Potential Path for Phase 3 Study of AOC 1001 in Myotonic Dystrophy Becomes Clear After FDA Ease’s Clinical Hold


The phase 1/2 MARINA trial assessed the activity of AOC 1001 across key biomarkers, including spliceopathy, an important biomarker for myotonic dystrophy type 1, and knockdown of DMPK mRNA.

Sarah Boyce, president and chief executive officer, Avidity

Sarah Boyce

The FDA has eased its partial hold on Avidity Biosciences’ investigational agent AOC 1001, a product in development for myotonic dystrophy type 1 (DM1), to allow for additional recruitment in the 4 mg/kg dose cohort currently being tested in the open-label extension (OLE) phase of the phase 1/2 MARINA trial (NCT05027269). Avidity expects that results from the trial will be used to finalize the pivotal dose of the therapy, leading to a phase 3 study.1

With the FDA’s decision to ease the hold, the company is expected to double the number of participants receiving the 4-mg dose by escalating approximately 12 participants currently on 2 mg/kg of AOC 1001 in the OLE. All other participants will remain on their current dose of either 2 mg/kg or 4 mg/kg of AOC 1001, with findings from the OLE expected to be shared at the end of 2023.

For context, the FDA originally placed a partial hold on enrollment for the trial in September 2022, citing a serious adverse event reported in a single patient treated in the 4-mg arm of the study as the reason for the decision.2 At the time of the partial hold, the FDA noted that all participants, whether on AOC 1001 or placebo, could continue their current dosing as planned, and that the hold would not impact those who choose to enter the OLE. Avidity concluded the trial the MARINA trial with 38 participants enrolled and continues to dose 36 of those participants at both 2 mg/kg and 4 mg/kg of AOC 1001 in the OLE.

"This positive step forward in our discussions with FDA provides the opportunity to gather additional data on the 2-4 mg/kg dose range of AOC 1001 while, in parallel, finalizing our Phase 3 study design and aligning with health authorities on a global regulatory path for AOC 1001,” Sarah Boyce, president and chief executive officer, Avidity, said in a statement.1 "We recently announced positive topline data for AOC 1001 demonstrating functional improvement across multiple clinical outcome measures and look forward to sharing a first look at data from the MARINA-OLE study at the end of this year."

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DM1, caused by a toxic CTG repeat expansion in the 3’ untranslated region of the DMPK gene, has no disease-modifying therapies approved to treat the condition. AOC 1001, an RNA therapeutic designed to target the pathogenic driver of DM1, is a DMPK siRNA conjugated to humanized antibody targeting human transferrin receptor 1 (TfR1). The antibody is designed to target muscles for delivery of siRNA into the cytoplasm and nucleus where it mediates DMPK mRNA degradation.3

MARINA, a double-blind, placebo-controlled study of adults aged 18 to 65 years with genetically confirmed DM1, had preliminary data read out in December 2022, showing the first-ever successful targeted delivery of siRNA into muscle. Following a single dose of 1 mg/kg or 2 doses of 2 mg/kg of AOC 1001, findings showed a mean reduction of 45% in DMPK. Additionally, investigators a 31% splicing improvement in a key set of muscle-specific genes and a splicing improvement of 16% across a broad 22-gene panel in the 2 mg/kg cohort, suggesting AOC 1001’s activity in the nucleus.4

Months later, at the 2023 American Academy of Neurology (AAN) Annual Meeting, held April 22-27, in Boston, Massachusetts, topline findings from MARINA were presented. All told, treatment with the therapy resulted in directional improvement in multiple functional assessments including measures of myotonia, strength, and mobility. Those on AOC 1001 continued to show meaningful reduction in DMPK and splicing changes. Additionally, the therapy demonstrated broad splicing improvements in more than a thousand genes impacted by DM1, confirming activity in the nucleus.5

Boyce added, "We are focused on advancing AOC 1001 into a pivotal trial as quickly as possible as we know that the patient community is desperate for a treatment. We are extremely grateful to the DM1 community for their trust, support and ongoing partnership."

1. Avidity Biosciences announces FDA eases partial clinical hold on AOC 1001 providing a clear path forward to finalize pivotal dose and phase 3 design in adults with myotonic dystrophy type 1. News release. Avidity Biosciences. May 17, 2023. Accessed May 18, 2023. https://www.prnewswire.com/news-releases/avidity-biosciences-announces-fda-eases-partial-clinical-hold-on-aoc-1001-providing-a-clear-path-forward-to-finalize-pivotal-dose-and-phase-3-design-in-adults-with-myotonic-dystrophy-type-1-301826781.html
2. Avidity Biosciences announces FDA partial clinical hold on new participant enrollment in phase 1/2 MARINA trial. News release. September 27, 2022. Accessed May 18,2023. 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. Study design of AOC 1001-CS1, a phase 1/2 clinical trial evaluating the safety, tolerability, pharmacokinectics and pharmcodyamics of AOC 1001 administered intravenously to adult patients with myotonic dystrophy type 1 (DM1) (MARINA). Neurology. 2022;98(18 supplement).
4. Avidity announces positive AOC 1001 phase 1/2 MARINA data demonstrating first-ever successful targeted delivery of RNA to muscle – revolutionary advancement for the field of RNA therapeutics. News release. Avidity Biosciences. December 14, 2022. Accessed May 18, 2023. https://www.prnewswire.com/news-releases/avidity-announces-positive-aoc-1001-phase-12-marina-data-demonstrating-first-ever-successful-targeted-delivery-of-rna-to-muscle---revolutionary-advancement-for-the-field-of-rna-therapeutics-301702506.html
5. Johnson N, Day J, Hamel J, et al. Preliminary assessment of the phase 1/2 clinical trial evaluating the safety, tolerability, pharmacokinectics and pharmacodynamics of AOC 1001 administered intravenously in adult patients with myotonic dystrophy. Presented at: 2023 AAN Annual Meeting; April 22-27; Boston, MA. Abstract 002405
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