Erythromycin for myotonic dystrophy type 1: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

Masayuki Nakamori; Daisaku Nakatani; Tomoharu Sato; Yuhei Hasuike; Seiko Kon; Toshio Saito; Harumasa Nakamura; Masanori P Takahashi; Eisuke Hida; Hirofumi Komaki; Tsuyoshi Matsumura; Hiroto Takada; Hideki Mochizuki

doi:10.1016/j.eclinm.2023.102390

Erythromycin for myotonic dystrophy type 1: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

EClinicalMedicine. 2023 Dec 26:67:102390. doi: 10.1016/j.eclinm.2023.102390. eCollection 2024 Jan.

Authors

Affiliations

¹ Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
² Department of Neurology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan.
³ Medical Centre for Translational Research, Department of Medical Innovation, Osaka University Hospital, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
⁴ Department of Biostatistics & Data Science, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
⁵ Department of Neurology, NHO Aomori National Hospital, 155-1 Hirano, Namioka, Aomori, 038-1331, Japan.
⁶ Department of Neurology, NHO Osaka Toneyama Medical Centre, 5-1-1 Toneyama, Toyonaka, Osaka, 560-8552, Japan.
⁷ Translational Medical Centre, National Centre of Neurology and Psychiatry, 4-1-1 Ogawahigashimachi, Kodaira, Tokyo, 187-8502, Japan.
⁸ Department of Clinical Laboratory and Biomedical Sciences, Osaka University Graduate School of Medicine, 1-7 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Abstract

Background: Myotonic dystrophy type 1 (DM1) is a devastating multisystemic disorder caused by a CTG repeat expansion in the DMPK gene, which subsequently triggers toxic RNA expression and dysregulated splicing. In a preclinical study, we demonstrated that erythromycin reduces the toxicity of abnormal RNA and ameliorates the aberrant splicing and motor phenotype in DM1 model mice.

Methods: This multicentre, randomised, double-blind, placebo-controlled, phase 2 trial was conducted at three centres in Japan to translate preclinical findings into practical applications in patients with DM1 by evaluating the safety and efficacy of erythromycin. Between Nov 29, 2019, and Jan 20, 2022, a total of 30 adult patients with DM1 were enrolled and randomly assigned in a 1:2:2 ratio to receive either placebo or erythromycin at two daily doses (500 mg or 800 mg) for 24 weeks. The primary outcome included the safety and tolerability of erythromycin. The secondary efficacy measures included splicing biomarkers, 6-min walk test results, muscle strength, and serum creatinine kinase (CK) values. This trial is registered with the Japan Registry of Clinical Trials, jRCT2051190069.

Findings: Treatment-related gastrointestinal symptoms occurred more frequently in the erythromycin group, but all adverse events were mild to moderate and resolved spontaneously. No serious safety concerns were identified. The CK levels from baseline to week 24 decreased in the overall erythromycin group compared with the placebo group (mean change of -6.4 U/L [SD 149] vs +182.8 [SD 228]), although this difference was not statistically significant (p = 0.070). Statistically significant improvements in the overall erythromycin treated groups compared to placebo were seen for two of the eleven splicing biomarkers that were each evaluated in half of the trial sample. These were MBNL1 (p = 0.048) and CACNA1S (p = 0.042).

Interpretation: Erythromycin demonstrated favourable safety and tolerability profiles in patients with DM1. A well-powered phase 3 trial is needed to evaluate efficacy, building on the preliminary findings from this study.

Funding: Japan Agency for Medical Research and Development.

Keywords: Erythromycin; Myotonic dystrophy; RNA toxicity; Splicing.