Inhibition of complement C3 in geographic atrophy with NGM621: Phase 1 study results

Abstract

Purpose : Complement dysregulation is implicated in geographic atrophy (GA). Complement component 3 (C3) is the convergence point for all three activation pathways. NGM621, a potent (K_D=0.34 nM) monoclonal antibody that inhibits C3 cleavage and blocks the complement cascade and downstream effects, is under development to reduce GA progression. The Phase 1 study (NCT04014777) evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of NGM621.

Methods : Fifteen enrolled patients had GA secondary to age-related macular degeneration in at least one eye, were ≥50 years of age, and had GA lesion area of ≥2.5 mm² and ETDRS best-corrected visual acuity (BCVA) between 54 and 4 letters in the study eye. In the single-dose cohort (n=9), intravitreal NGM621 (2, 7.5, or 15 mg) was administered to three patients per dose; in the multidose cohort (n=6), patients received two 15-mg doses 4 weeks apart. Patients were monitored and assessed for 12 weeks. Assessments included BCVA, intraocular pressure (IOP), optical coherence tomography, fundus autofluorescence, serum NGM621 concentrations, and systemic complement activity (CH₅₀).

Results : All 15 patients completed the study; 60% were men, the median age was 80.0 years (68-90), the mean (SD) GA lesion area measured 14.9 mm² (10.8), and 86.7% of lesions involved the fovea at baseline. There were no observed drug-related AEs, no SAEs or deaths, no endophthalmitis, no intraocular inflammation, and no cases of choroidal neovascularization in any eyes. The maximum evaluated dose, 15 mg, was well tolerated in the single-dose and multidose cohorts. As expected, IOP showed acute increases 15 minutes after injection, returned to normal levels within 60 minutes, and was not meaningfully impacted over time. Serum exposures appeared dose proportional, indicating linear PK in the studied range. NGM621 serum exposure was below concentrations that produce systemic complement inhibition at the highest intravitreal dose of 15 mg, and all patients were ADA negative at all time points. GA lesion area and BCVA were generally stable over the 12-week study duration.

Conclusions : In this Phase 1 dose-escalation study, NGM621 up to 15 mg was well tolerated and had a favorable PK/PD profile in patients with GA. NGM621 is being further studied in GA in the ongoing Phase 2 CATALINA study (NCT04465955).

This is a 2021 ARVO Annual Meeting abstract.