Del-desiran Shows Muscle Delivery and Splicing Improvements in Phase 1/2 DM1 Trial

Final results from the Phase 1/2 MARINA trial of delpacibart etedesiran (del-desiran) in people living with myotonic dystrophy type 1 were published in the February 19 issue of The New England Journal of Medicine. The trial demonstrated effective delivery of the investigational antibody-oligonucleotide conjugate to muscle tissue, resulting in approximately 40% mean reduction in toxic DMPK mRNA and improvements across multiple functional measures.

The Phase 1/2 MARINA trial was a randomized, double-blind, placebo-controlled study designed to evaluate the safety and tolerability of single and multiple ascending doses of del-desiran administered intravenously in adults with DM1 for six months. Data were assessed from 38 participants who were randomized 3:1 to receive one dose of 1 mg/kg del-desiran, three doses of either 2 mg/kg del-desiran or 4 mg/kg del-desiran (reflected as siRNA dose), or placebo.

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 received placebo. The primary endpoint of the study was to evaluate the safety and tolerability of del-desiran. Exploratory endpoints were to evaluate the clinical activity of del-desiran across multiple efficacy measures.

The percent change in DMPK mRNA levels in muscle-biopsy samples was −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. Maximum plasma concentrations of small interfering RNA (siRNA) and the area under the curve increased proportionally with dose escalation, and a minor fraction of siRNA was recovered in urine. Reductions in the mean composite missplicing score from baseline were 3%, 17%, 16%, and 7%, respectively, consistent with amelioration of missplicing in the 2-mg and 4-mg groups.

Treatment demonstrated improvements in exploratory functional measures including hand function/myotonia (video hand opening time, or vHOT), muscle strength (Quantitative Muscle Testing, or QMT total score), mobility (10-Meter Walk/Run Test, or 10mWRT, and Timed Up and Go test, or TUG), and DM1-Activ, a patient-reported outcome that measures activities of daily living (e.g., taking a shower, visiting family or friends, and walking up stairs).

Mild or moderate adverse events occurred in 35 of the 38 participants who received an infusion. Two severe, serious adverse events occurred in 2 participants in the 2-mg and 4-mg groups; 1 of these participants discontinued participation in the trial. One of these SAEs was deemed drug-related. Most treatment emergent adverse events (TEAEs) were mild or moderate in participants with DM1 and did not result in discontinuation.

DM1 is an underrecognized, progressive and often fatal neuromuscular disease with no disease modifying therapies. Del-desiran is an investigational treatment designed to address the underlying genetic root cause of DM1 by reducing total levels of the toxic, DMPK (myotonic dystrophy protein kinase) mRNA. The accumulation of these toxic mRNA sequester key RNA-regulatory proteins that subsequently lead to missplicing of several downstream genes, resulting in the diverse clinical manifestations of disease.

Myotonic dystrophy type 1 is a rare, dominantly inherited, progressive, disabling, neuromuscular disease that leads to decreased life expectancy and has no approved therapies. The disease is caused by a trinucleotide repeat expansion in DMPK, which encodes myotonic dystrophy type 1 protein kinase and imparts a toxic gain of function to the transcribed messenger RNA (mRNA), resulting in dysregulated alternative splicing (missplicing). Delpacibart etedesiran (del-desiran [AOC 1001]) is a monoclonal antibody–oligonucleotide conjugate. The antibody component targets transferrin receptor 1, and the oligonucleotide component targets DMPK mRNA.

Del-desiran (4 mg/kg) is currently being assessed in the global Phase 3 HARBOR study in people living with DM1 who are age 16 and older and in the ongoing HARBOR open-label extension (HARBOR-OLE) trial with all the participants who completed the Phase 1/2 MARINA trial. The global Phase 3 HARBOR study completed enrollment in 2025.

The HARBOR trial, a phase 3, double-blind, randomized, placebo-controlled trial (NCT06411288), is evaluating del-desiran at a dose of 4 mg per kilogram. The global Phase 3 HARBOR trial is a randomized, placebo-controlled, double blind pivotal study designed to evaluate del-desiran in approximately 150 people (age 16 and older) living with DM1. The trial is being conducted at approximately 40 sites globally. Patients are administered either del-desiran or placebo (1:1) every eight weeks. HARBOR is designed to assess multiple key functional aspects of DM1. The primary endpoint is video hand opening time (vHOT), a measurement of myotonia, which is a hallmark symptom of DM1. Key secondary endpoints include muscle strength as measured by hand grip strength and quantitative muscle testing (QMT) total score, and activities of daily living as measured by DM1-Activ.

Del-desiran has received Breakthrough Therapy, Orphan Drug and Fast Track designation. Del-desiran was also the first investigational treatment for DM1 to receive Orphan Drug designation in Japan.