A Phase 2 Study of AMO-02 (Tideglusib) in Congenital and Childhood-Onset Myotonic Dystrophy Type 1 (DM1)
Joseph Horrigan, Tiago Bernardino Gomes, Mike Snape, Nikoletta Nikolenko, Alison McMorn, Stuart Evans, Alex Yaroshinsky, Oscar Della Pasqua, Sean Oosterholt, Hanns Lochmüller, Joseph Horrigan, Tiago Bernardino Gomes, Mike Snape, Nikoletta Nikolenko, Alison McMorn, Stuart Evans, Alex Yaroshinsky, Oscar Della Pasqua, Sean Oosterholt, Hanns Lochmüller
Abstract
Background: GSK3β is an intracellular regulatory kinase that is dysregulated in multiple tissues in type 1 myotonic dystrophy, a rare neuromuscular disorder that manifests at any age. AMO-02 (tideglusib) inhibits GSK3β activity in preclinical models of type 1 myotonic dystrophy and promotes cellular maturation as well as normalizes aberrant molecular and behavioral phenotypes. This phase 2 study assessed the pharmacokinetics, safety and tolerability, and preliminary efficacy of AMO-02 in adolescents and adults with congenital and childhood-onset type 1 myotonic dystrophy.
Methods: Sixteen subjects (aged 13 to 34 years) with congenital and childhood-onset type 1 myotonic dystrophy received 12 weeks of single-blind fixed-dose oral treatment with either 400 mg (n = 8) or 1000 mg (n = 8) AMO-02 (NCT02858908). Blood samples were obtained for pharmacokinetic assessment. Safety assessments, such as laboratory tests and electrocardiograms, as well as efficacy assessments of syndromal, cognitive, and muscular functioning, were obtained.
Results: AMO-02 plasma concentrations conformed to a two-compartment model with first-order absorption and elimination, and dose-dependent increases in exposure (area under the curve) were observed. AMO-02 was generally safe and well-tolerated. No early discontinuations due to adverse events or dose adjustments of AMO-02 occurred. The majority of subjects manifested clinical improvement in their central nervous system and neuromuscular symptoms after 12 weeks of treatment compared with the placebo baseline, with a larger response noted at the 1000 mg/day dose level. AMO-02 exposure (cumulative area under the curve) was significantly correlated (P < 0.01) with change from baseline on several key efficacy assessments.
Conclusion: AMO-02 has favorable pharmacokinetic and clinical risk/benefit profiles meriting further study as a potential treatment for congenital and childhood-onset type 1 myotonic dystrophy.
Keywords: CDM-1; Clinical trial; DM-1; GSK-3β; PK/PD.
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Source: PubMed