Avidity's Del-desiran Shows Promise for Myotonic Dystrophy Type 1 in Phase 1/2 MARINA Trial Published in NEJM
核心洞察
Avidity Biosciences (搜索)' del-desiran achieved approximately 40% reduction in toxic DMPK (搜索) mRNA levels and demonstrated improvements in myotonia, muscle strength, and mobility in the Phase 1/2 MARINA trial.
The New England Journal of Medicine published final results showing acceptable safety and tolerability, with most adverse events being mild or moderate in 38 DM1 (搜索) patients.
Del-desiran represents the first investigational RNA therapeutic to successfully target muscle tissue for myotonic dystrophy type 1 (搜索), a progressive neuromuscular disease with no approved treatments.
Avidity Biosciences (搜索) announced that The New England Journal of Medicine has published final results from its Phase 1/2 MARINA trial of delpacibart etedesiran (del-desiran) for myotonic dystrophy type 1 (搜索) (DM1 (搜索)), demonstrating the first successful targeted delivery of RNA therapeutics to muscle tissue for this rare neuromuscular disease. The study showed del-desiran effectively reduced toxic DMPK (搜索) mRNA levels by approximately 40% while improving multiple functional measures in patients with DM1.
Novel RNA Therapeutic Targets Disease Root Cause
Del-desiran utilizes Avidity's proprietary Antibody Oligonucleotide Conjugate (AOC) platform technology, combining a monoclonal antibody that binds to transferrin receptor 1 (搜索) (TfR1 (搜索)) with a siRNA targeting DMPK (搜索) mRNA. This approach addresses the underlying genetic cause of DM1 (搜索) by reducing levels of toxic DMPK (myotonic dystrophy protein kinase (搜索)) mRNA that accumulate and sequester key RNA-regulatory proteins, leading to missplicing of downstream genes and the diverse clinical manifestations of the disease.
"DM1 (搜索) is a progressive disorder that is often fatal, increases in severity from generation to generation, and impacts thousands of people and families in the U.S. alone," said Nicholas E. Johnson, M.D., M.Sci., FAAN, professor and vice chair of research in the Department of Neurology at Virginia Commonwealth University and lead author of the MARINA trial. "There is an urgent need for an approved therapy that can address the underlying genetic cause of this disease."
Phase 1/2 MARINA Trial Results
The randomized, double-blind, placebo-controlled study enrolled 38 adults with DM1 (搜索) who received single and multiple ascending doses of del-desiran administered intravenously over six months. Participants were randomized 3:1 to receive one dose of 1 mg/kg del-desiran, three doses of either 2 mg/kg or 4 mg/kg del-desiran, or placebo.
The trial demonstrated effective delivery of siRNA to muscle tissue, resulting in splicing improvements in muscle-specific genes following treatment with del-desiran 2 mg/kg and 4 mg/kg doses. Exploratory functional measures showed improvements across multiple domains:
- Hand function and myotonia: Measured by video hand opening time (vHOT), addressing a hallmark symptom of DM1
- Muscle strength: Assessed through Quantitative Muscle Testing (QMT) total score
- Mobility: Evaluated using 10-Meter Walk/Run Test (10mWRT) and Timed Up and Go test (TUG)
- Activities of daily living: Measured by DM1-Activ, a patient-reported outcome assessing tasks like showering, visiting family, and walking up stairs
Safety Profile and Adverse Events
Del-desiran demonstrated acceptable safety and tolerability, with most treatment emergent adverse events (TEAEs) being mild or moderate and not resulting in study discontinuation. Two severe, serious adverse events occurred in participants receiving 2 mg/kg and 4 mg/kg doses, with one participant discontinuing from the 4 mg/kg cohort. One of these serious adverse events was deemed drug-related.
Advancing to Phase 3 Development
Based on these results, Avidity is conducting the global Phase 3 HARBOR trial, a randomized, placebo-controlled, double-blind pivotal study evaluating del-desiran in approximately 150 people aged 16 and older with DM1 (搜索). The trial, conducted at approximately 40 sites globally, completed enrollment in July 2025 with topline data expected in the second half of 2026.
The HARBOR study's primary endpoint is video hand opening time (vHOT) as a measurement of myotonia. Key secondary endpoints include muscle strength measured by hand grip strength and QMT total score, and activities of daily living assessed by DM1 (搜索)-Activ. Patients receive either del-desiran (4 mg/kg) or placebo every eight weeks.
"We remain focused on advancing the ongoing Phase 3 HARBOR study of del-desiran, which is on track to be the first globally approved drug for DM1 (搜索)," said Sarah Boyce, President and Chief Executive Officer at Avidity.
Regulatory Recognition and Unmet Medical Need
Del-desiran has received multiple regulatory designations recognizing its potential therapeutic value, including Breakthrough Therapy, Orphan Drug, and Fast Track designations from the U.S. Food and Drug Administration (FDA), Orphan designation from the European Medicines Agency (EMA), and was the first investigational treatment for DM1 (搜索) to receive Orphan Drug designation in Japan.
DM1 (搜索) is described as an underrecognized, progressive, and often fatal neuromuscular disease with no currently approved disease-modifying therapies. The hereditary autosomal dominant condition is caused by a triplet-repeat in the DMPK (搜索) gene, resulting in toxic gain-of-function mRNA. The disease presents with multisystemic manifestations including myotonia and progressive muscle weakening, potentially affecting cardiovascular, gastrointestinal, respiratory, ocular, and endocrine systems.
Long-term data from the ongoing MARINA open-label extension trial have shown reversal of disease progression across multiple endpoints including video hand opening time, muscle strength, and activities of daily living when compared to natural history data, supporting the continued development of this novel therapeutic approach for DM1 (搜索).