PMID- 33755924 OWN - NLM STAT- MEDLINE DCOM- 20220110 LR - 20220110 IS - 1179-1934 (Electronic) IS - 1172-7047 (Print) IS - 1172-7047 (Linking) VI - 35 IP - 3 DP - 2021 Mar TI - First-in-Human Randomized Trial to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the KDM1A Inhibitor Vafidemstat. PG - 331-344 LID - 10.1007/s40263-021-00797-x [doi] AB - 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. FAU - Antonijoan, Rosa Maria AU - Antonijoan RM AD - Centre d'Investigacio del Medicament, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau (IIB-Sant Pau), Barcelona, Spain. AD - Pharmacology and Therapeutics Department, Universitat Autonoma de Barcelona (UAB), Bellaterra, Spain. FAU - Ferrero-Cafiero, Juan Manuel AU - Ferrero-Cafiero JM AD - Centre d'Investigacio del Medicament, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau (IIB-Sant Pau), Barcelona, Spain. FAU - Coimbra, Jimena AU - Coimbra J AD - Centre d'Investigacio del Medicament, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau (IIB-Sant Pau), Barcelona, Spain. FAU - Puntes, Montse AU - Puntes M AD - Centre d'Investigacio del Medicament, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau (IIB-Sant Pau), Barcelona, Spain. FAU - Martinez-Colomer, Joan AU - Martinez-Colomer J AD - Centre d'Investigacio del Medicament, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau (IIB-Sant Pau), Barcelona, Spain. FAU - Arevalo, Maria Isabel AU - Arevalo MI AD - Oryzon Genomics S.A. Carrer Sant Ferran 74, Cornella de Llobregat, 08940, Barcelona, Spain. FAU - Mascaro, Cristina AU - Mascaro C AD - Oryzon Genomics S.A. Carrer Sant Ferran 74, Cornella de Llobregat, 08940, Barcelona, Spain. FAU - Molinero, Cesar AU - Molinero C AD - Oryzon Genomics S.A. Carrer Sant Ferran 74, Cornella de Llobregat, 08940, Barcelona, Spain. FAU - Buesa, Carlos AU - Buesa C AD - Oryzon Genomics S.A. Carrer Sant Ferran 74, Cornella de Llobregat, 08940, Barcelona, Spain. FAU - Maes, Tamara AU - Maes T AUID- ORCID: 0000-0001-5104-6867 AD - Oryzon Genomics S.A. Carrer Sant Ferran 74, Cornella de Llobregat, 08940, Barcelona, Spain. tmaes@oryzon.com. LA - eng SI - EudraCT/2015-003721-33 PT - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20210323 PL - New Zealand TA - CNS Drugs JT - CNS drugs JID - 9431220 RN - 0 (Monoamine Oxidase Inhibitors) RN - 0 (Oxadiazoles) RN - EC 1.14.11.- (Histone Demethylases) RN - EC 1.5.- (KDM1A protein, human) RN - LZ82JLT4UP (vafidemstat) SB - IM MH - Area Under Curve MH - Central Nervous System/drug effects MH - Double-Blind Method MH - Female MH - Histone Demethylases/*antagonists & inhibitors MH - Humans MH - Leukocytes, Mononuclear/drug effects/metabolism MH - Male MH - Monoamine Oxidase Inhibitors/pharmacokinetics/pharmacology MH - Oxadiazoles/*pharmacokinetics/*therapeutic use PMC - PMC7985749 COIS- RMA has received personal fees from Centre d'Investigacio del Medicament, Institut de Recerca de l'Hospital de la Santa Creu(c) Sant Pau (IIB-Sant Pau) and Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. JMF-C, JC, MP, and JM-C have received personal fees from Centre d'Investigacio del Medicament, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau (IIB-Sant Pau), Barcelona, Spain. MIA, CMa, CMo, CB, and TM have received personal fees from Oryzon Genomics, during the conduct of the study. In addition, CMa is listed as inventor on patent application WO2017/158136 (pending), assigned to Oryzon Genomics; CMo owns company shares on the stock exchange (Oryzon Genomics); and CB reports patent WO2012/013728 (issued in multiple countries), assigned to Oryzon Genomics. CB is executive director and shareholder of Oryzon Genomics. TM has received other compensation from the Alzheimer's Drug Discovery Foundation, outside the submitted work; is listed as inventor in WO2017/158136 (pending), WO2017/212061 (issued in multiple countries), and WO2019/025588 (pending) and further reports patent WO2012/013728 (issued in multiple countries), all assigned to Oryzon Genomics; is executive director and shareholder of Oryzon Genomics; and is a member of the Scientific Review Board of the Alzheimer's Drug Discovery Foundation, for which no compensation is received. EDAT- 2021/03/24 06:00 MHDA- 2022/01/11 06:00 PMCR- 2021/03/23 CRDT- 2021/03/23 17:59 PHST- 2021/02/12 00:00 [accepted] PHST- 2021/03/24 06:00 [pubmed] PHST- 2022/01/11 06:00 [medline] PHST- 2021/03/23 17:59 [entrez] PHST- 2021/03/23 00:00 [pmc-release] AID - 10.1007/s40263-021-00797-x [pii] AID - 797 [pii] AID - 10.1007/s40263-021-00797-x [doi] PST - ppublish SO - CNS Drugs. 2021 Mar;35(3):331-344. doi: 10.1007/s40263-021-00797-x. Epub 2021 Mar 23.