Antisense Oligonucleotide AOC 1001 Demonstrates Long-Term Safety Open-Label Extension of MARINA Trial


AOC 1001 consistently demonstrated directional improvements across multiple aspects of myotonic dystrophy type 1, including measures of myotonia, strength, function, and patient reported outcome.

Nicholas E. Johnson, MD, MSc, FAAN, associate professor and vice chair of research in the department of neurology at Virginia Commonwealth University

Nicholas E. Johnson, MD, MSc, FAAN

At the 28th Annual Congress of the World Muscle Society, held October 3-7, in Charleston, South Carolina, new data from the open-label extension (OLE) of the phase 1/2 MARINA trial (NCT05027269) highlighted the long-term safety of AOC 1001 (Avidity Biosciences), an antisense oligonucleotide in development for patients with myotonic dystrophy type 1 (DM1). Based on the data, Avidity is finalizing the pivotal dose to be used in a follow-up phase 3 study, with additional data from the OLE to be announced in the first half of 2024.1,2

MARINA was a double-blind, placebo-controlled study in which 38 patients with DM1 were randomly assigned 3:1 to either 1 dose of 1 mg/kg of AOC 1001, 3 doses of either 2 mg/kg of AOC 1001 or 4 mg/kg of AOC 1001, or placebo. All 37 participants that completed the double-blind portion of the study entered the OLE, where they received either 2 or 4 mg/kg of AOC 1001. This included 10 participants who were previously on placebo.

Looking at the OLE data, with over 200 infusions of AOC 1001 totaling 46.2 patient-years of exposure, the therapy demonstrated a safe and tolerable profile. Throughout the OLE, the most common adverse events (AEs) were procedural pain (22%) and pain in extremity and headache (16%). Of note, there were no discontinuations during the OLE and no reports of anemia. In the MARINA clinical program, anemia has been asymptomatic except for 1 participant who did not require treatment. In addition, there was 1 resolved AE of mild increase in liver enzymes.

Additional data from MARINA showed that treatment with AOC 1001 led to improvements in functional measures of hand grip, muscle strength, and patient reported outcomes, further adding to its efficacy profile. Using video hand opening time, patients showed visible improvements in hand flexor myotonia and hand extensor muscle strength at week 12 following the third dose at 4 mg/kg. Quantitative Muscle Testing total score, a measure based on 6 muscle groups from both upper and lower body, was improved after treatment with AOC 1001.

"The new AOC 1001 data presented today demonstrating improvements in muscle strength and patient reported outcomes add to the previously reported positive topline data showing improvements in myotonia and mobility. The AOC 1001 data continues to be quite remarkable with consistent improvements across multiple functional endpoints,” lead investigator Nicholas E. Johnson, MD, MSc, FAAN, associate professor and vice chair of research in the department of neurology at Virginia Commonwealth University, said in a statement.1 "The AOC 1001 functional data coupled with the long-term favorable tolerability and safety data provide us with hope that AOC 1001 has the potential to help patients with DM1, who are in desperate need of treatments."

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Functional and patient reported outcome measures such as the 10-Meter Walk Run test, Timed Up and Go, and the DM1-Activ Patient Reported Outcome, all showed directional improvements through treatment with AOC 1001. In addition, patients who dose-escalated from 2 mg/kg to 4 mg/kg as part of the easement of the partial clinical hold showed no neurological events and no MRI changes following dosing.

For context, in September 2022, the FDA placed a partial clinical hold on new patient enrollment in MARINA as a response to a serious AE observed in a single patient in the 4 mg/kg cohort.3 The reported AE comprised of bilateral ischemia in the region of the lateral geniculate nuclei in the thalamus with subsequent hemorrhagic transformation that was described as thalamic hemorrhage. Following a comprehensive investigation, Avidity noted it found no plausible link to any component of AOC 1001, the AOC platform, the transferring receptor delivery mechanism or reduction of DMPK, and thus the partial hold was eased.

The FDA’s decision earlier this year to ease the partial hold allowed for additional recruitment in the 4 mg/kg dose group, doubling the number of participants from approximately 12 to 24. AOC 1001, Avidity’s lead product candidate, is designed to address the root cause of DM1 by reducing levels of disease-related mRNA called DPMK. The agent consists of a propriety monoclonal antibody that binds to the transferrin receptor 1 conjugated with a siRNA targeting DMPK mRNA.

"Data from MARINA and MARINA-OLE reinforce our belief in the potential of AOC 1001 to become an effective treatment option for people living with DM1, a devastating rare disease for which there are no treatment options available. With this robust data package, we are finalizing the Phase 3 study design and global regulatory path for AOC 1001 and look forward to sharing a first look at efficacy data from the MARINA-OLE study in the first half of 2024," Sarah Boyce, president and chief executive officer, Avidity, said in a statement.1 "In addition to our DM1 program, we continue to advance our DMD and FSHD clinical development programs and plan to report data from all three of our programs by mid-2024 while continuing to expand our discovery and development pipeline."

1. Avidity Biosciences announces new positive AOC 1001 data demonstrating improvement in multiple additional functional end points and favorable long-term safety and tolerability in people with myotonic dystrophy type 1. News release. Avidity Biosciences. October 7, 2023. Accessed October 12, 2023.
2. 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.
3. Avidity Biosciences announces FDA partial clinical hold on new participant enrollment in phase 1/2 MARINA trial. News release. September 27, 2022. Accessed October 12, 2023.
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