MARINA (Delpacibart Etedesiran for Myotonic Dystrophy Type 1)
(2026)Objective
To evaluate the safety and efficacy of delpacibart etedesiran, an antibody-oligonucleotide conjugate targeting DMPK mRNA, in adults with myotonic dystrophy type 1
Study Summary
• Most AEs mild/moderate (35/38 treated participants); 2 serious adverse events in higher-dose groups; first disease-modifying therapy to show meaningful biomarker and clinical improvements in DM1
Intervention
Delpacibart etedesiran (antibody-oligonucleotide conjugate targeting DMPK mRNA via transferrin receptor 1) at 1, 2, or 4 mg/kg IV
Inclusion Criteria
Adults with genetically confirmed myotonic dystrophy type 1
Study Design
Arms: Delpacibart 1 mg/kg vs 2 mg/kg vs 4 mg/kg vs Placebo
Patients per Arm: 1 mg/kg: 6, 2 mg/kg: 9, 4 mg/kg: 13, Placebo: 10
Outcome
• Improvements in splicing (composite missplicing score), myotonia, muscle strength, and mobility
• AEs: 35/38 (92%) had mild/moderate AEs; 2 SAEs in higher-dose groups
Bottom Line
Delpacibart etedesiran produced dose-dependent reductions in DMPK mRNA (up to 46%) with improvements in RNA splicing, myotonia, muscle strength, and mobility in adults with DM1. This is the first disease-modifying therapy to demonstrate meaningful biomarker and clinical improvements in myotonic dystrophy, leading to FDA Breakthrough Therapy Designation and Phase 3 HARBOR trial initiation.
Major Points
- Delpacibart etedesiran (DMPK-targeting ASO) for myotonic dystrophy type 1: Phase 2 dose-ranging study.
- Targets toxic CUG repeat RNA by reducing DMPK mRNA, the fundamental molecular cause of DM1.
- Splice biomarkers (misregulated alternative splicing) showed dose-dependent improvement.
- Clinical endpoints: myotonia, grip strength, functional measures — assessed at multiple dose levels.
- First RNA-targeting therapy to reach Phase 2 for DM1.
- DM1 is the most common adult muscular dystrophy (~1:8000). No approved disease-modifying therapy.
- ASO administered subcutaneously. Avidity Biosciences / Ionis approach.
- Represents paradigm shift: targeting the molecular cause rather than symptoms of DM1.
- Multiple competing DM1 programs (CRISPR, small molecules) — RNA approach most advanced clinically.
- Phase 3 trials planned based on biomarker and preliminary clinical data.
Study Design
- Study Type
- Phase 1/2, randomized, double-blind, placebo-controlled, dose-escalation trial
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 48
Primary Outcome
Definition: DMPK mRNA reduction from baseline
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | - | - |
Limitations & Criticisms
- Small sample size across dose cohorts (6-13 per group)
- Short follow-up for a slowly progressive disease
- Dose-response not strictly linear (4 mg/kg showed less DMPK reduction than 1 mg/kg)
- Open-label extension ongoing; long-term safety unknown
Citation
Johnson NE et al. N Engl J Med. 2026;394(8):763-772. DOI: 10.1056/NEJMoa2407326