First targeted delivery of siRNA into muscle

A Phase I/II trial demonstrated the first successful targeted delivery of siRNA into muscle, using monoclonal antibody AOC 1001.

First targeted delivery of siRNA into muscle - to treat myotonic dystrophy type 1

AOC 1001, a monoclonal antibody (mAb) by Avidity Biosciences, Inc. successfully targeted delivery of siRNA into muscle for the first time, producing meaningful DM1 Protein Kinase (DMPK) reduction in all myotonic dystrophy type 1 (DM1) participants in a Phase I/II trial (NCT05027269).

The treatment is a part of a new class of RNA therapeutics called Antibody Oligonucleotide Conjugates (AOCs™). AOC 1001, delivered using Avidity’s AOC platform, binds to the transferrin receptor 1 (TfR1) conjugated with a siRNA targeting DMPK mRNA to address the underlying cause in DM1.

The preliminary assessment from the randomised, double-blind, placebo-controlled Phase I/II MARINA trial 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, with the biomarker data obtained six weeks after dosing. Participants received a single dose of 1mg/kg AOC 1001, two doses of 2mg/kg AOC 1001 (reflected as siRNA dose), or placebo.

Phase I/II data from the preliminary assessment also showed:

  • Mean reduction of 45 percent in DMPK after only a single dose of 1mg/kg or two doses of 2mg/kg of AOC 1001
  • Splicing improvement demonstrating AOC 1001 activity in the nucleus was observed in 31 percent in a key set of muscle-specific genes and 16 percent across a broad 22-gene panel in the 2mg/kg cohort.

Safety and tolerability data showed the majority of adverse events (AEs) were mild or moderate.

Promising early clinical activity when treating myotonic dystrophy type 1

“… the MARINA trial demonstrated the cascade of delivery to muscle, DMPK reduction and splicing improvements and are seeing early signs of clinical activity with improvement in myotonia (impairment of muscle relaxation), just weeks after only one or two doses of AOC 1001,” shared Sarah Boyce, President and Chief Executive Officer at Avidity. “AOC 1001 has the potential to significantly impact the underlying disease mechanism of DM1, a devastating disease where there are currently no approved therapies.”

Myotonia, a hallmark of DM1 was measured by video hand opening time (vHOT).

Art Levin, PhD, Chief Scientific Officer at Avidity stated that the preliminary assessment trial results demonstrate “… a major breakthrough for the field of RNA therapeutics.”

He added: “These data [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.”

“We look forward to sharing top-line data from the MARINA trial in 2023,” added Boyce.

All current participants may continue current dosing cohort and roll over into the MARINA-OLE™ trial (NCT05479981) where they will receive AOC 1001. To date, all participants who have completed the MARINA trial have opted to roll over into the MARINA open label extension (MARINA-OLE™).