First-in-Human Randomized Trial to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the KDM1A Inhibitor Vafidemstat

Abstract

Background: Vafidemstat, an inhibitor of the histone lysine-specific demethylase KDM1A, corrects cognition deficits and behavior alterations in rodent models. Here, we report the results from the first-in-human trial of vafidemstat in healthy young and older adult volunteers. A total of 110 volunteers participated: 87 were treated with vafidemstat and 23 with placebo.

Objectives: The study aimed to determine the safety and tolerability of vafidemstat, to characterize its pharmacokinetic and pharmacodynamic profiles, to assess its central nervous system (CNS) exposure, and to acquire the necessary data to select the appropriate doses for long-term treatment of patients with CNS disease in phase II trials.

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.

Fig. 1

Clinical trial design. a Chemical structure of vafidemstat. b Impact of vafidemstat on platelet levels in nonclinical species, represented as % inhibition compared with control animals. All values are expressed as mg/m²/day to allow for direct comparison. Differences in administration (once daily by oral gavage in rats and dogs vs. drinking water in mice) were accounted for. Doses in mg/kg/day were converted to mg/m²/day by multiplication with the Km factor for each species (3, 6, 20, 37 for mouse, rat, dog, human, respectively). Black triangles indicate the SAMP8 efficacy studies in mouse; gray circles indicate the 28-day toxicity in rats; white squares indicate the 28-day toxicity in dogs; black arrows represent the doses chosen for the SAD and MAD cohorts; gray arrows represent those for the CSF cohorts in the phase I trial. The maximum recommended starting dose was 0.2 mg. c Clinical trial doses per cohort. d Study design of the SAD, MAD, and CSF cohorts. Dark gray rectangle indicates the sentinel subject, light gray rectangles indicate subjects in active treatment; white rectangles indicate subjects receiving placebo. CSF cerebrospinal fluid, MAD multiple ascending dose, p.o. oral administration, PLT platelet, QD once daily, SAD single ascending dose

Fig. 2

Hematological impact of vafidemstat. Impact of vafidemstat on platelet levels at a 1.5 mg/day, b 2.5 mg/day, and (c) the extra dose level of 4 mg/day, represented as % change from baseline levels. Black dots indicate vafidemstat (volunteers analyzed n = 6 in [a/b] or n = 3 in [c]); open circles indicate placebo treatment (volunteers analyzed n = 2 in [a/b] or n = 1 in [c]); black arrows represent dosing occasions. Data are presented as means and standard error of the mean. CFB change from baseline

Fig. 3

Vafidemstat pharmacokinetics. (a) Plasma concentrations after single and (b) multiple ascending doses in healthy young (full lines) and older adult (dotted line) subjects. Light blue circles 0.2 mg; white squares 0.6 mg; light blue triangles 1 mg; white triangles 1.5 mg; blue diamonds 2.5 mg; white circles 4 mg. Data are presented as mean and standard error of the mean. Volunteers analyzed at each datapoint, n = 6 except for MAD 4 mg, n = 3. (c) Cerebrospinal fluid (full lines) and plasma (unbound, dotted lines) concentrations after a single dose of 2 mg (diamonds) or 4 mg (circles)

Fig. 4

Vafidemstat pharmacodynamics. a The KDM1A chemoprobe OG-881 used to capture uninhibited protein. b Graphical representation of the chemoprobe and sandwich ELISA used to determine free and total KDM1A. c KDM1A TE after SAD and d MAD in healthy young subjects. Light blue dots 12 h; medium blue dots 108 h; dark blue dots 72 h (SAD) or 192 h (MAD) after the first dose. Data are presented as mean and standard error of the mean. Volunteers sampled at each dose: n = 6 except MAD 4 mg, n = 3. e, f Pharmacokinetic/pharmacodynamic relationship between exposure, as reflected by C_max,ss or AUCss, and KDM1A TE. g, h Pharmacokinetic/pharmacodynamic relationship between exposure, as reflected by C_max,ss or AUCss, and platelet dynamics (represented as % CFB levels). All values correspond to independent subjects. Calculated EC₅₀/EC₈₀ values are also shown in the respective graphs. Light blue circles 0.2 mg; white squares 0.6 mg; light blue triangles 1 mg; white triangles 1.5 mg; blue diamonds 2.5 mg; white circles 4 mg; full lines nonlinear fit; dotted lines 95% confidence interval. Volunteers sampled at each dose: n = 6 except MAD 4 mg, n = 3. Samples that did not pass quality control were omitted. AUC,ss area under the plasma concentration–time curve at steady state, CFB change from baseline, C_max,ss maximum concentration at steady state, EC₅₀ half maximal effective concentration, EC₈₀ 80% maximal effective concentration, ELISA enzyme-linked immunosorbent assay, HRP horseradish peroxidase, MAD multiple ascending dose, PBMCs peripheral blood mononuclear cells, SAD single ascending dose, SS steady state, TE target engagement