MARINA (AOC 1001): Biomarker Engagement and Safety Signals in DM1

Adults with myotonic dystrophy type 1 (DM1) treated with delpacibart etedesiran (AOC 1001) were described in a recent report summarizing phase 1/2 findings from the MARINA program, including muscle biomarker readouts, pharmacokinetics of the siRNA component, and the occurrence of severe serious adverse events. Key findings included changes in muscle biomarkers (DMPK mRNA and downstream missplicing measures), pharmacokinetic results (including plasma siRNA concentrations and urinary recovery), and reported adverse events. The report outlines the trial design and endpoints, biomarker and pharmacokinetic findings, safety results, and exploratory clinical assessments.

The multicenter, double-blind, placebo-controlled MARINA trial (NCT05027269) enrolled 39 adults with genetically confirmed DM1, and 38 participants received at least one infusion and were included in the safety analysis, according to the report. MARINA was conducted in two parts: Part A randomized participants 3:1 to a single dose of delpacibart etedesiran 1 mg/kg or placebo, and Part B randomized participants 3:1 to three infusions of 2 mg/kg or 4 mg/kg delpacibart etedesiran or placebo at approximately 6-week intervals. The primary endpoint was treatment-emergent adverse events; secondary endpoints included pharmacokinetics, muscle siRNA concentrations, percent change in DMPK mRNA levels, and composite missplicing scores derived from muscle-biopsy samples.

At the treatment biopsy, percent change in muscle DMPK mRNA levels was −46% (1 mg/kg), −44% (2 mg/kg), and −37% (4 mg/kg) with delpacibart etedesiran versus 0.9% with placebo.

Downstream, the report described mean changes in a muscle-biopsy–derived composite missplicing score of −3% (1 mg/kg), −17% (2 mg/kg), and −16% (4 mg/kg), versus −7% with placebo. Maximum plasma small interfering RNA (siRNA) concentrations increased proportionally with dose, and 3% to 4% of administered siRNA was recovered in urine.

Two severe, serious adverse events were described with differing attributions. In the 4-mg group, one participant experienced bilateral thalamic ischemia with hemorrhagic transformation that was deemed related to delpacibart etedesiran and led to treatment discontinuation, while in the 2-mg group, one 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 higher dose levels; however, the study was not powered to evaluate clinical efficacy.

Key Takeaways:

• Muscle DMPK mRNA reductions were reported across active dose groups compared with placebo in treatment-biopsy samples.
• Muscle-derived composite missplicing score changes and dose-proportional plasma siRNA exposure with 3%–4% urinary recovery were reported as biomarker and pharmacokinetic readouts.
• Two severe serious adverse events were described with different attributions, alongside exploratory functional signals that the report noted were not evaluated for efficacy because the study was not powered for that purpose.