Multiple-ascending doses of ACT-1014-6470, an oral complement factor 5a receptor 1 (C5a1 receptor) antagonist: Tolerability, pharmacokinetics and target engagement.

Abstract

Targeting the complement factor 5a receptor 1 (C5a1 receptor) offers potential to treat various autoimmune diseases. The C5a1 receptor antagonist ACT-1014-6470 was well tolerated in a single-ascending dose study in healthy subjects. This double-blind, randomized, placebo-controlled study aimed to investigate the safety, tolerability, pharmacokinetics (PK) and target engagement of multiple-ascending doses of ACT-1014-6470. Per dose level, 10 healthy male and female subjects of nonchildbearing potential (1:1 sex ratio) were enrolled to assess 30, 60 and 120 mg ACT-1014-6470 administered twice daily for 4.5days under fed conditions. Adverse events, clinical laboratory data, vital signs, electrocardiogram and PK blood samples were collected up to 120h post last dose and ex vivo stimulated matrix metalloproteinase 9 was quantified as target engagement biomarker. At the 60-mg dose level, PK samples were collected until 8weeks post last dose. The total adverse event number was 57 and no treatment-related safety pattern was apparent. At steady state, ACT-1014-6470 reached maximum plasma concentrations after 2-3h and the half-life estimated up to Day 10 was 115-146h across dose levels. Exposure parameters increased dose-proportionally, steady state was attained between Day 3-5, and ACT-1014-6470 accumulated 2-fold. At the 60-mg dose level, ACT-1014-6470 was quantifiable until 8weeks after the last dose. Matrix metalloproteinase 9 release was suppressed to endogenous background concentrations up to the last sampling time point, confirming sustained target engagement of ACT-1014-6470. The compound was generally safe and well tolerated at all dose levels, warranting further clinical investigations.