RARE Daily

FDA Eases Partial Clinical Hold on Avidity’s AOC 1001 for Myotonic Dystrophy Type 1

May 17, 2023

Rare Daily Staff

The U.S. Food and Drug Administration has eased the partial clinical hold on Avidity Biosciences’ AOC 1001, allowing it to double the number of participants in the MARINA Open-Label Extension study receiving 4 mg/kg of AOC 1001 in myotonic dystrophy type 1.

The FDA is also allowing new participant enrollment for AOC 1001 at 2 mg/kg. Data from the MARINA-OLE study will be used to finalize the AOC 1001 pivotal dose and phase 3 study design for adults with myotonic dystrophy type 1 (DM1).

DM1 is an underrecognized, progressive, and often fatal disease caused by a triplet-repeat in the DMPK gene, resulting in a toxic gain of function mRNA. The disease is highly variable with respect to severity, presentation, and age of onset, however all forms of DM1 are associated with high levels of disease burden and may cause premature mortality. DM1 primarily affects skeletal and cardiac muscle, however patients can suffer from a constellation of manifestations including myotonia and muscle weakness, respiratory problems, fatigue, hypersomnia, cardiac abnormalities, severe gastrointestinal complications, and cognitive and behavioral impairment. Currently, there are no approved treatments for people living with DM1.

“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,” said Sarah Boyce, president and CEO at Avidity.

AOC 1001, Avidity’s lead product candidate utilizing its Antibody Oligonucleotide Conjugate platform, is designed to address the root cause of DM1 by reducing levels of a disease-related mRNA called DMPK. AOC 1001 consists of a proprietary monoclonal antibody that binds to the transferrin receptor 1 (TfR1) conjugated with a siRNA targeting DMPK mRNA. In preclinical studies, AOC 1001 successfully delivered siRNAs to muscle cells, resulting in durable, dose-dependent reductions of DMPK RNA across a broad range of muscles including skeletal, cardiac, and smooth muscles.

The easing of the partial clinical hold allows a number of current participants to be dose escalated to 4 mg/kg of AOC 1001 in the MARINA-OLE study and allows new participant enrollment at 2 mg/kg of AOC 1001. In September 2022, FDA placed a partial clinical hold on all new participant enrollment of AOC 1001 due to a rare serious adverse event reported in a single participant in the 4 mg/kg cohort of the Phase 1/2 MARINA trial.

Avidity announced positive topline AOC 1001 data from the phase 1/2 MARINA trial demonstrating functional improvement in multiple clinical outcome measures, disease modification and a favorable safety and tolerability profile in adults with DM1 at the 75th American Academy of Neurology (AAN) Annual Meeting in April 2023.

Avidity concluded 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 MARINA-OLE study to evaluate the long-term safety and tolerability of AOC 1001 in adults with DM1. Avidity plans to double the number of participants receiving 4 mg/kg of AOC 1001 by dose escalating approximately 12 participants currently receiving AOC 1001 2 mg/kg in the MARINA-OLE study. All other participants will remain on their current dose of either 2 mg/kg or 4 mg/kg of AOC 1001. Avidity remains on track to share a first look at the data from the MARINA-OLE study at the end of 2023.

MARINA-OLE is an open-label, multi-center trial designed to evaluate the long-term safety and tolerability of AOC 1001 in participants with DM1 who were previously enrolled in the MARINA phase 1/2 trial. This trial will continue to evaluate the safety, tolerability, PK, PD, and efficacy of AOC 1001 in participants enrolled in the randomized, placebo-controlled, phase 1/2 MARINA clinical trial. Participants who enroll in the MARINA-OLE study currently receive quarterly doses of AOC 1001 regardless of whether they received active treatment or placebo in the MARINA study. The total duration of active treatment with AOC 1001 in the MARINA-OLE study is approximately 24 months. Once patients have completed active treatment, there will be a nine-month safety follow-up period. Avidity may extend active treatment beyond 24 months at a future timepoint.

AOC 1001 is currently in phase 1/2 development with the completed MARINA trial and the ongoing MARINA-OLE trial in adults with DM1. The FDA and European Medicines Agency have granted Orphan Designation for AOC 1001 and the FDA has granted AOC 1001 Fast Track designation.

Photo: Sarah Boyce, president and CEO at Avidity


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