First-in-Human Randomized Trial to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the KDM1A Inhibitor Vafidemstat
Antonijoan Arbós, Rosa Ma (Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia)
Ferrero-Cafiero, Juan Manuel (Institut d'Investigació Biomèdica Sant Pau)
Coimbra, Jimena (Institut d'Investigació Biomèdica Sant Pau)
Puntes, Montserrat (Institut d'Investigació Biomèdica Sant Pau)
Martínez-Colomer, Joan (Institut d'Investigació Biomèdica Sant Pau)
Arévalo, M. Isabel (Parc Científic de Barcelona. Oryzon Genomics)
Mascaró, Cristina (Parc Científic de Barcelona. Oryzon Genomics)
Molinero, Cesar (Parc Científic de Barcelona. Oryzon Genomics)
Buesa, Carlos (Parc Científic de Barcelona. Oryzon Genomics)
Maes, Tamara (Parc Científic de Barcelona. Oryzon Genomics)

Fecha:	2021
Resumen:	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. 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. 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. 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. 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. EUDRACT No. 2015-003721-33, filed 30 October 2015. The online version contains supplementary material available at 10. 1007/s40263-021-00797-x.
Ayudas:	Ministerio de Ciencia e Innovación CIIP-20152001-E9683
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Publicado en:	CNS Drugs, march 2021, p. 1-14, ISSN 1179-1934

DOI: 10.1007/s40263-021-00797-x
PMID: 33755924

14 p, 2.2 MB

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Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut de Recerca Sant Pau
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