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 is comprised of a monoclonal antibody (mAb) that targets 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 has delivered the siRNA to a broad range of muscle cells and reduced levels of DMPK mRNA in a dose-dependent manner. AOC 1001 has a favorable safety profile in preclinical studies that supports clinical development. 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.

We have commenced clinical testing for AOC 1001 with the ongoing Phase 1/2 MARINA study of AOC 1001 in adults with DM1.The MARINA trial 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, a key biomarker for DM1, and knockdown of DMPK mRNA, the disease-related mRNA responsible for DM1. 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. Patients will have the option to enroll in 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.