Evaluating the Therapeutic Potential of Del-Desiran in Myotonic Dystrophy Type 1: The HARBOR Trial

Myotonic dystrophy type 1 (DM1) is known as a progressive neuromuscular disorder that impacts multiple organ systems, including skeletal and smooth muscles, the heart, eyes, and both the endocrine and central nervous systems. The condition is caused by an expansion of CUG triplet repeats in the myotonic dystrophy protein kinase (DMPK) gene, with healthy individuals typically exhibiting fewer than 35 repeats. In contrast, those with DM1 may have thousands of these repeats, which contribute to the characteristic symptoms of the disease.¹

The progression of DM1 can vary widely among patients, but in most cases, symptoms develop gradually. The most common form of the disease can begin during adolescence or young adulthood, often presenting as muscle weakness in the face, neck, fingers, and ankles. Over time, this weakness tends to progress to other muscle groups. Currently, there is no cure for DM1, as the disease is managed through various symptomatic therapeutic options, none of which focus on the underlying cause of the condition.

In response to the challenges faced by individuals living with DM1, the HARBOR phase 3 registrational study (NCT06411288) aims to evaluate the safety and efficacy of Avidity Biosciences’ del-desiran (formerly AOC 1001) as a potential treatment for the disease. Developed in collaboration with patients, caregivers, advocates, and healthcare professionals, the study is designed to address the specific needs of the DM1 community. The trial's main goal is to assess del-desiran's impact on multiple aspects of the disease, including myotonia, muscle strength, and overall functional ability in daily life. Notably, the primary end point will focus on the effects of del-desiran on hand function, a critical aspect of DM1-related disability.²

Sub Subramony, MD

(Credit: University of Florida)

“Del-desiran is an interfering RNA that targets and degrades mRNA transcribed from the DMPK gene. In DM1, the mRNA transcribed from the expanded allele acquires novel properties that are deleterious. Specifically, the mRNA sequesters RNA binding proteins such as MBNL, leading to a paucity of MBNL in the nuclei of cells,” lead researcher Sub Subramony, MD, professor in the Department of Neurology at University of Florida, told NeurologyLive^® in a recent interview. “This, in turn, alters the splicing pattern of numerous other genes, and it is believed that altered splicing of these other genes contributes to much of the cellular dysfunction. Del-desiran degrades the DMPK mRNA, leading to restoration of MBNL and reversing the abnormal splicing pattern. This can be expected to reduce the cellular dysfunction and pathology.”

The HARBOR study is a randomized, double-blind, placebo-controlled trial set to enroll approximately 150 patients with DM1 across several countries. Following eligibility screening, participants will be randomly assigned to receive either del-desiran or a placebo. Both treatments will be administered through intravenous infusions every eight weeks, with a 1:1 randomization ratio. As a double-blind study, neither participants nor study investigators will know which treatment each participant is receiving.

The study will include a screening phase of up to 6 weeks, followed by a 54-week treatment phase, with the entire study lasting approximately 60 weeks. Participants will receive 7 doses of either del-desiran or placebo, with the final dose administered at Week 48. The final assessment will take place at Week 54, at which point eligible participants may have the opportunity to enroll in an open-label extension (OLE) study, contingent on regulatory approval.

To ensure the safety and integrity of the study, an Independent Data Monitoring Committee (IDMC) will oversee the trial at regular intervals, reviewing data related to safety, tolerability, and efficacy. This committee will provide recommendations to ensure that participants are receiving the safest and most effective treatment options.

Participants in the HARBOR study must meet specific inclusion criteria, including a clinical and genetic diagnosis of DM1 with a CTG repeat length of 100 or more. Additionally, they must have the ability to walk independently for at least 10 meters during the screening phase, with the use of orthoses or ankle braces allowed. Key exclusion criteria include pregnancy, breastfeeding, uncontrolled diabetes, recent treatment with investigational drugs or anti-myotonic medications, a history of decompensated heart failure within the last three months, and a body mass index greater than 35 kg/m² at screening.

Eligible participants will take part in the study for approximately 14 months, which includes both the screening phase and the treatment period. Following the conclusion of the treatment phase, participants who do not enroll in the open-label extension (OLE) study will continue to be monitored in the extended follow-up period for up to 2 months. The OLE study will allow all participants, regardless of whether they received del-desiran or placebo, the option to continue receiving treatment. This extension study, pending regulatory approval, will provide further insights into the long-term effects and potential benefits of del-desiran for individuals with DM1.

“Initial studies selected patients with minimal comorbidities for safety considerations. Disease characteristics indicated mild to moderate disease, allowing measurement of clinical responses,” Subramony said in the interview. “OLE allows for long-term safety monitoring. The potential exists to assess long-term efficacy in comparison to natural history cohorts.”

In March 2024, data reported from the long-term, OLE of the phase 2 MARINA trial (NCT05479981) further highlighted del-desiran’s potential as a treatment for patients with DM1.³ As of January 2024, the MARINA-OLE included over 265 infusions of AOC 1001 totaling 61.1 patient-years of experience. All 37 participants entered the OLE where they received either 2 mg/kg doses of AOC 1001 escalating to 4 mg/kg or continued to be dosed at 4 mg/kg throughout.

In the OLE, 35 patients (95%) experienced adverse events (AEs), most of which were mild or moderate. The most common related AEs reported in 2 or more participants included nausea and headache. There were no discontinuations from the OLE and all patients remain in the ongoing study. Several serious AEs such as nausea/vomiting, worsening of atrial fibrillation, and chest pain, were unrelated to AOC 1001 and consistent with DM1. Of note, 1 participant had acute cholelithiasis and biliary pancreatitis.

In terms of efficacy, the 4 mg/kg group of AOC 1001 provided consistent and durable improvements in a number of measure of strength, including hand grip and Quantitative Muscle Testing total score. In addition, treated patients demonstrated improvements in myotonia and DM1-Activ, a patient reported outcome that measures activities of daily living. These data were consistent with previously reported findings from MARINA-OLE at the 28th Annual Congress of the World Muscle Society, held October 3-7, 2024.⁴

REFERENCES
1. Habor Trial. Accessed March 20, 2025. https://harbor-trial.com/
2. Global Study of Del-desiran for the Treatment of DM1 (HARBOR). Clinical Trials. Accessed March 20, 2025. https://clinicaltrials.gov/study/NCT06411288?term=NCT06411288&rank=1
3. Avidity Biosciences announces positive AOC 1001 long-term data showing reversal of disease progression in people living with myotonic dystrophy type 1 across multiple end points; same key endpoints agreed for phase 3 HARBOR study. News release. Avidity Biosciences. March 4, 2024. Accessed March 20, 2025. https://www.prnewswire.com/news-releases/avidity-biosciences-announces-positive-aoc-1001-long-term-data-showing-reversal-of-disease-progression-in-people-living-with-myotonic-dystrophy-type-1-across-multiple-endpoints-same-key-endpoints-agreed-for-phase-3-harbor-trial-302078020.html
4. Johnson N, Day J, Hamel J, et al. Initial results of the phase 2 open-label extension study of AOC 1001 in adults with myotonic dystrophy type 1: MARINA-OLE. Presented at: MDA Clinical and Scientific Conference; March 3-6, 2024; Orlando, FL. POSTER POSTER T307