FDA Grants Breakthrough Therapy Designation for AOC 1001 in Myotonic Dystrophy Type 1


Avidity Biosciences is anticipated to initiate its phase 3 HARBOR trial assessing AOC 1001 as a treatment for patients with myotonic dystrophy type 1 in the second quarter of 2024.

Sarah Boyce  (Credit: Avidity)

Sarah Boyce

(Credit: Avidity)

According to a recent announcement, the FDA has granted breakthrough therapy designation to AOC 1001 (Avidity Biosciences), an investigational treatment based on Avidity’s Antibody Oligonucleotide Conjugates (AOC) platform, for the treatment of myotonic dystrophy type 1 (DM1).1 The therapy, also known as del-desiran, consists of a monoclonal antibody that binds to the transferrin receptor 1 conjugated with a small interfering RNA targeting DMPK mRNA, the underlying cause of DM1.

"We are pleased that the FDA has granted breakthrough therapy designation to del-desiran for DM1, underscoring the potential of del-desiran to be an effective treatment and the urgency of bringing this treatment to patients living with DM1," Sarah Boyce, president and chief executive officer at Avidity, said in a statement.1 "Initiation is underway for our global phase 3 HARBOR study as we focus on rapidly advancing del-desiran for patients living with DM1, who currently have no treatment options to address the underlying cause of this devastating rare muscle disease."

Top Clinical Takeaways

  • AOC 1001, utilizing the company's Antibody Oligonucleotide Conjugates platform, shows promise as a targeted therapy for myotonic dystrophy type 1 (DM1).
  • FDA's breakthrough therapy designation highlights the urgent need for effective treatments for DM1.
  • The planned phase 3 HARBOR study aims to further evaluate AOC 1001's efficacy and safety profile in patients with DM1.

In March 2024, the company announced additional data from the long-term, open-label extension (OLE) of the phase 2 MARINA trial (NCT05479981) which further highlighted AOC 1001’s potential as a treatment for patients with DM1.2 These results were recently presented at the 2024 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, held March 3-6, in Orlando, Florida, by lead author John W. Day, MD, PhD, medical advisor and care center director at the MDA.3 The phase 3 HARBOR study, a subsequent trial to MARINA, is expected to initiate in the second quarter of 2024.

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HARBOR is expected to include the same key end points as MARINA, with change in video hand opening time as the primary end point, along with 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 prior 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 patients with DM1 compared to natural history data is remarkable," Day, who also serves as a professor of neurology and pediatrics, and director, Division of Neuromuscular Medicine, Stanford University School of Medicine, said in a statement.2 "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 patients with DM1. I am very encouraged by the prospect of del-desiran as a potential treatment for DM1."

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 measures 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

1. Avidity Biosciences Receives FDA Breakthrough Therapy Designation for Delpacibart Etedesiran (AOC 1001) for Treatment of Myotonic Dystrophy Type 1. News Release. Avidity Biosciences. Published May 8, 2024. Accessed May 8, 2024. https://aviditybiosciences.investorroom.com/2024-05-08-Avidity-Biosciences-Receives-FDA-Breakthrough-Therapy-Designation-for-Delpacibart-Etedesiran-AOC-1001-for-Treatment-of-Myotonic-Dystrophy-Type-1
2. 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 May 8, 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
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
4. 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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