Japan: Erythromycin Phase 2 Trial for Myotonic Dystrophy Type 1 (DM1)

A phase 2 trial has provided promising evidence of the safety, tolerability, and potential efficacy of erythromycin in treating patients with myotonic dystrophy type 1 (DM1). The study findings, published online in Lancet's eClinicalMedicine, showed that erythromycin was well-tolerated, with no serious safety concerns observed.

The researchers indicate the need for a well-powered phase 3 trial to evaluate efficacy, building on the preliminary findings from this study.

The trial introduces splicing biomarkers as a novel way to evaluate treatment effects and paves the way for further clinical trials and research in the pursuit of effective therapies for DM1, which currently lacks fundamental treatment options.

"If successful, erythromycin may present a novel therapeutic option for patients with myotonic dystrophy type 1, offering hope for improving their quality of life and addressing the unmet medical need in this devastating disease," the researchers wrote.

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

Against the above background, Masayuki Nakamori, Osaka University Graduate School of Medicine, Osaka, Japan, and colleagues conducted a randomized, multicenter, placebo-controlled, double-blind, phase 2 trial to translate preclinical findings into practical applications in patients with DM1 by evaluating the efficacy and safety of erythromycin.

For the trial, 30 adult patients with DM1 enrolled. They were randomly assigned in the ratio of 1:2:2 to receive either a placebo or erythromycin at two daily doses (500 mg or 800 mg) for 24 weeks.

The study's primary outcome was the tolerability and safety of erythromycin. The secondary efficacy measures included splicing biomarkers, 6-minute walk test results, serum creatinine kinase (CK) values, and muscle strength.

Trial 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 vs +182.8), although this difference was not statistically significant.
• 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 and CACNA1S.

"Based on the results observed, it is prudent to proceed with a subsequent phase 2b trial that meticulously defines the choice of pertinent splicing biomarkers and clinical endpoints," the researchers wrote.

"Additionally, a well-powered phase 3 trial with extended treatment durations to further substantiate the potential benefits of erythromycin in treating DM1 is warranted," they concluded.

Reference

Masayuki Nakamori et al, Erythromycin for myotonic dystrophy type 1: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial, eClinicalMedicine (2023). DOI: 10.1016/j.eclinm.2023.102390