FDA Places Temporary Hold on Trial for Myotonic Dystrophy Agent AOC 1001


Enrollment for the phase 1/2 study will be partially stopped; however, all participants included in the trial, whether on AOC 1001 or placebo, are eligible to continue their current dosing regimen.

Sarah Boyce, president and chief executive officer, Avidity

Sarah Boyce

According to a recent announcement by Avidity Biosciences, the FDA placed a partial clinical hold on enrollment for the phase 1/2 MARINA clinical trial (NCT05027269) currently assessing AOC 1001, its investigational agent designed to treat the root cause of myotonic dystrophy type 1 (DM1). The company noted it is still on track to conduct a preliminary assessment of safety, tolerability, and key biomarkers in half of the study participants in MARINA in fourth quarter of 2022.1

The reason for the hold was because of a serious adverse event reported in a single patient treated in the 40-mg arm of the study. To date, nearly 40 of an anticipated 44 participants were enrolled in MARINA and its open-label extension (OLE); although, the company did note that all participants, whether on AOC 1001 or placebo, may continue their current dosing as planned. Avidity also noted that the clinical hold does not impact those who choose to enter in the OLE.

"The safety of participants enrolled in our clinical studies is our first priority. We are doing a thorough analysis and will work diligently with the FDA and the trial investigator to follow the progress of this participant and to resume new participant enrollment as soon as we can," Sarah Boyce, president and chief executive officer, Avidity, said in a statement.1 "We share the sense of urgency with the DM1 community for effective therapies and we remain confident that AOC 1001 has the potential to address important unmet needs of people living with DM1. We want to thank each participant in the study, their families and the investigators for their continued contributions."

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.2

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MARINA is a double-blind, placebo-controlled trial aimed at evaluating the safety and tolerability of single and multiple ascending doses of AOC 1001 administered intravenously. The primary outcome measure is frequency of treatment-emergent adverse events (TEAEs), followed by secondary outcomes such as plasma pharmacokinetic measurements of AOC 1001 and pharmacodynamic measurements, including DMPK mRNA knockdown and spliceopathy in muscle biopsies. Patients included in the study were between 18 to 65 years with genetically confirmed DM1, as expressed by CTG repeat length greater of at least 100.

"We continue to look forward to the preliminary assessment of the MARINA study in Q4 and, with our two recent IND clearances, we are now advancing AOC 1020 for FSHD and AOC 1044 for DMD into the clinic this year as planned," Boyce added.1

Days after Avidity announced the clinical hold of AOC 1001, the company received news from the FDA about the clearance of an investigational new drug application (IND) to assess its other agent—AOC 1020, an RNA therapeutic—in adults with facioscapulohumeral muscular dystrophy (FSHD). Named FORTITUDE, the randomized, placebo-controlled, double-blind trial will include 68 patients with FSHD to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of intravenous administrations of AOC 1020. In addition to the double-blind treatment period, eligible patients who complete the trial will have the option to enter in an open-label extension. Similar to DM1, there are no approved treatments for FSHD.

1. Avidity Biosciences announces FDA partial clinical hold on new participant enrollment in phase 1/2 MARINA trial. News release. September 27, 2022. Accessed October 6, 2022. 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
2. 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).
3. Avidity Biosciences announces the phase 1/2 FORTITUDE trial of AOC1020 in adults with facioscapulohumeral muscular dystrophy. News release. Avidity Biosciences. September 29, 2022. Accessed October 6, 2022. https://www.prnewswire.com/news-releases/avidity-biosciences-announces-the-phase-12-fortitude-trial-of-aoc-1020-in-adults-with-facioscapulohumeral-muscular-dystrophy-301636385.html
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