Complement inhibition for the treatment of non-neovascular (dry) AMD

This piece was written by my research team and approved by Dr Leo Sheck.

Note: avacincaptad pegol (Zimura, IVERIC bio Inc, New York, NY) has also been approved by FDA in the United States for the treatment of geographic atrophy since August 2023.

Geographic atrophy (GA), a late-stage form of non-neovascular age-related macular degeneration (AMD), is characterised by progressive loss of retinal pigment epithelium and photoreceptors leading to vision loss. Up until February 2023, it was untreatable.

The pivotal FDA approval of intravitreal pegcetacoplan injection (Syfovre; Apellis Pharmaceuticals, Inc) marked the introduction of the first commercially available treatment for GA secondary to AMD, and finally addressed the longstanding dichotomy between treatable neovascular AMD and untreatable GA in non-neovascular/dry AMD. To date, intravitreal pegcetacoplan is not yet approved in New Zealand or Australia.

Pegcetacoplan is a pegylated, highly specific C3 inhibitor that targets the complement cascade of the innate immune system, the activation of which has been associated with GA pathogenesis. Three activation pathways are involved in the complement cascade – classic, lectin and alternative – and all three converge at C3, making C3 a potent therapeutic target.

As a C3 inhibitor, pegcetacoplan inhibits C3 convertase, preventing cleavage of C3 into C3a and C3b and inhibiting downstream effects of inflammation, opsonisation and, ultimately, the formation of membrane attack complex, potentially slowing GA progression.

Pegcetacoplan efficacy was assessed in a Phase 2 (FILLY) and two pivotal Phase 3 (OAKS and DERBY) trials.

FILLY (NCT02503332)

FILLY was a 246-patient, Phase 2, multicentre, randomised, single-masked, sham-controlled clinical trial that evaluated pegcetacoplan in patients with GA secondary to AMD across 40 sites in the United States, Australia and New Zealand. 

Patients received an intravitreal injection of pegcetacoplan monthly or every other month (EOM) for 12 months, with 6 months post-treatment follow-up. The primary efficacy endpoint was the change in GA lesion area from baseline to Month 12 in pegcetacoplan-treated patients compared to sham. 

In patients receiving pegcetacoplan monthly or EOM, the GA growth rate was reduced by 29% and 20%, respectively, compared with the sham treatment group. Post-hoc analysis showed a more pronounced effect in the second 6 months of treatment with reductions of 45% (P=0.0004) and 33% (P=0.009) for pegcetacoplan monthly and EOM, respectively. At 12 months, disappointingly, pegcetacoplan had no effect on foveal encroachment, visual acuity assessments, or low-luminance visual acuity deficit (LL-VD) when compared to sham treatment.

A post-hoc analysis of the FILLY trial assessed progression from incomplete retinal pigment epithelial (RPE) and outer retinal atrophy (iRORA), also known as nascent GA, to complete RPE and outer retina atrophy (cRORA or GA). At 12 months, treatment with pegcetacoplan monthly or EOM resulted in a 39% and 26% reduction in the risk of progression to cRORA, respectively, suggesting a potential role for pegcetacoplan therapy earlier in the progression of AMD, prior to the development of GA.

OAKS (NCT03525613) and DERBY (NCT03525600)

OAKS and DERBY were parallel Phase III, multicentre, double-masked, randomised sham-controlled trials evaluating the efficacy and safety of monthly and EOM intravitreal pegcetacoplan in reducing progression of GA secondary to AMD.

The studies enrolled 637 and 621 patients, respectively, aged ≥60 years, with best-corrected visual acuity ≥24 letters, and GA area between 2.5 and 17.5 mm², including foveal and extrafoveal lesions. The primary endpoint for both studies was change in GA lesion size from baseline measured by fundus autofluorescence. Safety measures included incidences of ocular and systemic adverse events. 

