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Avidity Reports Data That Shows Successful Delivery of RNA into Muscle in Humans

December 14, 2022

Avidity Biosciences reported positive preliminary results from the phase 1/2 MARINA study of its antibody oligonucleotide conjugates AOC 1001 in patients with myotonic dystrophy that demonstrated the first-ever successful targeted delivery of RNA into muscle, which the company called “a revolutionary advancement for the field of RNA therapeutics.”

Photo: Sarah Boyce, president and CEO of Avidity

“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, 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. “

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, but 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.

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 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. The U.S. Food and Drug Administration and European Medicines Agency have granted Orphan Designation for AOC 1001 and the FDA has granted AOC 1001 Fast Track Designation.

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.

The preliminary assessment demonstrated targeted delivery of siRNA to muscle, a tissue previously untreatable with existing RNA therapeutics. It also showed meaningful DMPK reduction in all of the participants treated with AOC 1001. Researchers found a mean reduction of 45 percent in DMPK after a single dose of 1 mg/kg or two doses of 2 mg/kg of AOC 1001.

The study also showed early signs of clinical activity with improvement in myotonia in some participants. Myotonia was measured by video hand opening time and is a hallmark of DM1 where relaxation of key muscle groups is impaired. The safety and tolerability data found the majority of adverse events were mild or moderate.

In September 2022, the 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 open label extension MARINA-OLE trial where they will receive AOC 1001. To date, all of participants who have completed the MARINA trial have opted to roll over into the MARINA open label extension.

“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 CEO of 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.”

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