints in patients treated with pegcetacoplan versus sham,¹¹ although post hoc analysis of the pooled data suggests that pegcetacoplan therapy may reduce risk of progression to severe visual impairment over 24 months.¹² The FDA approved the use of monthly or EOM pegcetacoplan for the treatment of AMD-associated GA in February 2023. 

Notably, pegcetacoplan was found to carry a dose-dependent risk of developing neovascular AMD (nAMD) in both the OAKS and DERBY trials, occurring in 11% to 13% of the monthly treatment cohorts, 6% to 8% of the EOM treatment cohorts, and 2% to 4% of the sham cohorts.^11,13 This is important, as patients with untreated GA are already at high risk of exudative conversion.^14,15 Patients with evidence of nAMD in the fellow eye appear to be at highest risk of exudation, likely due to preexisting occult macular neovascularization in the treated eye.¹³ There have also been reports of retinal vasculitis developing after first-time pegcetacoplan injections in clinical practice, although this complication was not observed in the phase 3 trials and remains exceedingly rare.¹⁶ An open-label, observational phase 4 study (GARLAND) is recruiting to assess long-term safety and tolerability of pegcetacoplan therapy in real-world practice.

Another C3 inhibitor, NGM621 (NGM Biopharmaceuticals), is a monoclonal antibody evaluated in the phase 2 CATALINA trial. Although the trial did not meet its primary endpoint and NGM621 is no longer in development, post hoc data analysis suggested significant reductions in GA growth rates of 21.9% and 16.8% with injections every 4 and 8 weeks, respectively, among a subgroup with narrower baseline GA areas than the initial inclusion criteria.¹⁷ 

Other investigational C3 inhibitors in preclinical testing include CB 2782-PEG (Catalyst Biosciences) and KNP-301 (Kanaph Therapeutics).⁴ 

Terminal Pathway

C5 is a promising complement target due to its direct role in MAC formation. Avacincaptad pegol is an intravitreal, pegylated RNA aptamer that inhibits C5 cleavage to slow the growth of GA. The phase 2/3 GATHER1 trial evaluated monthly 2 mg and 4 mg avacincaptad pegol therapy in patients aged ≥50 years with baseline BCVA 20/25 to 20/320.¹⁸ GA growth rate was reduced by 28.1% with 2 mg dosing and 30.0% with 4 mg dosing over 18 months compared to sham.¹⁹ The phase 3 GATHER2 trial further validated the efficacy of monthly avacincaptad pegol 2 mg, reporting a 14.3% reduction in mean GA growth rate over 12 months.²⁰ Although visual outcomes were not studied as primary endpoints in the GATHER trials, post hoc analysis of the pooled GATHER trial data suggests that treatment with avacincaptad pegol may reduce risk of progression to persistent vision loss over 12 months.²¹ The FDA approved the use of monthly avacincaptad pegol 2 mg for the treatment of AMD-associated GA in August 2023. 

Notably, it is important to understand that efficacy of the 2 FDA-approved therapies, avacincaptad pegol and pegcetacoplan, cannot be directly compared between trials because of different study designs. For example, the pivotal pegcetacoplan trials included eyes with subfoveal lesions, which progress more slowly than nonsubfoveal lesions, whereas the avacincaptad trials did not. 

As with pegcetacoplan, the GATHER1 and GATHER2 trials demonstrated an increase in risk of exudative transformation with avacincaptad pegol therapy, occurring in 7% to 9% of patients treated with the FDA-approved 2 mg monthly dose compared with 4% of sham.^18,20 However, avacincaptad pegol has not been associated with substantially increased risk of retinal vasculitis to date.²² A phase 3 open-label extension study is ongoing to assess the safety of monthly avacincaptad pegol through 24 months among patients from the GATHER2 trial.  

MAC inhibition is yet another therapeutic strategy for GA targeting the terminal pathway. JNJ-1887 (formerly HMR59; Janssen R&D) is a gene therapy designed to induce expression of the endogenous MAC-inhibitory protein CD59 that downregulates MAC activity. This approach aims to ease treatment burden by providing durable, continuous complement inhibition with a single dose. Following positive phase 1 safety data,²³ the drug is currently under investigation in the phase 2b PARASOL trial, with results expected by late 2025. 

Alternative Pathway

More than 80% of terminal complement activation results from alternative pathway activity, making this pathway an ideal therapeutic target. The alternative pathway is continuously activated by the spontaneous breakdown of complement component C3 into C3a and C3b fragments, which amplify the cascade through a positive feedback loop (Figure 2). Complement factors B, D, H, and I (CFB, CFD, CFH, and CFI) tightly regulate this amplification loop to prevent uncontrolled activity in host tissues. Selectively targeting the alternative pathway via these regulatory proteins can therefore significantly reduce spontaneous complement activation while preserving pathogen-activated responses mediated by the classical and lectin pathways. Moreover, as complete inhibition at the level of C3 or C5 has been shown to promote angiogenesis and retinal neovascularization in animal models,²⁴ maintaining partial C3 and C5 activity may help avoid the risk of exudation seen with drugs like pegcetacoplan and avacincaptad pegol.

