np-031112 and Myotonic-Dystrophy

Topics: Animals; CELF1 Protein; Enzyme Inhibitors; Glycogen Synthase Kinase 3 beta; Humans; Myotonic Dystrophy; Myotonin-Protein Kinase; Signal Transduction; Thiadiazoles

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.. 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.. 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.. 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.

Topics: Adolescent; Adult; Age of Onset; Enzyme Inhibitors; Female; Glycogen Synthase Kinase 3 beta; Humans; Male; Myotonic Dystrophy; Outcome Assessment, Health Care; Proof of Concept Study; Single-Blind Method; Thiadiazoles; Young Adult

Myotonic dystrophy type 1 (DM1) is a multisystem neuromuscular disease without cure. One of the possible therapeutic approaches for DM1 is correction of the RNA-binding proteins CUGBP1 and MBNL1, misregulated in DM1. CUGBP1 activity is controlled by glycogen synthase kinase 3β (GSK3β), which is elevated in skeletal muscle of patients with DM1, and inhibitors of GSK3 were suggested as therapeutic molecules to correct CUGBP1 activity in DM1. Here, we describe that correction of GSK3β with a small-molecule inhibitor of GSK3, tideglusib (TG), not only normalizes the GSK3β-CUGBP1 pathway but also reduces the mutant

Topics: Animals; CELF1 Protein; Disease Models, Animal; DNA-Binding Proteins; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Mice; Muscle, Skeletal; Myoblasts; Myotonic Dystrophy; Primary Cell Culture; RNA; RNA-Binding Proteins; RNA, Messenger; Thiadiazoles