FDA Removes Partial Hold for Myotonic Dystrophy Agent AOC 1001

John W. Day, MD, PhD

According to a recent announcement, the FDA has removed a partial clinical hold on Avidity Biosciences’ investigational agent AOC 1001 in development for patients with myotonic dystrophy type 1 (DM1). The hold, originally placed in September 2022, was related to a serious adverse event reported in a single patient treated in the 40-mg arm of the phase 1/2 MARINA trial (NCT05027269).^1,2

At the time of the partial hold, nearly 40 of the anticipated 44 participants had been enrolled in MARINA and its open-label extension (OLE); however, all participants, whether on AOC 1001 or placebo, were instructed to continue dosing as planned. The company also noted that the clinical hold was not going to impact those who choose to enter the OLE.²

AOC 1001, otherwise known as delpacibart etedesiran (del-desiran), consists of a proprietary monoclonal antibody that binds to the transferrin receptor 1 (TfR1) conjugated with a siRNA targeting DMPK, the root cause of DM1. The agent is currently being investigated in the global phase 3 HARBOR trial (NCT05479981) and the ongoing MARINA-OLE trial.

HARBOR, which includes 150 patients with DM1, is built similar to the previously completed MARINA study. It includes the same key end points, with change in video hand opening time as the primary end point, and outcomes of muscle strength and activities of daily living as secondary end points. The study, which was anticipated to initiate in the second quarter earlier this year, tests whether AOC 1001 at doses of 4 mg/kg every 8 weeks is more effective than placebo over a 54-week treatment period. HARBOR’s primary analysis is expected to cover the first 30 weeks of the study.

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In March, Avidity announced positive long-term data from the OLE of MARINA, with results showing that del-dersiran improved measures of disease progression in patients with DM1 compared with natural history data. Overall, the 4 mg/kg group of AOC 1001 provided consistent and durable improvements in a number of measures of strength, including hand grip and Quantitative Muscle Testing total score. Patients treated with the investigational agent also saw enhancements in myotonia and DM1-Activ, a patient-reported outcome that measures activities of daily living.³

At the time of the announced data, study investigator John W. Day, MD, PhD, said in a statement. "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," Day, professor of neurology and pediatrics, and director, Division of Neuromuscular Medicine, Stanford University School of Medicine, added, "I am very encouraged by the prospect of del-desiran as a potential treatment for DM1."

The OLE data, which included over 265 infusions of AOC 1001 across all 37 participants, showed that the drug was safe, with nausea and headache as the most commonly reported adverse events (AEs), most of which were mild or moderate. 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.

A few months after the data, the FDA granted breakthrough therapy designation to AOC 1001 as a potential treatment for DM1. To date, it has also received orphan drug and fast track designations by both the FDA and European Medicines Agency.

REFERENCES
1. 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
2. Avidity Biosciences announces FDA partial clinical hold on new participant enrollment in phase 1/2 MARINA trial. News release. September 27, 2022. Accessed October 9, 2024. https://aviditybiosciences.investorroom.com/2022-09-27-Avidity-Biosciences-Announces-FDA-Partial-Clinical-Hold-on-New-Participant-Enrollment-in-Phase-1-2-MARINA-TM-Trial
3. 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