Avidity to Begin Phase 3 HARBOR Trial in Myotonic Dystrophy Following Positive MARINA Results


Over 61.1 patient-years of treatment experience, AOC 1001 was well tolerated in patients with DM1, with nausea and headache the most commonly reported adverse events.

John W. Day, MD, PhD, professor of neurology and pediatrics, and director, Division of Neuromuscular Medicine, Stanford University School of Medicine

John W. Day, MD, PhD

Additional data from the long-term, open-label extension (OLE) of the phase 2 MARINA trial (NCT05479981) further highlighted AOC 1001’s (Avidity Biosciences) potential as a treatment for patients with myotonic dystrophy type 1 (DM1). The phase 3 HARBOR study, a subsequent trial to MARINA, is currently enrolling, with initiation expected in the second quarter of 2024.1,2

HARBOR is expected to include the same key end points as MARINA, with change in video hand opening time as the primary end point, and secondary outcomes of muscle strength and activities of daily living. The trial, spanning more than 40 global sites, will randomly assign 150 patients to either AOC 1001 4 mg/kg or placebo every 8 weeks for a 54-week treatment period, followed by an OLE. Of note, the primary analysis is expected to cover the first 30 weeks of the study.

In the announcement, Avidity wrote that it was accelerating the initiation of the study to begin earlier, as well as announced delpacibart etedesiran (abbreviated as del-desiran) as the newly approved international nonproprietary name of AOC 1001.

"The long-term data from the MARINA-OLE study demonstrating that del-desiran improved measures of disease progression in DM1 patients compared to natural history data is remarkable," study investigator John W. Day, MD, PhD, professor of neurology and pediatrics, and director, Division of Neuromuscular Medicine, Stanford University School of Medicine, said in a statement.1 "The favorable long-term safety data and consistent, durable improvement in myotonia, muscle strength and patient-reported outcomes measures show the potential of del-desiran to make a meaningful difference in the lives of DM1 patients. I am very encouraged by the prospect of del-desiran as a potential treatment for DM1."

AOC 1001 is an antibody oligonucleotide conjugate comprised of a human TfR1-targeting, effector function-null, humanized IgG monoclonal antibody, as well as a non-cleavable linker. It also contains a double-stranded siRNA oligonucleotide complementary to both wild-type and mutant DMPK mRNA. Overall, the drug is delivered to muscle, resulting in DMPK reduction and increased estimated functional MBNL levels.

READ MORE: Despite Limited Literature, Combination Therapy Occurring in Spinal Muscular Atrophy

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, one 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, 2024.3

"Initiating our global pivotal study for del-desiran in the coming months is a significant step forward in bringing a much-needed treatment to people living with DM1 as quickly as possible. We are pleased that the agreed upon functional endpoints in the Phase 3 HARBOR study are the same endpoints in which del-desiran has demonstrated consistent and durable improvements in the MARINA studies," Sarah Boyce, president and chief executive officer at Avidity, said in a statement.1 "Thank you to the DM1 community, in particular - the participants, their families, the investigators and their teams - for their support, dedication and commitment to the MARINA program. The depth and breadth of del-desiran data that we have gathered from these studies offer hope for people living with DM1, a devastating rare disease for which there are no treatment options available."

1. 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 12, 2024. 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
2. 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
3. Johnson N, Day J, Hamel J, et al. Topline safety and efficacy data analysis of phase 1/2 clinical trial evaluating AOC 1001 in adults with myotonic dystrophy type 1: MARINA. Presented at: World Muscle Society 2023; October 3-7; Charleston, SC.
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