Myotonic dystrophy type 1 is caused by a trinucleotide repeat expansion in the DMPK gene, leading to a toxic gain of function in mRNA and consequently, global missplicing that results in various symptoms. Delpacibart etedesiran (del-desiran [AOC 1001]), a monoclonal antibody-oligonucleotide conjugate, is a system delivering siRNA that leads to degradation of DMPK mRNA. Conjugation with a monoclonal antibody targeting transferrin receptor 1 improves delivery to muscle and cardiac tissue.
MARINA was a multicenter, 6-month, two-part, double-blind, randomized, placebo-controlled trial. Thirty-eight participants were recruited through eight centers in the US between 2021 and 2022. Six participants received del-desiran at a dose of 1 mg per kilogram, 9 at a dose of 2 mg per kilogram, and 13 at a dose of 4 mg per kilogram; 10 participants were randomized to a placebo group. Patients were followed up for 3 months after treatment. The primary endpoint was safety, and secondary endpoints were the pharmacokinetic and pharmacodynamic profiles. Exploratory clinical endpoints were also assessed.
Two serious adverse events occurred. One serious adverse event in the 4 mg group was associated with the medication. The participant experienced memory loss and visual impairment during the 24-hour post-treatment observation period, and MRI showed a bilateral thalamic infarction. The participant discontinued the study.
There was an ameliorative effect on missplicing in the treatment biopsy samples. DMPK mRNA levels in muscle-biopsy samples changed as follows: −46% in the 1-mg group, −44% in the 2-mg group, −37% in the 4-mg group, and 0.9% in the placebo group. Reductions in the mean composite missplicing score from baseline were in line with improvement of missplicing in the 2-mg and 4-mg groups.
Exploratory endpoints included: change in hand-opening time as assessed by video at day 92; muscle strength as assessed by a composite score on quantitative muscle testing at day 183; mean change in hand-grip strength at day 183; change in mean time on the 10-m walk–run test at day 183; mean time on the timed up-and-go test; and participant-reported outcome measures of activities of daily living (DM1-ActivC) at day 183. Exploratory endpoints were consistent with amelioration of missplicing at 2 mg and 4 mg per kilogram doses. Limitations of the study include a small sample size, limited follow-up time, and underrepresentation of men.
An open-label extension trial is underway for participants who completed the MARINA trial to evaluate treatment effects over a longer duration (NCT05479981). The HARBOR trial, a phase 3, double-blind, randomized, placebo-controlled trial (NCT06411288), assessing 4 mg delpacibart etedesiran every 8 weeks, is underway.
Key Points:
- MARINA trial, a 6-month, two-part, double-blind, placebo-controlled RCT investigated the safety and pharmacokinetic and pharmacodynamic profiles of delpacibart etedesiran, a monoclonal antibody–oligonucleotide conjugate, in myotonic dystrophy type 1.
- Two serious adverse events occurred. One participant in the 4 mg group had bilateral thalamic ischemia and discontinued participation.
- There was an ameliorative effect on missplicing in the treatment biopsy samples, consistent with a reduction in mutant DMPK mRNA levels at the 2 mg and 4 mg per kilogram dose levels.
References:
Johnson NE, Tai LJ, Hamel JI, Day JW, Statland JM, Soltanzadeh P, Subramony SH, Thornton CA, Arnold WD, Wicklund M, Freimer ML, Eichinger K, Dekdebrun J, Chen CY, Goel V, McEvoy B, Zhu Y, Hughes SG, Ackermann EJ, Levin AA. An Antibody-Oligonucleotide Conjugate for Myotonic Dystrophy Type 1. N Engl J Med. 2026 Feb 19;394(8):763-772. doi: 10.1056/NEJMoa2407326.
Publish on behalf of the Scientific Panel on Muscle and NMJ disorders