034: Novel Oral Complement Factor 5a Receptor 1 Antagonist ACT-1014-6470 for the Treatment of Rare Inflammatory Diseases: Single-ascending Dose Study Including Food Effect Assessment
Statement of Purpose: The complement cascade generates the anaphylatoxin C5a, which binds to C5aR1, comprising an important part of host defense. Abnormal complement activation or regulation of the cascade is involved in various rare inflammatory diseases. In this study, the safety, tolerability, and pharmacokinetics (PK) of single-ascending doses (SAD) of ACT-1014-6470, a novel, orally available, potent, selective novel oral complement factor 5a receptor 1 (C5aR1) antagonist, were investigated in humans for the first time.
Description of Methods & Materials: In this double-blind, placebo-controlled, randomized SAD study, six ACT-1014-6470 dose levels (0.5–200 mg) were studied sequentially in 8 healthy male subjects per dose level (6 on active, 2 on placebo). After screening for eligibility, subjects were dosed in the morning of Day 1 under fed conditions. PK blood sampling and safety assessments (adverse events [AEs], clinical laboratory, vital signs, 12-lead ECG) were performed regularly over 72 h post-dose. At the 10 mg dose level, a two-period crossover part was conducted to assess the effect of food on the PK of ACT-1014-6470. Subjects returned to the study site 4 weeks after the first administration to receive a second dose under fasted conditions. PK parameters of ACT-1014-6470 were determined by non-compartmental analysis.
Data & Results: Under fed conditions, ACT-1014-6470 was absorbed with a median time to maximum plasma concentrations (tmax) of 2.5–3.5 h, while the geometric mean terminal half-life (t½) was 10 h at the lowest dose and 30–46 h at doses ≥ 2.5 mg. According to a power analysis, the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from zero to infinity (AUC0–∞) increased slightly more than dose-proportionally. Geometric mean ratios (90% confidence intervals [CI]) of fed vs fasted Cmax, AUC0–∞, and t½ were 1.7 (1.5–1.9), 2.2 (1.9–2.5), and 0.7 (0.6–0.7), respectively. Under fed conditions, tmax was delayed with a median difference (90% CI) to fasted conditions of 1.5 h (0.8–3.0 h). All subjects completed the study, and no serious or severe AEs occurred. In total, 46 AEs were reported by 18 subjects (38%) with a comparable incidence between ACT-1014-6470 and placebo. Neither the number of subjects affected by AEs nor the total number of AEs showed dose‑dependency. Under active treatment and placebo, 33 and 10 AEs were of mild and 1 and 2 of moderate intensity, respectively. The most frequently reported AEs were vessel puncture site hematoma, nausea, and dyspepsia. No clinically relevant findings or changes from baseline in clinical laboratory, vital signs, ECG variables, or physical examination were observed.
Interpretation, Conclusion or Significance: Almost dose-proportional exposure, improved absorption under fed conditions, and the good safety and tolerability profile at all assessed dose levels support further clinical development of ACT-1014-6470, which could provide a novel treatment option for inflammatory diseases with aberrant complement activation, comprising a more patient-friendly route of administration compared to biological complement inhibitors.
