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A Phase 2 Study of AMO-02 (tideglusib) in Congenital and Childhood Onset Myotonic Dystrophy Type 1 (DM1)

Horrigan, J; Gomes, TB; Snape, M; Nikolenko, N; McMorn, A; Evans, S; Yaroshinsky, A; ... Lochmüller, H; + view all (2020) A Phase 2 Study of AMO-02 (tideglusib) in Congenital and Childhood Onset Myotonic Dystrophy Type 1 (DM1). Pediatric Neurology 10.1016/j.pediatrneurol.2020.08.001. (In press). Green open access

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Abstract

Background: GSK3β is an intracellular regulatory kinase that is dysregulated in multiple tissues in Type 1 myotonic dystrophy (DM1), a rare neuromuscular disorder that manifests at any age. AMO-02 (tideglusib) inhibits GSK3β activity in preclinical models of DM1 and promotes cellular maturation as well as normalizing 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 DM1. Methods: Sixteen subjects (aged 13 to 34) with Congenital and Childhood-onset DM1 received 12 weeks of single-blind fixed-dose oral treatment with either 400 mg (n=8) or 1000 mg (n=8) of AMO-02 (NCT02858908). Blood samples were obtained for pharmacokinetic assessment. Safety assessments, such as laboratory tests and ECGs, 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, or AUC) were observed. AMO-02 was generally safe and well-tolerated. No early discontinuations due to adverse events nor dose adjustments of AMO-02 occurred. The majority of subjects manifested clinical improvement in their CNS and neuromuscular symptoms after 12 weeks of treatment compared to the placebo baseline, with a larger response noted at the 1000 mg/day dose level. AMO-02 exposure (cumulative AUC) 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 DM1.

Type: Article
Title: A Phase 2 Study of AMO-02 (tideglusib) in Congenital and Childhood Onset Myotonic Dystrophy Type 1 (DM1)
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.pediatrneurol.2020.08.001
Publisher version: https://doi.org/10.1016/j.pediatrneurol.2020.08.00...
Language: English
Additional information: This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/10107104
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