029: Multiple-ascending Dose Study With ACT-1014-6470, an Oral Complement Factor 5a Receptor 1 Antagonist, Demonstrated Target Engagement by Ex Vivo Matrix Metalloproteinase 9 Stimulation

Statement of Purpose: In a variety of inflammatory diseases such as atypical hemolytic uremic syndrome, lupus nephritis, or immunoglobulin A nephropathy, aberrant complement activation promotes tissue damage. Multiple-ascending doses (MAD) of ACT-1014-6470, an orally available, potent, selective complement factor 5a receptor 1 (C5aR1) antagonist, were investigated for safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD).

Description of Methods & Materials: This was a double-blind, placebo-controlled, randomized MAD study. In three dose levels (30–60–120 mg), ACT-1014-6470 was administered twice daily under fed conditions for 4.5 days to 10 healthy male and female subjects per dose level (8 on active, 2 on placebo, 1:1 ratio male to female). Blood samples for PK and safety assessments (adverse events [AEs], clinical laboratory, vital signs, 12-lead ECG) were performed regularly until 120 h post last dose and, at the 60 mg dose level, up to 8 weeks post last dose. In PD plasma samples, matrix metalloproteinase 9 (MMP-9), a protein released by neutrophils upon C5aR1 stimulation, was determined after ex vivo stimulation with C5a. PK parameters of ACT-1014-6470 were determined by non-compartmental analysis.

Data & Results: The shape of the ACT-1014-6470 PK profile was comparable after the first administration on Day 1 and the last administration on Day 5. Median time to maximum plasma concentrations was 2–3 h on both days. Most subjects attained steady state between Day 3 and Day 5. Exposure increased by 1.8- to 2.2-fold from the first to the last dose across dose levels and was dose-proportional. After a short distribution phase, the terminal elimination phase was slow with a geometric mean terminal half-life of 115–146 h. At the 60 mg dose level, ACT-1014-6470 was quantifiable beyond 120 h post last dose at concentrations corresponding to 0.5–1.1% of individual maximum plasma concentrations at steady state. Pre-dose MMP-9 concentrations were comparable between subjects on active treatment and on placebo and, in the latter, remained constant over the course of the study. For subjects on ACT-1014-6470, post-dose MMP-9 concentrations decreased to background levels across the entire sampling period, confirming target engagement of ACT-1014-6470. No serious or severe AEs occurred and all subjects completed the study. Seventeen subjects (57%) reported a total of 57 AEs, 49 of them after ACT-1014-6470 and 8 after placebo administration. The majority of AEs was mild, while all 10 moderate AEs were reported after active treatment. The most frequently reported AEs were medical device site reaction, headache, feeling hot, and hyperhidrosis. No treatment-related pattern was apparent in any safety assessment.

Interpretation, Conclusion or Significance: Sustained inhibition of C5aR1-mediated effects after multiple-dose ACT-1014-6470, together with swift attainment of steady state and its good safety and tolerability data warrant continued assessment of ACT-1014-6470 as a novel orally available treatment for inflammatory diseases.