AOC 1001 Eases Symptoms of DM1, Early Clinical Trial Data Show

Experimental therapy eased myotonia in adults with myotonic dystrophy type 1

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by Steve Bryson, PhD |

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Treatment with AOC 1001 eased myotonia, when muscles are unable to relax after a contraction, in adults with myotonic dystrophy type 1 (DM1), according to early data from the Phase 1/2 MARINA clinical trial.

MARINA data also showed — in all treated participants — AOC 1001 was successfully delivered to muscle cells and meaningfully reduced the activity of the DMPK gene, which is overactive in DM1, thereby addressing the underlying cause of the condition. Top-line results are expected in 2023, according to Avidity Biosciences, the therapy’s developer.

AOC 1001 is based on the company’s proprietary class of RNA therapeutics called Antibody Oligonucleotide Conjugates (AOC), which are composed of small interfering RNA molecules (siRNA), designed to lower DMPK activity.

“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, in a press release. “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.”

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Addressing the underlying cause of DM1

In DM1, a form of muscular dystrophy, defects in the DMPK gene lead to an abnormally long messenger RNA (mRNA) — the intermediary molecule that carries instructions from a gene to make a protein. Such long mRNA segments form toxic clumps in cells, primary muscle cells, ultimately driving DM1 progression.

The siRNA in AOC 1001 — a specialized RNA molecule that can target mRNA for destruction — was designed to address the underlying cause of DM1 by reducing the levels of toxic mRNA in cells. To help gain access to muscle cells, the siRNA is attached to an antibody that binds to a muscle-cell receptor.

“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,” said Sarah Boyce, Avidity’s president and CEO.

Preclinical studies demonstrated AOC 1001 safely reduced the levels of toxic DMPK mRNA in cells and nonhuman primates.

After receiving clearance from the U.S. Food and Drug Administration (FDA), the company launched the six-month Phase 1/2 MARINA clinical trial (NCT05027269) to evaluate AOC 1001 in adults with DM1.

Administered directly into the bloodstream, participants received a single dose of AOC 1001 at 1 mg/kg, two at 2 mg/kg, or a placebo. A total of 38 out of the planned 44 patients have enrolled in the study. Researchers assessed biomarker data in 19 participants six weeks after dosing.

Early data showed that, along with a meaningful drop in toxic DMPK mRNA in all treated participants, there was a 45% mean reduction in mRNA after a single dose of 1 mg/kg or two doses of 2 mg/kg of AOC 1001.

Following the higher dose, the processing of other RNA molecules, called splicing, which is impeded by toxic mRNA clumping, showed an improvement of 31% in a set of muscle-specific genes and 16% across a wider 22-gene panel. Slicing improvements demonstrate that AOC 1001 is active in the cell’s nucleus.

Early signs of reduction in myotonia were observed in some participants, as measured by video hand opening time (vHOT) to assess the relaxation of key muscle groups after contraction, which is impaired in DM1.

Safety and tolerability, as assessed in all 38 participants, showed the majority of adverse events were mild or moderate.

“We are very pleased with this early data set of AOC 1001 from the MARINA trial,” Boyce said. “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.”

MARINA-OLE trial open to MARINA trial participants

Participants who completed MARINA can enter the 2-year MARINA-OLE (NCT05479981), an open-label extension (OLE) study to monitor the long-term safety of AOC 1001.

OLE participants will receive AOC 1001 doses every three months regardless of whether they were treated or received a placebo in the MARINA study. A nine-month safety follow-up will be conducted once patients complete active treatment. Avidity has indicated they may extend active therapy beyond 24 months.

In addition to AOC 1001 in DM1, the company is also developing similar treatments for two other types of muscular dystrophy: Duchenne muscular dystrophy (DMD) and facioscapulohumeral muscular dystrophy (FSHD).

“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,” Boyce added.

Recently, the FDA placed a partial clinical hold on new patient enrollment in MARINA due to a serious adverse event in a single participant who received a higher dose of 4 mg/kg. Avidity continues to work with the agency to resolve the hold as soon as possible.

All MARINA participants, whether on AOC 1001 or placebo, may continue their regimen and enter the OLE to continue/receive treatment. So far, all participants who have completed MARINA have opted to join MARINA-OLE.

“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,” Levin said.

Last year, the FDA granted fast-track designation to AOC 1001 for MD1, to aid and accelerate the development and review process. In addition, because of its potential to treat a rare disease, the U.S. and Europe have designated orphan drug status to AOC 1001.