By Enrico Bugiardini


Antisense oligonucleotide targeting DMPK in patients with myotonic dystrophy type 1: a multicentre, randomised, dose-escalation, placebo-controlled, phase 1/2a trial. Thornton CA, Moxley RT 3rd, Eichinger K, Heatwole C, Mignon L, Arnold WD, Ashizawa T, Day JW, Dent G, Tanner MK, Duong T, Greene EP, Herbelin L, Johnson NE, King W, Kissel JT, Leung DG, Lott DJ, Norris DA, Pucillo EM, Schell W, Statland JM, Stinson N, Subramony SH, Xia S, Bishop KM, Bennett CF. Lancet Neurol. 2023 Mar;22(3):218-228. doi: 10.1016/S1474-4422(23)00001-7. PMID: 36804094


The neuromuscular field is transitioning to an exciting era where clinical trials and treatments are finally available for people affected by muscular dystrophies.

In this context, the paper by Thornton et al. assessed for the first-time safety and tolerability of ASOs for patients with myotonic dystrophy type 1 (DM1). In DM1, the DMPK transcript contains the expanded CUG repeats and is known to misregulate the splicing of several mRNAs and lead to the multi-system pathology typical of DM1.

In this dose-escalation phase 1/2a trial, the authors investigate the use of Baliforsen, an antisense oligonucleotide (ASOs) that specifically targets the DMPK mRNA and leads to its degradation.

The study was performed at seven sites in the USA. Forty-nine participants with myotonic dystrophy type 1, aged 20-55 were enrolled and randomly allocated to subcutaneous injections of baliforsen 100 mg (n=7), 200 mg (n=6), 300 mg (n=6), 400 mg (n=10), 600 mg (n=10) or placebo (n=10). The participants received eight doses in six weeks and were followed for 14-weeks post-treatment.

95% of participants on Baliforsen and 90% on placebo reported treating-emergent adverse events, the majority represented by headache, nausea and contusion. The injection-site treatment-emergent adverse events were more common in people on Baliforsen than placebo (82% vs 10 % respectively).  Adverse events were mostly mild, and no participants had to stop the treatment. Only one participant on the highest dose of baliforsen (600 mg) developed a serious adverse event (transient thrombocytopenia) that was considered potentially related to the treatment.

Higher doses increased the concentration of baliforsen in muscle but the dose achieved in muscle was lower than what was expected and did not lead to a significant group reduction in the composite splicing index used as a downstream biomarker of DMPK transcript reduction. Interestingly, two patients in the highest dose group had an improvement in the splicing index. Exploratory clinical endpoints (including six-min walk test, quantitative muscle testing, mean change of grip relaxation time, mean change of video-recorded hand-opening time, SF-36) did not show significant differences between placebo-treated and Baliforsen-treated dose cohorts.

In conclusion, the study showed for the first time that ASO treatment could be a tolerated and promising approach for people with myotonic dystrophy type 1 and pave the way to the development of further clinical trials in DM1.

About the author:

Charles Thornton, MD is the Saunders Family Distinguished Professor in Neuromuscular Research at University of Rochester, New York. He studies disease mechanisms and treatment for myotonic dystrophy, and directs the Wellstone Muscular Dystrophy Cooperative Research Center in Rochester.

Reviewer: Enrico Bugiardini

A headshot of Enrico Bugiardini. Enrico is looking at the camera and is in front of a dark background.

Published on 15 November 2023.


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