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.

Data Update at the 2023 28th Annual Congress of the World Muscle Society (WMS)

In October 2023, Avidity announced new positive AOC 1001 data demonstrating improvement in multiple additional functional endpoints and favorable long-term safety and tolerability in people with Myotonic Dystrophy Type 1 (DM1). The new data demonstrate improvement in additional functional measures including hand grip, muscle strength and patient reported outcomes, augmenting previously reported positive data showing improvements in myotonia, muscle strength and mobility. New long-term safety data of AOC 1001 continue to demonstrate favorable safety and tolerability. The data were highlighted in an oral presentation at WMS in Charleston, South Carolina. A first look at MARINA-OLE™ data is planned for the first half of 2024. 

Topline Data from MARINA®

In April 2023, Avidity announced positive topline data from the Phase 1/2 MARINA clinical trial of AOC 1001 for the treatment of DM1 demonstrating functional improvement, DMPK reduction, splicing improvements and a favorable safety and tolerability profile. The AOC 1001 topline data were highlighted in an oral presentation at the 75th American Academy of Neurology (AAN) Annual Meeting in Boston, Mass.

The MARINA® trial is a randomized, double-blind, placebo-controlled, Phase 1/2 clinical trial that enrolled 38 adults with DM1. The primary objective of this study was to evaluate the safety and tolerability of single and multiple ascending doses of AOC 1001 administered intravenously. The MARINA trial assessed 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 was not powered to assess functional benefit, it explored the clinical activity of AOC 1001 in multiple measures of muscle function including myotonia, muscle strength, measures of mobility as well as patient reported outcomes and quality of life measures. Patients have the option to enroll in MARINA-OLE, an open label extension study, at the end of the post-treatment period. 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 myotonic dystrophy type 1 (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 that enrolled in the randomized, placebo-controlled, 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 the MARINA-OLE is approximately 24 months. Once patients 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 May 2023, the FDA eased the partial clinical hold to allow 12 participants to be dose-escalated to 4 mg/kg of AOC 1001 and new participant enrollment at 2 mg/kg of AOC 1001.