AOC 1001 for Myotonic Dystrophy Type 1

Myotonic dystrophy type 1 (DM1) is a progressive disease that impacts skeletal and cardiac muscle. More than 40,000 people are affected in the U.S. and the condition has no approved therapies. Individuals with DM1 suffer from 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 from patient to patient and 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 a disease-related mRNA called DMPK. 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 benefiting the spectrum of symptoms and impacts of the disease that people with myotonic dystrophy type 1 (DM1) experience. 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. AOC 1001 is currently in Phase 1/2 development with the ongoing MARINA trial in adults with DM1. Participants in the MARINA study are eligible to enroll in the MARINA-OLE study. The U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) have granted Orphan Designation for AOC 1001 and the FDA has granted AOC 1001 Fast Track Designation.

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. In the fourth quarter of 2022, Avidity plans to conduct a preliminary assessment of safety, tolerability and key biomarkers in approximately half of the study participants in the MARINA study. For more information on this study click here or visit www.clinicaltrials.gov and search for NCT05027269.

We have commenced enrolling participants from the Phase 1/2 MARINA study into a Phase 2 open-label extension study (MARINA-OLE) of AOC 1001* in adults with DM1. All current participants enrolled in the randomized, placebo-controlled MARINA™ clinical trial with AOC 1001 are eligible to enroll in MARINA-OLE. MARINA-OLE is an open-label, multi-center study designed to evaluate the long-term safety and tolerability of AOC 1001 in DM1 patients who were previously enrolled in the MARINA Phase 1/2 study. This study will continue to evaluate the safety, tolerability, PK, PD, and efficacy of AOC 1001 in participants that enrolled in the Phase 1/2 MARINA clinical study. 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 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 www.clinicaltrials.gov 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 where they will receive AOC 1001 as planned. Avidity is working closely with the FDA and the trial investigator to resolve the partial clinical hold on new participant enrollment as quickly as possible.