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Safety and efficacy of novel antibody-oligonucleotide therapy for myotonic dystrophy type 1
1. In this phase 1-2 randomized controlled trial involving adults with myotonic dystrophy type 1, del-desiran was well-tolerated in most patients
2. The treatment was also associated with decreased biochemical markers of disease and improved muscle function.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Myotonic dystrophy type 1 is a progressive genetic neuromuscular disease that severely affects life expectancy and quality. This study, termed the MARINA trial, aimed to evaluate the safety and efficacy of a monoclonal antibody-oligonucleotide conjugate delpacibart etedesiran (del-desiran) in adults with myotonic dystrophy type 1. This drug targets DMPK mRNA in muscle tissue to prevent the missplicing responsible for disease expression. Patients received either placebo, a single del-desiran infusion of 1 mg per kilogram of body weight (mg/kg), or three infusions of either 2mg or 4mg/kg. After a follow-up period of thirteen weeks, it was found that most patients experienced a mild to moderate adverse event. There were two serious adverse events, one of which was attributed to the del-desiran. All but this participant continued throughout the entire trial. All three treatment groups experienced a significantly greater decrease in DMPK mRNA levels versus placebo, and the higher dosage groups saw the largest reductions in missplicing. On tests of muscle function and degree of disability, participants receiving del-desiran experienced more improvement than placebo in a dose-dependent manner. This study was limited by its small sample size, short treatment period with limited follow-up duration, and overrepresentation of women. However, strengths included exploration of biochemical effects of del-desiran and inclusion of a range of myotonic dystrophy severities. Overall, these results suggested that del-desiran has a short-term safety profile and promising signals of efficacy which are being further characterized through an open-label extension trial.
Click to read the study in NEJM
In-Depth [randomized controlled trial]: The phase 1-2 double-blind, randomized controlled trial, titled MARINA, evaluated the safety, pharmacological profile, and molecular effects of delpacibart etedesiran (del-desiran), a monoclonal antibody-oligonucleotide conjugate, in patients with myotonic dystrophy type 1. Participants were adults aged 18 to 65 years with genetic diagnosis of myotonic dystrophy type 1, a DMPK CTG repeat length of 100 or more, and scores within certain thresholds on impairment rating tests. These patients were then randomly assigned in a 3:1 ratio to receive placebo or del-desiran in two parts; Part A (n=10 placebo; n= 6 experimental) delivered a single 1mg/kg infusion dose, while Part B (n=21) received three infusions of either 2mg/kg or 4mg/kg every six weeks. The primary endpoint was adverse events during the treatment period. Secondary endpoints included drug levels, change in DMPK mRNA levels, and change in composite missplicing scores across four clinically relevant genes. Most participants had one or more adverse event, most with mild to moderate severity. There was one severe, serious adverse event of bilateral thalamic infarction, which was attributed to del-desiran. The other severe, serious adverse event was respiratory failure deemed to be unrelated to the trial medication. The percent change in DMPK mRNA levels was 0.9% in placebo, -46% in the 1mg group, -44% in the 2mg group, and -37% in the 4mg group. The mean change in composite missplicing score was -7% in the placebo group, -3% in the 1mg group, -17% in the 2mg group, and -16% in the 4mg group. A timed measure of hand function saw a .55 second improvement in placebo, 1.49 seconds in the 2-mg group, and 3.45 seconds in the 4-mg group. Scores in other measures of clinical efficacy, such as muscle strength and hand-grip strength, followed a similar dose-dependent pattern of improvement. Overall, the study found that del-desiran had an acceptable safety profile to justify further study as a potential treatment for the spliceopathy characterizing myotonic dystrophy type 1.
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