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NEJM Publishes Phase 1/2 MARINA Trial Results for Delpacibart Etedesiran in DM1 Treatment
Avidity Biosciences, Inc., a company pioneering a new class of RNA therapeutics known as Antibody Oligonucleotide Conjugates (AOCs™), has reached a significant milestone. The final results from the completed Phase 1/2 MARINA® trial investigating delpacibart etedesiran (del-desiran) for the treatment of Myotonic Dystrophy Type 1 (DM1) are being published in the esteemed New England Journal of Medicine (NEJM) in the February 19 issue. The manuscript is titled “An Antibody Oligonucleotide Conjugate for Myotonic Dystrophy Type 1.”
Addressing the Genetic Root of DM1
Myotonic Dystrophy Type 1 is a severe, progressive, and often fatal neuromuscular disease that currently lacks disease-modifying therapies. Del-desiran is an investigational treatment specifically engineered to target the underlying genetic cause of DM1 by significantly reducing the levels of toxic messenger RNA produced by the DMPK gene. The accumulation of this toxic mRNA sequesters vital RNA-regulatory proteins, leading to the incorrect splicing of numerous downstream genes, which manifests as the varied and debilitating clinical symptoms characteristic of DM1.
Phase 1/2 MARINA Trial Highlights
The MARINA trial was a critical randomized, double-blind, placebo-controlled study designed to assess the safety, tolerability, and initial clinical activity of single and multiple ascending doses of intravenously administered del-desiran over a six-month period in adults with DM1. Thirty-eight participants were randomized across various dose groups or received a placebo. While the primary endpoint focused on safety and tolerability, numerous exploratory endpoints evaluated the treatment’s potential efficacy.
The results published in NEJM provide compelling evidence for del-desiran’s mechanism and clinical potential:
- Effective Muscle Delivery: Del-desiran successfully delivered its siRNA payload to muscle tissue, resulting in an approximate 40% mean reduction in toxic DMPK mRNA across all treated participants.
- Splicing Correction: Treatment with del-desiran at 2 mg/kg and 4 mg/kg doses led to improvements in the splicing patterns of a key set of muscle-specific genes.
- Functional Improvements: Exploratory measures demonstrated encouraging clinical activity, including improvements in:
- Myotonia and Hand Function: Assessed via video hand opening time (vHOT).
- Muscle Strength: Measured using Quantitative Muscle Testing (QMT total score).
- Mobility: Evaluated through the 10-Meter Walk/Run Test (10mWRT) and Timed Up and Go test (TUG).
- Patient-Reported Outcomes: The DM1-Activ scale, which measures the ability to perform activities of daily living such as showering, visiting others, and climbing stairs, showed positive responses.
- Acceptable Safety Profile: Most treatment-emergent adverse events (TEAEs) were mild or moderate and did not necessitate treatment discontinuation. However, two serious adverse events (SAEs) occurred in the higher dose cohorts, with one deemed potentially drug-related, leading to one participant’s discontinuation from the 4 mg/kg group.
Expert and Leadership Commentary
Dr. Nicholas E. Johnson, M.D., M.Sci., FAAN, professor and vice chair of research in the Department of Neurology at Virginia Commonwealth University and the trial’s lead author, emphasized the urgency of the findings: “These final results from the MARINA study further reinforce del-desiran data reported thus far showing acceptable safety profile and improvements across a range of key functional assessments including myotonia, a hallmark symptom of DM1… There is an urgent need for an approved therapy that can address the underlying genetic cause of this disease, and these del-desiran data… are very encouraging for the DM1 community.”
Sarah Boyce, President and Chief Executive Officer at Avidity, stated, “We are pleased that The New England Journal of Medicine recognizes the significance of the Phase 1/2 MARINA data. The favorable safety profile, coupled with robust analyses of exploratory endpoints in our del-desiran program reinforce our belief that this investigational therapy may offer a transformational treatment option for people living with DM1 and their families.” She added that the company remains dedicated to advancing the ongoing global Phase 3 HARBOR study.
Path to Approval: The HARBOR Study
Del-desiran (4 mg/kg) is currently being evaluated in the pivotal global Phase 3 HARBOR™ trial for individuals aged 16 and older with DM1. This study is designed to assess multiple key functional aspects, with the primary endpoint being vHOT (myotonia measurement). Enrollment for the HARBOR study was completed in July 2025, and the company anticipates a topline data readout for the 54-week assessment in the second half of 2026. Participants completing MARINA are continuing in the HARBOR open-label extension (HARBOR-OLE™) trial.
Del-desiran has already received significant regulatory attention, including Breakthrough Therapy, Orphan Drug, and Fast Track designations from the U.S. FDA, and Orphan designation from the EMA and Japan, underscoring the critical unmet medical need in the DM1 community.