Safety, pharmacokinetics and pharmacodynamics of TAK-418, a novel inhibitor of the epigenetic modulator lysine-specific demethylase 1A

Wei Yin, Dimitrios Arkilo, Polyna Khudyakov, Jim Hazel, Saurabh Gupta, Maria S Quinton, Jie Lin, Deborah S Hartman, Martin M Bednar, Laura Rosen, Jens R Wendland, Wei Yin, Dimitrios Arkilo, Polyna Khudyakov, Jim Hazel, Saurabh Gupta, Maria S Quinton, Jie Lin, Deborah S Hartman, Martin M Bednar, Laura Rosen, Jens R Wendland

Abstract

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.

Keywords: KMT2D protein; Kabuki syndrome; LSD1 inhibitor; healthy volunteer; histone demethylase; phase 1 clinical trial; randomized controlled trial.

Conflict of interest statement

All authors are current or former employees of Takeda Pharmaceutical Company Limited and own stocks or stock options.

© 2021 Takenda Inc. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Figures

FIGURE 1
FIGURE 1
Mean (SD) plasma TAK‐418F concentration over time following multiple doses of TAK‐418 (Study 1003) on (A) Day 1 and (B) Day 10 SD, standard deviation; TAK‐418F, TAK‐418 free base
FIGURE 2
FIGURE 2
Mean (SD) CSF and plasma TAK‐418F concentration over time following multiple doses of TAK‐418 60 mg on Day 10 Note: n = 6 (female participants). CSF, cerebrospinal fluid; SD, standard deviation; TAK‐418F, TAK‐418 free base
FIGURE 3
FIGURE 3
Dose‐dependent increase in F‐FAD following multiple doses of TAK‐418 (Study 1003; non‐Japanese participants) Note: A simple linear regression model was fitted to describe the relationship between AUEC24 on Day 10 and the corresponding dose levels. AUEC24, area under the effect curve at 24 hours; F‐FAD, formyl flavin adenine dinucleotide; PBMC, peripheral blood mononuclear cells

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