AOC Del-desiran Demonstrates Target Engagement in Phase 1/2 MARINA Trial for Myotonic Dystrophy Type 1

An investigational antibody–oligonucleotide conjugate (AOC), delpacibart etedesiran (AOC 1001; del-desiran), demonstrated skeletal muscle delivery of small interfering RNA (siRNA) and reductions in mutant DMPK messenger RNA (mRNA) in adults with myotonic dystrophy type 1 (DM1) in the phase 1/2 MARINA clinical trial (NCT05027269).¹ Results from the study were published in The New England Journal of Medicine.

DM1 is a rare, autosomal-dominant multisystem disorder caused by a CTG repeat expansion in the 3′ untranslated region of the DMPK gene.² The expanded transcript forms toxic RNA hairpins that sequester muscleblind-like (MBNL) proteins, leading to widespread RNA missplicing and progressive skeletal, cardiac, respiratory, and gastrointestinal dysfunction.²˒³ Adult-onset DM1 is characterized by myotonia, distal muscle weakness, dysphagia, respiratory insufficiency, and conduction abnormalities, with reduced life expectancy.³˒⁴ There are currently no disease-modifying therapies approved for DM1.⁴

MARINA was a randomized, placebo-controlled, phase 1/2 study evaluating single and multiple ascending doses of del-desiran in adults with DM1.¹ Participants were assigned to placebo or intravenous del-desiran at 1 mg/kg, 2 mg/kg, or 4 mg/kg. Thirty-eight participants received at least 1 dose and were included in the safety population; 37 patients completed the trial.

The mean age was 42 years, and most participants who received at least 1 dose of the AOC were women (74%). Baseline disease severity was moderate, with most participants having a Muscular Impairment Rating Scale score of 4 to 5 and a mean 10-meter walk–run time of 6.82 seconds.

Muscle biopsy samples demonstrated dose-dependent increases in siRNA concentrations, with mean levels of 0.16 nmol/L at 1 mg/kg, 0.45 nmol/L at 2 mg/kg, and 1.43 nmol/L at 4 mg/kg. Reductions in DMPK mRNA from baseline were observed across active-dose groups (−46% at 1 mg/kg, −44% at 2 mg/kg, −37% at 4 mg/kg) compared with minimal change in placebo (0.9%).¹ Composite missplicing scores improved primarily at 2 mg/kg and 4 mg/kg (mean changes of −17% and −16%, respectively), compared to mean changes of -3% in the 1-mg group and -7% in the placebo group.¹ These findings support delivery of siRNA to skeletal muscle and engagement of the intended molecular target. The plasma half-life of siRNA ranged from 28 to 50 hours, and urinary excretion accounted for 3% to 4% of administered siRNA.

Exploratory end points suggested potential clinical signals at higher doses. Improvements in hand-opening time and quantitative muscle testing were observed in the 2-mg/kg and 4-mg/kg groups compared with placebo. At day 183, composite quantitative muscle testing scores had increased by 3.84 points in the 4-mg/kg group versus a decline of −1.01 in placebo.¹ Hand-grip strength and manual muscle testing similarly favored higher-dose treatment at day 183

Changes in mobility-based measures, including the 10-meter walk–run and timed up-and-go tests, were variable. Participant-reported activities of daily living (DM1-Activ^C) improved in the 4-mg/kg group but declined in placebo.

With regard to safety, most adverse events were mild to moderate. The most common treatment-emergent events included muscle biopsy–related pain, anemia, COVID-19 infection, headache, and nausea.¹

One participant in the 4-mg/kg group experienced a severe, serious adverse event deemed related to treatment: memory loss and visual impairment within 24 hours of infusion. MRI indicated probable bilateral ischemia with subsequent hemorrhagic transformation. The event led to treatment discontinuation and a temporary FDA enrollment pause, which has since been lifted. Another severe serious event in a patient in the 2 mg group—respiratory failure—was judged unrelated to study drug and attributed to opioid pain medication taken after an elective surgery. No protocol-defined dose-stopping criteria were met in the trial.

Although MARINA demonstrated biochemical target engagement and preliminary signals in exploratory functional measures, the study was limited by small sample size, short duration, underrepresentation of men, and heterogeneity in disease severity between study parts. Variability in biopsy sampling and clinical measures may also have influenced results.

Importantly, reductions in DMPK mRNA were similar across dose levels, suggesting a potential plateau effect in mRNA knockdown, while missplicing improvements appeared dose dependent. The relationship between molecular corrections and sustained clinical benefit remains to be determined.

Longer-term data from the extension and phase 3 trials will be critical to clarify efficacy, safety, and the clinical relevance of splicing correction in DM1. An open-label extension study (NCT05479981) is evaluating longer-term safety and dosing every 8 weeks at 4 mg/kg. A phase 3, double-blind, placebo-controlled trial (HARBOR; NCT06411288) is currently ongoing.

"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," lead author and primary investigator Nicholas E. Johnson, MD, MSci, FAAN, a professor and vice chair of research in the Department of Neurology at Virginia Commonwealth University, said in a press release.⁹ "DM1 is a progressive disorder that is often fatal, increases in severity from generation to generation, and impacts thousands of people and families in the United States alone. There is an urgent need for an approved therapy that can address the underlying genetic cause of this disease, and these del-desiran data, as well as available data from the ongoing OLE study, are very encouraging for the DM1 community."

REFERENCES

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3. Harper PS. Myotonic dystrophy. Lancet. 2001;358(9298):1477-1483. https://doi.org/10.1016/S0140-6736(01)06522-4

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5. Avidity Biosciences. MARINA trial (NCT05027269). https://clinicaltrials.gov/study/NCT05027269

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7. Wheeler TM, Leger AJ, Pandey SK, et al. Targeting nuclear RNA for in vivo correction of myotonic dystrophy. Nature. 2012;488(7409):111-115. https://doi.org/10.1038/nature11362

8. ClinicalTrials.gov. HARBOR trial (NCT06411288). https://clinicaltrials.gov/study/NCT06411288

9. The New England Journal of Medicine publishes results from phase 1/2 MARINA® trial of delpacibart etedesiran (del-desiran) for treatment of myotonic dystrophy type 1. News release. Avidity Biosciences, Inc. February 18, 2026. Accessed February 26, 2026. https://investors.aviditybiosciences.com/2026-02-18-The-New-England-Journal-of-Medicine-Publishes-Results-from-Phase-1-2-MARINA-R-Trial-of-Delpacibart-Etedesiran-del-desiran-for-Treatment-of-Myotonic-Dystrophy-Type-1