Background
Vafidemstat, an inhibitor of the histone lysine-specific demethylase KDM1A, corrects cognition deficits and behavior alterations in rodent models. Here, we report the
Conclusions
Vafidemstat displayed good safety and tolerability. This phase I trial confirmed KDM1A TE and CNS penetration and permitted characterization of platelet dynamics and selection of phase IIa doses.
Methods
This single-center, randomized, double-blind, placebo-controlled phase I trial included a single and 5-day repeated dose-escalation and open-label CNS penetration substudy. Primary outcomes were safety and tolerability; secondary outcomes included analysis of the pharmacokinetics and pharmacodynamics, including chemoprobe-based immune analysis of KDM1A target engagement (TE) in peripheral blood mononuclear cells (PBMCs) and platelet monoamine oxidase B (MAOB) inhibition. CNS and cognitive function were also evaluated.
Results
No severe adverse events (AEs) were reported in the dose-escalation stage. AEs were reported at all dose levels; none were dose dependent, and no significant differences were observed between active treatment and placebo. Biochemistry, urinalysis, vital signs, electrocardiogram, and hematology did not change significantly with dose escalation, with the exception of a transient reduction of platelet counts in an extra dose level incorporated for that purpose. Vafidemstat exhibits rapid oral absorption, approximate dose-proportional exposures, and moderate systemic accumulation after 5 days of treatment. The cerebrospinal fluid-to-plasma unbound ratio demonstrated CNS penetration. Vafidemstat bound KDM1A in PBMCs in a dose-dependent manner. No MAOB inhibition was detected. Vafidemstat did not affect the CNS or cognitive function. Conclusions: Vafidemstat displayed good safety and tolerability. This phase I trial confirmed KDM1A TE and CNS penetration and permitted characterization of platelet dynamics and selection of phase IIa doses.
Trial registration
EUDRACT No. 2015-003721-33, filed 30 October 2015.