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

Abstract

Funding informationThese studies were funded by Takeda Development Center Americas 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.

Targeting epigenetic regulators to overcome drug resistance in cancers

“…The participants were divided into five groups, six of them received TAK-418 and two received matching placebo. The results showed that TAK-418 was well tolerated and exhibited a nearly linear pharmacokinetic profile with a t 1/2 of 4.35-5.36 h. 248 Moreover, other two phase I studies in healthy volunteers after oral dose of TAK-418 administration have been terminated because of administrative reasons and business decision, respectively (ClinicalTrials.gov Identifier: NCT04202497, NCT03501069).…”

LSD1 in drug discovery: From biological function to clinical application

“…This research was terminated prematurely due to administrative reasons. Another two phase I clinical trials NCT03228433 and NCT03501069 revealed that TAK‐418 exhibited a favorable tolerability profile and had no serious adverse effects 169 . Besides, TAK‐418 demonstrated a PK profile that was nearly linear, characterized by swift absorption and a short terminal half‐life 169 .…”

Biological and therapeutic role of LSD1 in Alzheimer’s diseases

“…In addition, TAK-418 and TAK-448 ( Figure 5A ) are highly enzyme-specific LSD1 inhibitors without impact on LSD1 complex, and both compounds are reported to show therapeutic potentials for cancer, AD, autism symptom disorder and Kabuki syndrome et al ( Baba et al, 2021 ; Yin et al, 2021 ; Baba et al, 2022 ). ORY-2001 (also known as Vafidemstat, Figure 5A ) is being evaluated in clinical assessments for treating CNS diseases such as AD and borderline personality disorder.…”