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Published on: May 7, 2020
Erythromycin for myotonic dystrophy type 1: a multicentre, randomised, double-blind, placebo-controlled, phase 2
Masayuki Nakamori1,2, Daisaku Nakatani3, Tomoharu Sato4
1Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
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.
Insights
Erythromycin showed a good safety profile in a phase 2 trial for myotonic dystrophy type 1 (DM1). While not statistically significant, some biomarkers improved, suggesting potential efficacy for future studies.
Area of Science:
- Neurology
- Genetics
- Pharmacology
Background:
- Myotonic dystrophy type 1 (DM1) is a genetic disorder caused by CTG repeat expansion in the DMPK gene.
- This expansion leads to toxic RNA and disrupted splicing, causing multisystemic effects.
- Preclinical studies indicated erythromycin could reduce RNA toxicity and improve splicing in DM1 mouse models.
Purpose of the Study:
- To evaluate the safety and efficacy of erythromycin in adult patients with DM1.
- To translate promising preclinical findings into a clinical setting.
- To assess erythromycin's impact on safety, tolerability, splicing biomarkers, and clinical outcomes.
Main Methods:
- A multicentre, randomized, double-blind, placebo-controlled phase 2 trial involving 30 adult DM1 patients.
- Participants received placebo or erythromycin (500 mg or 800 mg daily) for 24 weeks.
- Outcomes included safety, tolerability, splicing biomarkers (MBNL1, CACNA1S), 6-minute walk test, muscle strength, and CK levels.
Main Results:
- Erythromycin was safe and well-tolerated, with mild to moderate, self-resolving adverse events.
- Creatine kinase (CK) levels showed a trend towards decrease in the erythromycin group but was not statistically significant (p=0.070).
- Significant improvements were observed in two splicing biomarkers, MBNL1 (p=0.048) and CACNA1S (p=0.042), in erythromycin-treated groups compared to placebo.
Conclusions:
- Erythromycin exhibits a favorable safety and tolerability profile for DM1 patients.
- Preliminary efficacy signals in splicing biomarkers warrant further investigation.
- A larger, well-powered phase 3 trial is recommended to confirm efficacy in DM1 treatment.
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