Byungwook Kim

Aims CG‐750 is an oral formulation of ivaltinostat, a newly developing histone deacetylase (HDAC) inhibitor. This study aimed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of an oral formulation (CG‐750) of ivaltinostat compared to an intravenous (IV) formulation (CG‐745). Methods A randomized, double‐blind, placebo‐controlled study was conducted in three cohorts. Subjects received either CG‐745 (Cohorts 1 and 3: 125 mg; Cohort 2: 250 mg) or placebo followed by CG‐750 (Cohort 1: 125 mg; Cohort 2: 375 mg; Cohort 3: 750 mg) or placebo. Blood samples for PK and PD assessment were collected up to 72 h post‐dose. Histone H3 acetylation at sites K9, K9/K14 and K27 was assessed for area under the % acetylation induction versus time curve (AUEC). Results A total of 25 subjects were randomized, and 23 subjects completed the study (Cohort 1, n = 6; Cohort 2, n = 6; Cohort 3, n = 6; placebo, n = 5). The mean bioavailability of CG‐750 was 10.6% (range: 4.18%–21.33%) and displayed linear PK in the dose range of 125–750 mg. The comparison of AUEC between formulations and the evaluation of the dose–AUEC relationship were inconclusive, due to the small sample sizes and significant variability observed in PD markers. All adverse events (AEs) were transient and of mild or moderate intensity. Conclusions The oral formulation of ivaltinostat (CG‐750) was generally well tolerated after a single dose. CG‐750 displayed a mean bioavailability of 10.6%.