The following is a summary of the “Antisense oligonucleotide targeting DMPK in patients with myotonic dystrophy type 1: a multicentre, randomized, dose-escalation, placebo-controlled, phase 1/2a trial,” published in the March 2023 issue of Neurology by Thornton, et al.

DM1 protein kinase (DMPK) transcripts with enlarged trinucleotide repeats cause type 1 myotonic dystrophy by a gain-of-function mutation in RNA. Since antisense oligonucleotides (ASOs) work by decreasing amounts of harmful RNA, they represent a viable approach to treating myotonic dystrophy type 1. Therefore, Baliforsen (ISIS 598769), an ASO targeting DMPK mRNA, was the target of our study into its potential side effects. Participants in this dose-escalation phase 1/2a trial were adults aged 20 to 55 with type 1 myotonic dystrophy and were randomly assigned via an interactive web or phone response system to receive subcutaneous injections of baliforsen 100 mg, 200 mg, or 300 mg, or placebo (6:2 randomization at each dose level), or baliforsen 400 mg or 600 mg, or placebo (10:2 randomization at each dose level), on days 1, 3, 5, 8, 15, 22, 29, and 36. All participants, research staff, and sponsor employees involved in the trial were blinded to treatment allocations. For all trial participants who took at least one dose through Day 134, safety was the key indicator of success.

Between December 12, 2014, and February 22, 2016, 49 people were enrolled and given either 100 milligrams of baliforsen (n=7, one patient not dosed), 200 milligrams (n=6), 300 milligrams (n=6), 400 milligrams (n=10), 600 milligrams (n=10), or a placebo (n=10). 48 people who took part in the trial and were given at least one dose were considered safe to continue the research. 36 (95%) of 38 subjects randomized to baliforsen, and 9 (90%) of 10 participants assigned to placebo suffered treatment-emergent side events. Common treatment-emergent adverse events included headache (10 [26%] of 38 participants on baliforsen; 4 [40%] of 10 participants on placebo), contusion (7 [18%] of 38 on baliforsen; 1 [10%] of 10 on placebo), and nausea (6 [16%] of 38 on baliforsen; 2 [20%] of 10 on placebo).

Almost all reported side effects were minor (425 (86%) of 494 (baliforsen) and 62 (85%) of 73 (placebo) cases. One person who took 600 milligrams of baliforsen experienced temporary thrombocytopenia that the medication may have caused. The concentration of baliforsen in skeletal muscle rose in direct proportion to the administered dose. In most cases, people had no problems with Baliforsen. While the medication was present in the skeletal muscle, it was not at a concentration expected to significantly lower the goal. These findings encourage additional research into ASOs as a therapeutic option for myotonic dystrophy type 1, they also emphasize the necessity for enhanced medication delivery to muscle.

Source: sciencedirect.com/science/article/abs/pii/S1474442223000017