First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Oral Complement Factor D Inhibitor BCX9930 in Healthy Participants

Abstract

BCX9930 is a potent, selective oral inhibitor of complement Factor D that inhibits the activation of the complement alternative pathway (AP) and has the potential for treatment of complement-mediated diseases. This was a first-in-human, randomized, double-blind, placebo-controlled study that evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of BCX9930 in healthy participants. Safety and tolerability were evaluated via clinical and laboratory monitoring. Plasma concentrations of BCX9930 were measured using validated liquid chromatography-dual mass spectrometry; PD effects were assessed via multiple assays. Participants were enrolled into seven single dose cohorts (10-2000 mg) and eight multiple-dose cohorts (50-500 mg every 12 h [Q12h] and 1000-2000 mg every 24 h [Q24h]). Enrollment comprised 152 participants (122 received BCX9930 and 30 received placebo). Following BCX9930 administration, plasma exposure was approximately dose proportional across all doses. The effective half-life (t_1/2) ranged from 6.45 to 7.75 h for Q12h doses at steady state. Clearance and times to maximum concentration (T_max) were similar across all doses studied, without evidence of dose- or time-dependent clearance. BCX9930 administration resulted in rapid, potent, and dose-dependent AP inhibition. Doses ≥200 mg Q12h and ≥1000 mg Q24h achieved maximal suppression (>98% relative to baseline levels) of AP activity over the full dosing interval. No clinically significant dose-related trends in adverse events (AEs), laboratory values, vital signs, or electrocardiograms were noted. BCX9930 was safe and generally well tolerated in this first-in-human study and displayed highly favorable PK and PD profiles. These results support Factor D inhibition as a promising strategy for treatment of complement-mediated diseases.