152: Inhibition of the Complement Alternative Pathway in Healthy Subjects by an Oral Factor D Inhibitor

Statement of Purpose: Factor D, the rate-limiting enzyme of the complement alternative pathway (AP), is an attractive drug target for complement-mediated diseases such as immunoglobulin A nephropathy, paroxysmal nocturnal hemoglobinuria and C3 glomerulopathy. This abstract describes results from the completed first-in-human study for BCX9930, a potent and selective orally bioavailable Factor D inhibitor. This was a first-in-human randomized, double-blind, placebo-controlled evaluation of the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of oral BCX9930 in healthy subjects.

Description of Methods & Materials: Safety and tolerability were evaluated via clinical and laboratory monitoring. Plasma concentrations of BCX9930 were measured using a validated liquid chromatography-dual mass spectrometry assay; PD effects were assessed using multiple assays, including the AP specific Wieslab assay.

Data & Results: A total of 56 subjects (n=6 BCX9930 per cohort, n=2 placebo per cohort) were enrolled into 7 single ascending dose (SAD) cohorts, with doses ranging from 10 to 2,000 mg. A total of 96 subjects (n=10 BCX9930 per cohort, n=2 placebo per cohort) were enrolled into 8 multiple ascending dose (MAD) cohorts, with doses ranging from 50 to 500 mg every 12 hours (Q12h), and 1,000 to 2,000 mg every 24 hours (Q24h). The mean age of all enrolled subjects was 34.9 years and 52.0% were male. BCX9930 was safe and generally well tolerated at all SAD and MAD dose levels. In the SAD evaluation, 32% (18/56) of subjects reported a treatment-emergent adverse event (TEAE); all were mild. In the MAD evaluation, 59% (57/96) of subjects reported a TEAE; of these, most (37/57; 65%) reported only mild event(s). No serious adverse events, treatment-related grade 3 or 4 events, or clinically relevant laboratory abnormalities were reported. Following BCX9930 administration, exposure was approximately linear and dose proportional across all evaluated doses. The onset of AP suppression as observed in the AP Wieslab assay was rapid, occurring ≤1 hour after a single dose. Suppression >98% relative to predose levels was achieved following SAD doses ≥100 mg and for all MAD doses. The duration of suppression was dose dependent, with >98% suppression observed prior to and for at least 1 dosing interval following the last dose at steady state for MAD doses ≥200 mg Q12h and ≥1,000 mg Q24h.

Interpretation, Conclusion or Significance: BCX9930 was safe and generally well tolerated following SAD and MAD in healthy subjects, with no serious adverse events or safety signals across the dose range. BCX9930 administration resulted in predictable plasma exposure across the evaluated dose range and exhibited rapid, potent, and dose-dependent inhibition of AP activity. Doses ≥200 mg Q12h and ≥1,000 mg Q24h achieved >98% suppression of AP activity throughout the dosing interval. These results support Factor D inhibition as a promising strategy for treatment of complement-mediated diseases.

Disclosures: All authors are employees of BioCryst Pharmaceuticals, Inc.