A phase ia dose-escalation study of the anti-factor D monoclonal antibody fragment FCFD4514S in patients with geographic atrophy.

PURPOSE: Multicenter, open-label, single-dose, dose-escalation Phase Ia study to determine the safety, tolerability, maximum tolerated dose, and immunogenicity of FCFD4514S, an antigen-binding fragment from a humanized monoclonal antibody directed against complement factor D, in patients with geographic atrophy. METHODS: Eighteen patients with geographic atrophy (lesion size: ≥ 0.75 disk areas; best-corrected visual acuity: 20/125-20/400 Snellen equivalent) were sequentially enrolled and received 1 of 6 escalating doses of intravitreal FCFD4514S subject to dose-limiting toxicity criteria. Follow-up assessments (clinical examination, best-corrected visual acuity, intraocular pressure) were conducted at postadministration Days 1, 3, 7, 14, 30, 60, and 90. Serum pharmacokinetics, immunogenicity, and complement activity were also evaluated. RESULTS: All patients completed the study with no reported FCFD4514S-related dose-limiting toxicities or ocular or systemic adverse events. The maximum tolerated dose for this study was 10 mg, the highest dose tested. No antitherapeutic antibody response or adverse effects on systemic complement activity were observed. Time to maximum serum concentration was 1 day to 3 days postdosing; serum terminal half-life was 5.9 days. CONCLUSION: Single-dose intravitreal FCFD4514S administrations were safe and well tolerated and not associated with any study drug-related ocular or systemic adverse events. These data support a multidose safety and tolerability assessment of FCFD4514S in geographic atrophy.

Targeting factor D of the alternative complement pathway reduces geographic atrophy progression secondary to age-related macular degeneration.

Geographic atrophy is an advanced form of age-related macular degeneration (AMD) and a leading cause of vision loss for which there are no approved treatments. Genetic studies in AMD patients have implicated dysregulation of the alternative complement pathway in the pathogenesis of geographic atrophy. Lampalizumab is a potential therapeutic that targets complement factor D, a pivotal activator of the alternative complement pathway. The MAHALO phase 2 clinical trial was a multicenter, randomized, controlled study that evaluated lampalizumab administered by intravitreal injection monthly (n = 42) and every other month (n = 41) versus sham control (n = 40) in patients with geographic atrophy secondary to AMD. The primary endpoint was the mean change in lesion area from baseline to month 18 as measured by fundus autofluorescence. Specific AMD-associated genetic polymorphisms were also analyzed. The MAHALO study met its primary efficacy endpoint with an acceptable safety profile; monthly lampalizumab treatment demonstrated a 20% reduction in lesion area progression versus sham control [80% confidence interval (CI), 4 to 37%]. A more substantial monthly treatment benefit of 44% reduction in geographic atrophy area progression versus sham control (95% CI, 15 to 73%) was observed in a subgroup of complement factor I (CFI) risk-allele carriers (57% of the patients analyzed were CFI risk-allele carriers). The MAHALO study shows a potential treatment effect in patients with geographic atrophy and supports therapeutic targeting of the alternative complement pathway for treating AMD pathogenesis.