RESUMEN
AIMS: Dysregulation of histone methylation epigenetic marks may result in intellectual and developmental disability, as seen in Kabuki syndrome. Animal data suggest that increasing histone methylation by inhibiting lysine-specific demethylase 1A (LSD1) may improve cognitive outcomes in a model of Kabuki syndrome. TAK-418 is a novel LSD1 inhibitor, developed as a potential therapeutic agent for central nervous system disorders such as Kabuki syndrome. Here, we report safety, tolerability, pharmacokinetic and pharmacodynamic profiles of single and multiple doses of TAK-418 (ClinicalTrials.gov: NCT03228433, NCT03501069). METHODS: Two randomized, double-blind, placebo-controlled, phase 1 studies of oral TAK-418 were performed, a first-in-human single-rising-dose (SRD) study (5-60 mg) in healthy adult male and female volunteers (placebo, n = 10; TAK-418, n = 30), and an SRD (120-160 mg) and multiple-rising-dose (MRD) study (20-160 mg once daily for 10 days) in healthy female volunteers (placebo, n = 2 [SRD] and n = 6 [MRD]; TAK-418, n = 6 [SRD] and n = 18 [MRD]). RESULTS: TAK-418 was well tolerated. No clinically significant changes in laboratory test results or vital signs were observed and no serious adverse events were reported. TAK-418 had a nearly linear pharmacokinetic profile, with rapid absorption and short terminal half-life across the evaluated dose range. No obvious accumulation was observed after daily administration for 10 days. Administration with food delayed peak plasma concentrations but overall exposure was unaffected. TAK-418 rapidly crossed the blood-brain barrier and generally showed a dose-dependent response in the peripheral pharmacodynamic biomarker formyl-flavin adenine dinucleotide. CONCLUSION: The brain-penetrant LSD1 inhibitor TAK-418 was well tolerated, with pharmacokinetic and pharmacodynamic effects that support further investigation.