Diverse Therapies Emerge to Treat Geographic Atrophy

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Geographic atrophy (GA) is an advanced form of age-related macular degeneration that leads to progressive vision loss. Recent research has revealed the central role of complement system dysregulation, oxidative stress, and mitochondrial dysfunction in GA pathogenesis, guiding the development of novel therapeutic approaches. These include complement inhibitors, gene therapies, mitochondrial-targeted treatments, and cell-based therapies to replace damaged retinal cells. While the first two complement inhibitors, pegcetacoplan and avacincaptad pegol, have been approved, a diverse pipeline of emerging therapies aims to provide more targeted, durable, and function-preserving interventions for this debilitating condition.

Why it matters

The approval of pegcetacoplan and avacincaptad pegol represents an important milestone in the treatment of GA, a leading cause of irreversible central vision loss in older adults. However, challenges remain, including the need for chronic dosing, variable patient response, and the risk of conversion to exudative AMD. The evolving pipeline of therapies targeting specific disease mechanisms, providing long-term benefit through gene therapy, and aiming to preserve retinal function holds promise to address these limitations and improve outcomes for patients.

The details

Pegcetacoplan (Syfovre; Apellis Pharmaceuticals), an intravitreal C3 inhibitor, was the first therapy approved for GA secondary to AMD. It reduces downstream complement activation, including membrane attack complex (MAC) formation. In phase 2 and 3 trials, monthly and every-other-month dosing demonstrated modest but consistent reductions in lesion growth over 12 to 24 months, with monthly dosing associated with higher rates of conversion to exudative AMD. Avacincaptad pegol (Izervay; Astellas), an intravitreal C5 inhibitor, selectively blocks terminal complement activation. Approval was supported by the GATHER1 and GATHER2 trials, which showed reductions in lesion growth ranging from 14% to 30% depending on study and time point.

• In phase 2 and 3 trials, monthly and every-other-month dosing of pegcetacoplan demonstrated modest but consistent reductions in lesion growth over 12 to 24 months.
• The GATHER1 and GATHER2 trials, which supported the approval of avacincaptad pegol, showed reductions in lesion growth ranging from 14% to 30% depending on study and time point.

What they’re saying

What’s next

The phase 3 ARCHER II trial for vonaprument (Annexon), a monoclonal antibody targeting C1q, is expected to report top-line data in the second half of 2026. Additionally, the phase 3 ReNEW and ReGAIN trials are currently evaluating the efficacy and safety of once-daily, self-administered subcutaneous elamipretide (Stealth BioTherapeutics) in approximately 360 patients with dry AMD.