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Lookup NU author(s): Professor Hanns Lochmuller
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© 2020 The AuthorsBackground: 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.
Author(s): Horrigan J, Gomes TB, Snape M, Nikolenko N, McMorn A, Evans S, Yaroshinsky A, Della Pasqua O, Oosterholt S, Lochmuller H
Publication type: Article
Publication status: Published
Journal: Pediatric Neurology
Year: 2020
Volume: 112
Pages: 84-93
Print publication date: 01/11/2020
Online publication date: 04/08/2020
Acceptance date: 02/08/2020
ISSN (print): 0887-8994
ISSN (electronic): 1873-5150
Publisher: Elsevier Inc.
URL: https://doi.org/10.1016/j.pediatrneurol.2020.08.001
DOI: 10.1016/j.pediatrneurol.2020.08.001
PubMed id: 32942085
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