Myotonic Dystrophy Type 1

Myotonic dystrophy type 1 (DM1) is an underrecognized, progressive and often fatal neuromuscular disease with no approved therapies. More than 40,000 people are affected by DM1 in the U.S.. DM1 primarily affects skeletal and cardiac muscle, however people can suffer a range of symptoms including myotonia and muscle weakness, respiratory and cardiac problems, severe gastrointestinal complications, and cognitive and behavioral impairment—resulting in significant decline in quality of life and large caregiver burden. The disease is highly variable with respect to disease severity, presentation, and age of onset.

DM1 is caused by an increase in the number of CUG triplet repeats found in the myotonic dystrophy protein kinase (DMPK) gene. In a healthy individual the number of repeats is approximately 35 but in someone with DM1 there can be thousands. When there are too many CUG repeats, large hairpin loops form trapping DMPK mRNA in the nucleus, effectively sequestering muscleblind-like protein (MBNL) and reducing its activity. Specifically, mutated DMPK mRNA binds to MBNL, a critical CUG-binding protein, forming nuclear foci and preventing MBNL from performing its normal function of processing the mRNAs for many other genes. As a result, multiple mRNAs that encode key proteins are misprocessed, resulting in atypical proteins that ultimately are the cause of DM1. Our therapeutic approach is to reduce DMPK and CUG levels thereby reducing nuclear foci and relieving the sequestration of MBNL so that MBNL can perform its normal function.

DM1 Disease Process:

AOC 1001*

AOC 1001, Avidity’s lead product candidate utilizing its AOC platform, is designed to address the root cause of DM1 by reducing levels of DMPK mRNA. AOC 1001 consists of a monoclonal antibody (mAb) that binds to the transferrin receptor 1 (TfR1) conjugated with a small interfering RNA (siRNA) that is designed to reduce levels of DMPK RNA in skeletal, cardiac, and smooth muscle. This allows AOC 1001 to reduce DMPK mRNA and address the underlying cause of disease, potentially alleviating the spectrum of symptoms that people with DM1 experience. The U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) granted Orphan designation for AOC 1001 and the FDA has granted AOC 1001 Fast Track designation and Orphan Drug designation.

Data from Preliminary Assessment of MARINA

In December 2022, the preliminary assessment from the randomized, double-blind, placebo-controlled Phase 1/2 MARINA trial of AOC 1001 provided the first in-human data and a mid-study look at the safety and tolerability of all 38 participants and key biomarkers in 19 participants. The preliminary assessment included biomarker data six weeks after dosing. Participants received a single dose of 1 mg/kg of AOC 1001, two doses of 2 mg/kg of AOC 1001 (reflected as siRNA dose), or placebo. Avidity plans to report top-line data and program updates for MARINA in 2023.

AOC 1001 Phase 1/2 data from the preliminary assessment demonstrated:

  • Targeted delivery of siRNA to muscle, a tissue previously untreatable with existing RNA therapeutics;
  • Meaningful DMPK reduction in 100% of participants treated with AOC 1001;
  • Mean reduction of 45% in DMPK after only a single dose of 1 mg/kg or two doses of 2 mg/kg of AOC 1001;
  • Splicing improvement of 31% in a key set of muscle-specific genes and splicing improvement of 16% across a broad 22-gene panel in the 2 mg/kg cohort. Splicing improvements demonstrate AOC 1001 activity in the nucleus;
  • Early signs of clinical activity with improvement in myotonia in some participants. Myotonia was measured by video hand opening time (vHOT) and is a hallmark of DM1 where relaxation of key muscle groups is impaired; and
  • Safety and tolerability data with majority of adverse events (AEs) mild or moderate.

AOC 1001* is currently in Phase 1/2 development with the ongoing MARINA™ study in adults with DM1. MARINA is a randomized, double-blind, placebo-controlled, Phase 1/2 clinical trial expected to enroll approximately 44 adults with DM1. The primary objective of this study is to evaluate the safety and tolerability of single and multiple ascending doses of AOC 1001 administered intravenously. The MARINA trial will begin to assess the activity of AOC 1001 across key biomarkers, including spliceopathy, an important biomarker for DM1, and knockdown of DMPK mRNA. Though the Phase 1/2 trial is not powered to assess functional benefit, it will explore the clinical activity of AOC 1001 including measures of mobility and muscle strength as well as patient reported outcomes and quality of life measures. Participants have the option to enroll in MARINA-OLE™, an open label extension study, at the end of the post-treatment period. Avidity plans to report top-line data and program updates for MARINA in 2023. For more information on this study click here or visit and search for NCT05027269.

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 Phase 1/2 MARINA study. This study will continue to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of AOC 1001 in participants that enrolled in the Phase 1/2 MARINA clinical trial. Participants who enroll in the MARINA-OLE study will 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 MARINA-OLE is approximately 24 months. Once participants have completed active treatment, there will be a 9-month safety follow-up period. Avidity may extend active treatment beyond 24 months at a future timepoint. For more information on this study click here or visit and search for NCT05479981.

*In Sept. 2022, Avidity announced that the U.S. Food and Drug Administration (FDA) placed a partial clinical hold on new participant enrollment in the Phase 1/2 MARINA™ clinical trial of AOC 1001 in adults with DM1. All current participants, whether they are on AOC 1001 or placebo, may continue in their current dosing cohort although no additional participants may be enrolled until the partial clinical hold is resolved. All participants in MARINA may roll over into the MARINA-OLE™ trial where they will receive AOC 1001 as planned. Avidity continues to work to resolve the partial clinical hold on new participant enrollment as swiftly as possible.