Del-Desiran Fails to Meet Primary Endpoint in Phase 3 HARBOR Trial of Myotonic Dystrophy 1

Novartis announced that the phase 3 HARBOR study (NCT06411288) evaluating investigational delpacibartetedesiran (del-desiran; formerly AOC 1001) in people with myotonic dystrophy type 1 (DM1) did not meet its primary endpoint of video hand opening time (vHOT), a measure of hand myotonia. Novartis confirmed evidence of clinical activity that was observed in secondary endpoints and exploratory analyses, with full study data undergoing further evaluation.¹

The topline findings represent a setback for a program that had previously generated biochemical and exploratory functional signals in earlier-stage studies. Novartis said it is evaluating the complete HARBOR dataset and plans to engage with regulatory authorities to determine the appropriate development path for del-desiran.

“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, President, Development and Chief Medical Officer, Novartis, in a statement.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.”

HARBOR Does Not Meet Primary Endpoint

HARBOR is a global, randomized, double-blind, placebo-controlled phase 3 study evaluating del-desiran over 54 weeks in approximately 150 people with DM1. Participants were randomly assigned to receive del-desiran or placebo every 8 weeks. In addition to vHOT, the trial assessed muscle strength, activities of daily living, mobility, and physical function, including hand grip strength, quantitative muscle testing (QMT) total score, the DM1-Activ measure, and the 10-meter walk/run test (10mWRT).¹

In HARBOR, the primary endpoint was change in vHOT over 54 weeks. Novartis reported that del-desiran did not produce a statistically significant improvement compared with placebo on this measure.

The company did not provide numerical efficacy data for the primary or secondary endpoints in its September 8 announcement. It reported that signals of clinical activity were observed across secondary endpoints and exploratory analyses, but the full dataset remains under analysis.

The absence of detailed topline data limits interpretation of the secondary findings, including whether any observed differences were statistically significant, consistent across functional measures, or clinically meaningful.

Earlier MARINA Data Supported Target Engagement

The HARBOR readout follows phase 1/2 MARINA (NCT05027269) data that demonstrated evidence of target engagement with del-desiran. As previously reported by NeurologyLive, muscle biopsies demonstrated dose-dependent delivery of del-desiran's siRNA, along with reductions in DMPK mRNA and improvements in RNA missplicing at higher doses.²

Among the exploratory clinical findings from MARINA, higher-dose treatment was associated with improvements in hand-opening time and QMT measures. At day 183, the composite QMT score increased by 3.84 points in the 4-mg/kg group compared with a decline of 1.01 points in the placebo group. Changes in mobility measures were more variable, while DM1-Activ scores favored the 4-mg/kg group.

Those findings provided the rationale for continued development of del-desiran in the phase 3 setting, although the earlier trial was relatively small and short in duration. The MARINA study included 38 participants in the safety population, limiting the ability to establish the efficacy of the agent on functional outcomes.

NeurologyLive also previously reported on the FDA's removal of a partial clinical hold affecting AOC 1001 in October 2024. The hold had followed a serious adverse event in a participant in the 40-mg arm of MARINA. At the time, AOC 1001 was advancing into the HARBOR phase 3 program.³

Del-Desiran Program Faces Setback Amid Broader AOC Development

Del-desiran is one of 3 AOC therapies Novartis is advancing in neuromuscular disease following its acquisition of Avidity Biosciences. The company said its broader AOC pipeline remains active, including delpacibartzotadirsen (del-zota), an investigational therapy for Duchenne muscular dystrophy in patients with mutations amenable to exon 44 skipping, and delpacibartbraxlosiran (del-brax), an investigational therapy for facioscapulohumeral muscular dystrophy.¹

For del-desiran specifically, the HARBOR findings mark an important divergence from the earlier MARINA experience. Although MARINA provided evidence that the AOC could reach skeletal muscle, reduce disease-associated DMPK RNA, and influence downstream molecular measures, the phase 3 study did not meet its prespecified primary clinical endpoint.

Novartis said the full HARBOR dataset will be evaluated before decisions are made regarding the future of the program.

REFERENCES
1. Novartis provides update on delpacibartetedesiran (del-desiran) Phase III HARBOR study for the treatment of myotonic dystrophy type 1 (DM1). Novartis. News Release. September 8, 2026. Accessed: September 8, 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. Johnson N, Tai LJ, Hammel J, et al. An Antibody–Oligonucleotide Conjugate for Myotonic Dystrophy Type 1. N Engl J Med. 2026;394:763-772. Doi: 10.1056/NEJMoa2407326
3. Avidity Biosciences Announces FDA Removed Partial Clinical Hold on Delpacibart Etedesiran (del-desiran/AOC 1001). News release. Avidity Biosciences. October 3, 2024. Accessed October 9, 2024. https://aviditybiosciences.investorroom.com/2024-10-03-Avidity-Biosciences-Announces-FDA-Removed-Partial-Clinical-Hold-on-Delpacibart-Etedesiran-del-desiran-AOC-1001