Myotonic Dystrophy Agent AOC 1001 Demonstrates Successful Targeted Delivery of RNA


AOC 1001, an agent consisting of a proprietary monoclonal antibody that binds to the transferrin receptor 1, was safe, tolerable, and showed significant reductions in DMPK, a disease-related mRNA.

Art Levin, PhD, chief scientific officer, Avidity

Art Levin, PhD

Avidity Biosciences has announced preliminary findings from its phase 1/2 MARINA trial (NCT05027269) of AOC 1001 in myotonic dystrophy type (DM1), showing the first-ever successful targeted delivery of siRNA into muscle, a tissue previously untreatable with existing RNA therapeutics.1

In addition to a successful delivery of siRNA to muscle, investigators also observed meaningful reduction in DMPK, a disease-related mRNA, in all participants treated with the agent. The newly released data further reinforce the broad and disruptive potential of the company’s Antibody Oligonucleotide Conjugates (AOC) platform and expands the ability to address targets and diseases previously unreachable with existing RNA therapies.

"Utilizing our AOC platform technology, we have demonstrated for the first time ever the successful targeted delivery of siRNA to muscle in humans, a major breakthrough for the field of RNA therapeutics," Art Levin, PhD, chief scientific officer, Avidity, said in a statement. “These unprecedented data open up the RNA field and underscore the potential of our AOC platform to expand the possibilities of how we can treat diseases and target a range of different cells and tissues beyond the liver, which up until now have been inaccessible with existing RNA-based therapeutics."

AOC 1001 utilizes Avidity’s AOC platform and is designed to address the root cause of DM1 by reducing levels of the DMPK. It consists of a proprietary monoclonal antibody that binds to the transferrin receptor 1 (TfR1) conjugated with an siRNA-targeting DMPK mRNA. Additionally, the agent has also received fast track designation from the FDA and orphan drug designations from the FDA and European Medicines Agency.

The preliminary data from the randomized, double-blind, placebo-controlled trial included safety and tolerability on 38 participants and key biomarkers in 19 participants. Frequency of treatment-emergent adverse events (TEAEs) was the primary end point, followed by secondary outcomes such as plasma pharmacokinectic measures of AOC 1001 and pharmacodynamic measurements, including DMPK mRNA knockdown and spliceopathy in muscle biopsies. Those included in the study were between 18 to 65 years with genetically confirmed DM1, as expressed by CTG repeat length greater than at least 100.

Overall, following a single dose of 1 mg/kg or 2 doses of 2 mg/kg of AOC 1001, there was a mean reduction of 45% in DMPK. Additionally, investigators observed 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. Using video hand opening time, the preliminary findings also revealed signs of clinical activity with improvement in myotonia, a hallmark of DM1, in some participants. Above all, the agent was safe and well-tolerated, with a majority of AEs mild or moderate.

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High rates of treatment use were observed across all types of spinal muscular atrophy, with nusinersen, the first approved disease-modifying treatment, as the most commonly used.

"We are very pleased with this early data set of AOC 1001 from the MARINA trial. We have demonstrated the cascade of delivery to muscle, DMPK reduction and splicing improvements with AOC 1001 and are seeing early signs of clinical activity with improvement in myotonia, just weeks after only one or two doses of AOC 1001," Sarah Boyce, president and chief executive officer, Avidity, said in a statement.1 "AOC 1001 has the potential to deliver on the promise of the AOC platform and significantly impact the underlying disease mechanism of DM1, a devastating disease where there are currently no approved therapies. We look forward to sharing top-line data from the MARINA trial in 2023 and advancing our other clinical programs for the treatment of DMD and FSHD."

MARINA also includes a 40-mg arm of AOC 1001; however, in September 2022, the FDA placed a partial hold on enrollment for the trial, citing a serious AE reported in a single patient treated with that dosage. At the time, 40 of the anticipated 44 participants were enrolled in the trial and its open-label extension. Despite this, dosing in both the AOC 1001 and placebo groups continued. The company noted that the clinical hold does not impact those who choose to enter the OLE.2

1. 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 December 14, 2022.
2. Avidity Biosciences announces FDA partial clinical hold on new participant enrollment in phase 1/2 MARINA trial. News release. September 27, 2022. Accessed December 14, 2022.
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