Avidity Announces Positive AOC 1001 Phase 1/2 MARINA Data Demonstrating First-Ever Successful Targeted Delivery of RNA to Muscle - Revolutionary Advancement for the Field of RNA Therapeutics

Avidity Biosciences, Inc. recently announced positive AOC 1001 data from the preliminary assessment of the Phase 1/2 MARINA trial demonstrating the first-ever successful targeted delivery of RNA into muscle, a revolutionary advancement for the field of RNA therapeutics. The effective targeted delivery of siRNA into muscle further reinforces the broad and disruptive potential of Avidity’s proprietary AOC platform and expands the ability to address targets and diseases previously unreachable with existing RNA therapies. AOC 1001, Avidity’s lead clinical program utilizing its AOC platform, is designed to address the root cause of myotonic dystrophy type 1 (DM1), an underrecognized, progressive and often fatal neuromuscular disease with no approved therapies.

“Utilizing our AOC platform technology, we have demonstrated for the first time ever the successful targeted delivery of siRNA to muscle in humans, a major breakthrough for the field of RNA therapeutics,” said Art Levin, PhD, Chief Scientific Officer at Avidity. “These unprecedented data open up the RNA field and underscore the potential of our AOC platform to expand the possibilities of how we can treat diseases and target a range of different cells and tissues beyond the liver, which up until now have been inaccessible with existing RNA-based therapeutics. At Avidity, we look forward to advancing our three AOC clinical programs for the treatment of muscle diseases and to continuing to expand our pipeline and programs in cardiac, immunology and other diseases.”

The preliminary assessment from the randomized, double-blind, placebo-controlled Phase 1/2 MARINA trial of AOC 1001 provides 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 includes biomarker data six weeks after dosing. Participants received a single dose of 1 mg/kg AOC 1001, two doses of 2 mg/kg AOC 1001 (reflected as siRNA dose), or placebo. 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
• Safety and tolerability data with majority of adverse events (AEs) mild or moderate

“We are very pleased with this early data set of AOC 1001 from the MARINA trial. We have demonstrated the cascade of delivery to muscle, DMPK reduction and splicing improvements with AOC 1001 and are seeing early signs of clinical activity with improvement in myotonia, just weeks after only one or two doses of AOC 1001,” said Sarah Boyce, President and Chief Executive Officer at Avidity. “AOC 1001 has the potential to deliver on the promise of the AOC platform and significantly impact the underlying disease mechanism of DM1, a devastating disease where there are currently no approved therapies. We look forward to sharing top-line data from the MARINA trial in 2023 and advancing our other clinical programs for the treatment of DMD and FSHD.”

Avidity’s proprietary AOCs are designed to combine the specificity of monoclonal antibodies with the precision of oligonucleotide therapies to target the root cause of diseases previously untreatable with RNA therapeutics. AOC 1001 consists of a proprietary monoclonal antibody (mAb) that binds to the transferrin receptor 1 (TfR1) conjugated with a siRNA targeting DMPK mRNA to address the underlying cause in DM1.

In September 2022, the US FDA placed a partial clinical hold on new participant enrollment in the Phase 1/2 MARINA trial of AOC 1001 in adults with DM1 due to a serious adverse event reported in a single participant in the 4 mg/kg dose cohort. Avidity continues to work to resolve the partial hold on new participant enrollment as swiftly as possible. All current participants, whether they are on AOC 1001 or placebo, may continue in their current dosing cohort and roll over into the MARINA-OLE trial where they will receive AOC 1001. To date, 100% of participants who have completed the MARINA trial have opted to roll over into the MARINA open label extension (MARINA-OLE).

Avidity has three distinct rare disease programs in the clinic: AOC 1001 for DM1 is currently being evaluated in the Phase 1/2 clinical trial and the MARINA-OLE; AOC 1020 is advancing into the Phase 1/2 FORTITUDE trial for the treatment of facioscapulohumeral muscular dystrophy (FSHD); and, AOC 1044 is advancing into the Phase 1/2 EXPLORE44 trial 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 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 US 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. 

Avidity Biosciences, Inc.’s mission is to profoundly improve people’s lives by delivering a new class of RNA therapeutics – Antibody Oligonucleotide Conjugates (AOCs). Avidity’s proprietary AOCs are designed to combine the specificity of monoclonal antibodies with the precision of oligonucleotide therapies to target the root cause of diseases previously untreatable with RNA therapeutics. Avidity’s advancing and expanding pipeline has three programs in clinical development. AOC 1001 is designed to treat people with myotonic dystrophy type 1 (DM1) and is currently in Phase 1/2 development with the ongoing MARINA and MARINA-OLE trials. AOC 1020 is designed to treat people living with facioscapulohumeral muscular dystrophy (FSHD) and is currently in Phase 1/2 development with the FORTITUDE trial. AOC 1044 is designed for people with Duchenne muscular dystrophy (DMD) mutations amenable to exon 44 skipping and is currently in Phase 1/2 development with the EXPLORE44 trial. AOC 1044 is the first of multiple AOCs the company is developing for DMD. Avidity is also broadening the reach of AOCs beyond muscle tissues through both internal discovery efforts and key partnerships as the company continues to deliver on the RNA revolution. Avidity is headquartered in San Diego, CA. For more information, visit www.aviditybiosciences.com.