Antibody–Oligonucleotide Conjugate Shows Target Engagement in Myotonic Dystrophy Type 1

Treatment with delpacibart etedesiran (del-desiran [AOC 1001]; Avidity Biosciences, San Diego, CA), a monoclonal antibody (mAb) oligonucleotide conjugate, reduced DMPK mRNA levels and demonstrated improvement in downstream splicing biomarkers in adults with myotonic dystrophy type 1 (DM1). These findings from the phase 1/2 MARINA clinical trial (NCT05027269) were published in The New England Journal of Medicine, supporting further clinical investigation and development for delpacibart etedesiran. In 2024, delpacibart etedesiran was granted Breakthrough Therapy designation by the Food and Drug Administration as an investigational treatment for DM1. 

The multicenter, double-blind, placebo-controlled MARINA trial enrolled 39 adults with genetically confirmed DM1. Thirty-eight participants received at least 1 infusion and were included in the safety analysis. The study comprised 2 parts, with participants randomized 3:1 to in each part to receive a single dose of delpacibart etedesiran 1 mg/kg or placebo (Part A) or 3 infusions of 2 mg/kg or 4 mg/kg delpacibart etedesiran or placebo at approximately 6-week intervals (Part B). The primary end point was treatment-emergent adverse events. Secondary end points included pharmacokinetics, muscle siRNA concentrations, percent change in DMPK mRNA levels, and composite missplicing scores derived from muscle-biopsy samples.

Key findings include the following:

• Percent change in DMPK mRNA levels in muscle at the treatment biopsy was −46% (1 mg/kg), −44% (2 mg/kg), and −37% (4 mg/kg) for those treated with delpacibart etedesiran vs 0.9% in placebo.
• Mean change in composite missplicing score for those treated with delpacibart etedesiran was −3% (1 mg/kg), −17% (2 mg/kg), and −16% (4 mg/kg), vs −7% with placebo.
• Maximum plasma small interfering RNA (siRNA) concentrations increased proportionally with dose; 3% to 4% of administered siRNA was recovered in urine.

In terms of safety, 2 severe, serious adverse events occurred:

• In the 4-mg group, 1 participant experienced bilateral thalamic ischemia with hemorrhagic transformation that was deemed related to delpacibart etedesiran and led to treatment discontinuation.
• In the 2-mg group, 1 participant experienced respiratory failure attributed to opioid use following elective surgery.

Exploratory clinical assessments suggested potential improvements in hand-opening time and quantitative muscle testing at the higher dose levels; however, the study was not powered to evaluate clinical efficacy.

Source: Johnson NJ, Tai LJ, Hamel JI, et al. An antibody-oligonucleotide conjugate for myotonic dystrophy type 1. N Engl J. 2026;394(8):763-772. doi:10.1056/NEJMoa2407326