Treatment with pegcetacoplan intravitreal injection monthly or EOM resulted in a reduction of GA lesion growth versus sham at Month 24 across both studies (OAKS: 22% monthly, P<0.0001; 18% EOM, P=0.0003; DERBY: 18% monthly, P=0.0006; 17% EOM, P=0.0010). 

Encouragingly, the effect of the treatment appeared to increase over time. However, while reductions were observed in GA lesion growth, these did not translate into clinically meaningful improvements in measures of visual function (including best-corrected visual acuity [BCVA] and microperimetry [OAKS only]) so it remains to be seen whether pegcetacoplan will reduce rates of vision loss and quality of life decline. The ongoing long-term GALE extension study (NCT04770545) may shed further light on this.

Across both trials, pegcetacoplan was well tolerated over 24 months, with most ocular study eye adverse events being mild to moderate. The most common adverse events (incidence ≥5%) were ocular discomfort, new onset neovascular AMD (nAMD), vitreous floaters and conjunctival haemorrhage. 

A few words of caution

Higher rates of new onset neovascular AMD were seen in the treated eyes of patients receiving pegcetacoplan compared to patients in the control group, which appeared to be dose dependent. By Month 24, rates of new onset nAMD in the study eye were 12.2% for pegcetacoplan monthly, 6.7% for pegcetacoplan EOM and 3.1% in the control group (OAKS and DERBY combined). Almost all participants who developed nAMD continued treatment with pegcetacoplan and were also treated with anti-VEGF, adding to the lifelong treatment burden for patients.

More recently (July 2023), the American Society of Retina Specialists (ASRS) Research and Safety in Therapeutics (ReST) Committee notified its members of rare cases of mild, moderate, and severe intraocular inflammation after the initial injection of pegcetacoplan, as well as cases of retinal vasculitis. Further review of OAK and DERBY study data and imagery found no reported cases of retinitis or vasculitis (occlusive or nonocclusive). The outcomes of these real-world cases are continuing to be monitored.

GATHER1 (NCT02686658)

Inhibition of complement C5 by avacincaptad pegol (Zimura, IVERIC bio Inc, New York, NY) intravitreal injection in the GATHER1 study further supports the role of targeted complement inhibition therapies for the treatment of GA secondary to AMD. In GATHER1, a significant reduction of GA growth in eyes with AMD was observed over a 12 month period. Interestingly, the treatment effect occurred as early as Month 6, which was earlier than seen with C3 inhibitors. This may be due to downstream inhibition of the complement cascade at the C5 level. The authors also hypothesised that C5 inhibition theoretically preserves C3 activity, and  may offer additional safety advantages. A confirmatory pivotal phase 3 clinical trial, GATHER2 (NCT04435366) is underway to confirm these initial findings. I await the results with interest!

Future perspectives

Complement factor H (CFH) gene polymorphisms are strongly associated with the development of AMD and may influence treatment outcomes. This offers the potential for a personalised treatment approach where treatment could be specifically targeted at populations with predominantly complement-driven disease. Further research is required to determine feasibility. Dr Sheck has been in discussion with international experts on the possibility of starting an investigator initiated trial once pegcetacoplan is approved for use in New Zealand.

A final recommendation

Based on the research thus far, my recommendation would be to reserve the use of pegcetacoplan for patients with paracentral atrophy that is threatening central vision. I have previously discussed advanced phenotyping of geographic atrophy on my blog over a three part series. Pegcetacoplan may be a suitable treatment option until an alternative agent becomes available.

About Dr Leo Sheck

Dr Sheck is a RANZCO-qualified, internationally trained ophthalmologist. He combined his initial training in New Zealand with a two-year advanced fellowship in Moorfield Eye Hospital, London. He also holds a Doctorate in Ocular Genetics from the University of Auckland and a Master of Business Administration from the University of Cambridge. He specialises in medical retina diseases (injection therapy), cataract surgery, ocular genetics, uveitis and electrodiagnostics.