CFH plays a crucial role in physiologically downregulating complement activity via the alternative pathway. Mutations reducing CFH expression have been identified as some of the strongest genetic risk factors for AMD, increasing AMD risk by up to sevenfold.^25,26 GEM103 (Gemini Therapeutics) is an intravitreally administered human recombinant CFH protein that aims to restore CFH activity. However, despite early data suggesting a favorable safety profile, a subsequent phase 2a trial (ReGatta) was terminated early due to lack of efficacy. 

More recently, a novel intravitreal sialic acid-coated nanoparticle, AVD-104 (Aviceda Therapeutics), has been developed for the treatment of GA by using a dual mechanism of action that directly inhibits cell-mediated macrophage/microglial inflammation and also activates CFH to inhibit complement-mediated inflammation.²⁷ A phase 2/3 clinical trial is currently under way (SIGLEC), with anticipated completion by mid-2025.

Another intravitreal drug, GT005 (Gyroscope Therapeutics/Novartis), aims to increase local CFH activity by inducing expression of CFI, a key cofactor for CFH in the inhibition of C3 convertase. However, a pair of phase 2 trials—HORIZON and EXPLORE—were terminated early due to interim analysis suggesting treatment futility. A follow-up study, ORACLE, is enrolling to assess long-term safety. 

CFD and CFB are essential to forming the alternative pathway’s C3-convertase. Intravitreal lampalizumab (Genentech), an anti-CFD monoclonal antibody, appeared to slow GA in the phase 2 MAHALO trial,²⁸ but subsequent phase 3 randomized clinical trials CHROMA and SPECTRI were terminated prematurely due to lack of efficacy.²⁹ A phase 3 open-label extension study (OMASPECT) was similarly terminated early due to lack of efficacy.

Danicopan (ACH-4471; Alexion Pharmaceuticals) is a small-molecule CFD inhibitor developed primarily as systemic adjunct therapy for complement-mediated paroxysmal nocturnal hemoglobinuria. Preclinical trials have demonstrated that oral administration of danicopan results in sustained high concentrations in posterior ocular tissues of animal models, suggesting potential use as a systemic therapy for GA.³⁰ Danicopan is therefore currently under investigation for the treatment of GA in a phase 2 clinical trial, with anticipated completion in late 2025. 

Another complement inhibitor, IONIS-FB-LRx (Ionis Pharmaceuticals), is a subcutaneously administered antisense oligonucleotide that suppresses systemic CFB expression by degrading its messenger RNA.³¹ The drug has recently been investigated for the treatment of GA as well as IgA nephropathy. However, although the phase 2 GOLDEN trial investigating IONIS-FB-LRx therapy for GA recently concluded with positive safety data, the data did not suggest sufficient efficacy to proceed with phase 3 development.³²

Classical Pathway 

The classical pathway is initiated when antibody-antigen complexes bind and activate the C1q subunit of the C1 complex. Pathologic C1q activity is known to drive neurodegeneration33 and AMD pathogenesis.⁴ Abnormal C1q activity may also drive monocyte-dependent retinal atrophy.¹⁰ C1q inhibition is therefore an attractive target for slowing the progression of GA. 

ANX007 (Annexon, Inc), an intravitreal monoclonal antibody targeting C1q, is currently under investigation for the treatment of GA. The phase 2 ARCHER trial evaluated monthly and EOM dosing of ANX007 in patients with GA, with a primary endpoint of change in GA lesion size and secondary endpoints including impact on visual function. Although ANX007 did not significantly reduce lesion size over 12 months,³⁴ treatment with ANX007 was associated with functional benefits, including a reduced risk of BCVA loss and protection of low-light visual function.^34,35 A phase 3 trial, ARCHER 2, is currently recruiting, and an additional phase 3 injection-controlled head-to-head comparison study against intravitreal pegcetacoplan is planned (ARROW).

Conclusion

Complement inhibition offers a promising avenue to slow the progression of GA. However, significant challenges remain, including treatment burden of long-term monthly or bimonthly intravitreal injections, and the lack of well-defined therapeutic endpoints. Risks of exudative conversion must also be balanced against anticipated benefits, requiring careful patient selection and a personalized, patient-centered approach to therapy. Further characterization of real-world clinical outcomes of untreated GA may help identify patients who stand to benefit most from therapy to slow disease progression, as well as those who are at greatest risk of exudative complications.^14,15 Continued progress in this domain holds the potential to transform GA management and improve outcomes for millions of patients worldwide. RP

Aumer Shughoury, MD, is a uveitis fellow at Northwestern University Feinberg School of Medicine. He will be continuing on to fellowship in vitreoretinal surgery at the Cincinnati Eye Institute in July of this year. He reports no relevant disclosures. Dr. Shughoury can be reached at ashughoury@gmail.com.

Thomas A. Ciulla, MD, MBA, is chief medical officer at Viridian Therapeutics, chair of the scientific advisory board at Clearside Biomedical, and has served as a consultant to Nanoscope. He is a board member of Midwest Eye Institute of Indianapolis, Indiana, and a volunteer clinical professor of ophthalmology at Indiana University School of Medicine. Dr. Ciulla reports employment by Viridian Therapeutics, and holds equity in Viridian Therapeutics, Clearside Biomedical, and Nanoscope. Dr. Ciulla can be reached at thomasciulla@gmail.com.

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