Science News: An Antibody-Oligonucleotide Conjugate for Myotonic Dystrophy Type 1

Submitted by: Ben Becker, MD
Edited by: Shaohua Xu, MD

Citation: Johnson NE, Tai LJ, Hamel JI, et al. An Antibody-Oligonucleotide Conjugate for Myotonic Dystrophy Type 1. N Engl J Med. 2026;394(8):763-772. doi:10.1056/NEJMoa2407326

Summary: 
This article reports the final results from the completed phase 1-2 MARINA trial of delpacibart etedesiran (del-desiran [AOC1001]) in myotonic dystrophy type 1 (DM1) patients. DM1 is an autosomal dominant multisystem disorder caused by a trinucleotide repeat expansion in the DMPK gene, resulting in toxic gain‑of‑function to the messenger RNA (mRNA) and missplicing of the encoded myotonic dystrophy type 1 protein kinase. Delpacibart etedesiran is an antibody–oligonucleotide conjugate designed to deliver a small interfering RNA (siRNA) to skeletal muscle via transferrin receptor 1, promoting degradation of toxic DMPK mRNA.

This multicenter, 6‑month, double‑blind, randomized, placebo‑controlled phase 1-2 trial used a nested multiple‑ascending‑dose design (1, 2, and 4 mg/kg) to evaluate dose, delivery, biochemical activity, and safety.

Thirty-eight participants received the study drug or placebo in a 3:1 ratio: 10 received placebo, six received a single 1 mg/kg dose, nine received a 2 mg/kg dose, and 13 received a 4 mg/kg dose. Those in the 2-mg/kg and 4-mg/kg cohorts had more severe baseline characteristics due to expanded inclusion criteria.

Most participants experienced mild or moderate adverse events, most commonly muscle‑biopsy pain, anemia, COVID‑19, headache, and nausea, and no protocol‑specified stopping rules were met. One participant in the 4‑mg group developed acute memory loss and visual impairment and was found to have bilateral thalamic infarctions, which was deemed trial related and resulted in treatment discontinuation.

Muscle biopsies demonstrated dose‑dependent siRNA concentrations, with relatively consistent reductions in DMPK mRNA across doses (−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). The composite missplicing scores improved more in the 2‑mg and 4‑mg groups than in the 1‑mg or placebo groups.

Exploratory functional measures, including video‑assessed hand‑opening time, composite quantitative muscle testing, and hand‑grip strength, showed differences favoring the higher‑dose groups compared with placebo. An open-label extension trial is ongoing for participants who completed the MARINA trial to evaluate treatment effects over a longer duration, while the phase-3 HARBOR trial is underway in parallel. 

Comments: 
While this is a small phase 1-2 clinical trial, this represents a novel disease modifying approach in a hereditary condition with only symptomatic treatment options currently. Delpacibart etedesiran’s mechanism of siRNA delivery demonstrates a decrease in mRNA levels with appropriate ameliorative misplacing at higher dose (2mg/kg and 4mg/kg). Multiple exploratory end points showed promising findings in this initial trial. 

Why is this article interesting/relevant to the AANEM audience? The lack of disease modifying treatment in myotonic dystrophy type 1 would vastly benefit from any potential treatment aimed at reducing toxic gain of function DMPK protein. This novel mechanism by which siRNA is delivered by monoclonal antibody conjugation also provides plausible mechanism for many hereditary conditions marred by difficulties with drug delivery.