First-in-Human Study of Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor (HIF-PHI) AND017 in Healthy Participants

Background: AND017 is a novel oral HIF-PHI independently developed by Kind Pharmaceuticals LLC. The first-in-human study of AND017 was performed among healthy subjects in Australia to evaluate the safety, pharmacokinetics, and pharmacodynamics of AND017 (NCT04751539). Methods: This Phase I, randomized, double-blinded, placebo-controlled study consisted of two parts: a single ascending dose (SAD) part followed by a multiple ascending dose (MAD) part. In the SAD part, doses of 1, 4, 10, 20, 30, and 50 mg AND017 or placebo were assessed in 6 consecutive cohorts; In the MAD part, doses of 4, 10, 20 and 30 mg AND017 or placebo were administered daily for 10 days and assessed in 4 consecutive cohorts. After each cohort, a Safety Review Committee (SRC) reviewed blinded cumulative safety data to determine the safety of the study dose before proceeding to the next dose cohort. Results: A total of 78 subjects were enrolled in the study- 46 subjects in the SAD part and 32 subjects in the MAD part. All subjects were included in the PD and safety analysis set; all 58 subjects dosed with AND017 were included in PK analysis set. Subjects in all treatment groups were of similar demographic and baseline characteristics. AND017 was absorbed quickly with a median Tmax of 2-4.5 h after single and multiple dose administration. There was no tendency toward a change in Tmax, half-life, volume of distribution and clearance across the dose range investigated. AND017 steady state reached by 6 days dosing, with an approximate 1.2 to 1.6-fold accumulation after 10 days of administration. Dose proportionality in AND017 exposure was observed after single (1 to 50 mg) and multiple (4 to 30 mg) dosing. In the PD analysis, Emax,EPO, baseline-corrected Emax,EPO, AUEC0-24,EPO, and baseline-corrected AUEC0-24,EPO of erythropoietin (EPO) showed obvious dose dependence. The increase in EPO was significantly associated with the PK exposure. The most frequently reported treatment related adverse events in the SAD part were dizziness, headache, and fatigue occurred in 2 subjects of AND017 cohorts each; in the MAD part, headache occurred in 2 subjects of AND017 cohorts and 1 subjects of placebo cohort. Conclusion: AND017 appeared to be safe and well tolerated when administered to healthy adult subjects at oral doses ranging from 1 mg up to 50 mg in the SAD part and 4 mg up to 30 mg in the MAD part.