Novartis's Del-Desiran Misses Primary Endpoint in Phase 3 DM1 Trial

Novartis announced that its phase 3 HARBOR trial of delpacibart etedesiran (del-desiran) did not meet its primary endpoint of video hand opening time (vHOT) compared with placebo in patients with myotonic dystrophy type 1 (DM1), the company announced September 8, 2026.¹ The therapy showed evidence of clinical activity on secondary and exploratory endpoints, and its safety profile was generally consistent with previously reported data.

"Despite decades of research, there are still no approved treatment options for DM1, and patients and caregivers continue to face a significant daily burden," said Shreeram Aradhye, MD, president of development and chief medical officer at Novartis, in a company press release.¹ "Developing therapies for a complex disease like DM1 remains challenging, and setbacks are part of scientific progress. As we continue to evaluate the full HARBOR dataset, we remain committed to identifying the most appropriate development path for the del-desiran program and advancing innovative approaches for people living with DM1 and other serious neuromuscular diseases."

What did the HARBOR trial evaluate?

HARBOR (NCT06411288) is a global, randomized, double-blind, placebo-controlled phase 3 trial that evaluated del-desiran over 54 weeks in approximately 150 people with DM1, randomized to receive del-desiran or placebo every 8 weeks.¹^,² The primary endpoint was vHOT, a novel measure of hand myotonia, while key secondary endpoints included muscle strength via hand grip strength and quantitative muscle testing, activities of daily living via DM1-Activ, and mobility via the 10-meter walk/run test.¹ Novartis said it is evaluating the full HARBOR dataset and will engage with health authorities to determine the most appropriate development path for del-desiran.¹

How does del-desiran work, and what evidence supported its advancement to phase 3?

Del-desiran is an antibody oligonucleotide conjugate (AOC) consisting of a muscle-targeting monoclonal antibody that binds transferrin receptor 1, conjugated to a small interfering RNA designed to degrade toxic DMPK messenger RNA, the underlying molecular driver of DM1.¹ In the earlier phase 1/2 MARINA trial, del-desiran reduced toxic DMPK transcript levels and corrected aberrant splicing patterns in patients with DM1, with 2 serious adverse events reported among 38 participants.³ Del-desiran holds orphan drug, fast track, and breakthrough therapy designations from FDA, along with orphan medicinal product designation in the European Union.¹

Why is a treatment for DM1 significant?

DM1 is a progressive, multisystem neuromuscular disease caused by an expansion of CTG repeats in the DMPK gene, causing myotonia, muscle weakness, and impaired hand function that can affect daily activities and quality of life. There are currently no approved treatment options for DM1, according to Novartis.¹

What's next for Novartis's neuromuscular pipeline?

Del-desiran is 1 of 3 AOC therapies Novartis added to its neuromuscular pipeline through its acquisition of Avidity Biosciences.¹ The company's other AOC candidates continue to advance, including delpacibart zotadirsen, for Duchenne muscular dystrophy with mutations amenable to exon 44 skipping, which has been filed for accelerated approval and granted FDA priority review. Delpacibart braxlosiran, for facioscapulohumeral muscular dystrophy, is advancing toward an FDA meeting based on positive phase 1/2 biomarker data.¹ Novartis said it is maintaining its 5-6% 5-year sales compound annual growth rate guidance for 2025 to 2030.¹

What are the limitations?

Novartis has not yet disclosed detailed statistical results from HARBOR's secondary and exploratory endpoints, nor a timeline for determining del-desiran's development path. The trial's primary endpoint, vHOT, is a relatively novel outcome measure, and how its use may have influenced the topline result has not been addressed.

References

1. Novartis. Novartis provides update on delpacibart etedesiran (del-desiran) Phase III HARBOR study for the treatment of myotonic dystrophy type 1 (DM1). Press release. Published September 8, 2026. Accessed September 9, 2026. https://www.novartis.com/news/media-releases/novartis-provides-update-delpacibart-etedesiran-del-desiran-phase-iii-harbor-study-treatment-myotonic-dystrophy-type-1-dm1
2. Global study of del-desiran for the treatment of DM1 (HARBOR). ClinicalTrials.gov; NCT06411288. Updates September 1, 2026. Accessed September 9, 2026. https://clinicaltrials.gov/study/NCT06411288
3. 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