Avidity Biosciences, Inc. provided an update on the Phase 1/2 MARINA™ trial of AOC 1001 in adults with myotonic dystrophy type 1 (DM1), an underrecognized, progressive and often fatal neuromuscular disease with no approved treatment options. Discussions are ongoing with the U.S. Food and Drug Administration (FDA) regarding the partial clinical hold on new participant enrollment as Avidity continues to provide new AOC 1001 data as it emerges from the MARINA trial. AOC 1001 consists of a proprietary monoclonal antibody that binds to the transferrin receptor 1 (TfR1) conjugated with a siRNA targeting DMPK mRNA.

In September 2022, the FDA placed a partial clinical hold on new participant enrollment in the Phase 1/2 MARINA clinical trial after reviewing information provided by Avidity related to a serious adverse event reported in a single participant in the 4 mg/kg cohort of the MARINA study. As previously disclosed, the event was classified by the investigator as drug related. Avidity conducted a thorough analysis with the help of multiple independent experts and concluded that the participant most likely experienced an extremely rare neurological event comprising of bilateral ischemia in the region of the lateral geniculate nuclei in the thalamus with subsequent hemorrhagic transformation.

The location in the lateral geniculate nuclei and the bilateral nature of the event is what makes this event extremely rare. After this extensive investigation, Avidity cannot identify a plausible biological link to any component of AOC 1001, the AOC platform, the transferrin receptor delivery mechanism or reduction of DMPK. It is important to note that AOC 1001 does not cross the blood brain barrier.

In December 2022, the company announced positive data from a preliminary assessment of the Phase 1/2 MARINA study of AOC 1001 demonstrating the first-ever successful targeted delivery of RNA to skeletal muscle, DMPK reduction and splicing improvements, with early signs of clinical activity with improvement in myotonia after just one or two doses of AOC 1001. The top-line data from MARINA will be presented in an oral presentation on April 27, 2023 at the 75th American Academy of Neurology (AAN) Annual Meeting in Boston, Mass. Data from the preliminary assessment of AOC 1001 supports that the targeted dose range is between 2 mg/kg and 4 mg/kg.

Therefore, Avidity is concluding the MARINA trial with the 38 participants enrolled at 1mg/kg, 2mg/kg and 4mg/kg of AOC 1001 and will not move forward with the 8 mg/kg dose of AOC 1001. Avidity will continue to dose the participants at both 2 mg/kg and 4 mg/kg of AOC 1001 in the MARINA open-label extension study (MARINA-OLE™) to evaluate the long-term safety and tolerability of AOC 1001 in participants with DM1 who were previously enrolled in the MARINA Phase 1/2 trial. Avidity remains on track to share a first look at the data from the MARINA-OLE study at the end of 2023.

vidity is advancing its three distinct rare disease Phase 1/2 programs in the clinic: AOC 1001 for DM1, AOC 1020 for the treatment of facioscapulohumeral muscular dystrophy (FSHD) and AOC 1044 for the treatment of Duchenne muscular dystrophy (DMD) mutations amenable to exon 44 skipping (DMD44). The MARINA™ trial is a randomized, double-blind, placebo-controlled, Phase 1/2 clinical trial initially 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. 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 http://www.clinicaltrials.gov 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 http://www.clinicaltrials.gov and search for NCT05479981. 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 proprietary monoclonal antibody that binds to the transferrin receptor 1 (TfR1) conjugated with a siRNA targeting DMPK mRNA. 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.

Patients 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. Myotonic dystrophy type 1 (DM1) is an underrecognized, progressive and often fatal disease caused by a triplet-repeat in the DMPK gene, resulting in a toxic gain of function mRNA.

The disease is highly variable with respect to severity, presentation and age of onset, however all forms of DM1 are associated with high levels of disease burden and may cause premature mortality. DM1 primarily affects skeletal and cardiac muscle, however patients can suffer from a constellation of manifestations including myotonia and muscle weakness, respiratory problems, fatigue, hypersomnia, cardiac abnormalities, severe gastrointestinal complications, and cognitive and behavioral impairment. Currently, there are no approved treatments for people living with DM1.