RARE Daily

FDA Places Partial Clinical Hold on New Participant Enrollment in Avidity’s Phase 1/2 DM1 Trial

September 27, 2022

The U.S. Food and Drug Administration has placed a partial clinical hold on new participant enrollment in Avidity Biosciences’ phase 1/2 MARINA clinical trial of lead antibody oligonucleotide conjugate AOC 1001 in adults with myotonic dystrophy type 1.

Photo: Sarah Boyce, president and CEO at Avidity

All participants, whether they are on AOC 1001 or placebo, may continue in their current dosing cohort although no additional participants may be enrolled until the partial clinical hold is resolved. All participants in MARINA may roll over into the MARINA-OLE where they will receive AOC 1001 as planned. DM1 is an underrecognized, progressive and often fatal neuromuscular disease with no approved treatment options. There are close to 40 participants are currently enrolled in the MARINA and MARINA open label extension trials.

The partial clinical hold is in response to a serious adverse event reported in a single participant in the 4mg/kg cohort of the MARINA study. Avidity says it is working closely with the FDA and the trial investigator to assess the cause of this event and will take all necessary steps to resolve the partial clinical hold on new participant enrollment as quickly as possible.

“We are doing a thorough analysis and will work diligently with the FDA and the trial investigator to follow the progress of this participant and to resume new participant enrollment as soon as we can,” said Sarah Boyce, president and CEO at Avidity. “We share the sense of urgency with the DM1 community for effective therapies and we remain confident that AOC 1001 has the potential to address important unmet needs of people living with DM1.”

Myotonic dystrophy type 1 (DM1) is a rare progressive disease that impacts skeletal and cardiac muscle. Individuals with DM1 suffer from muscle weakness, respiratory and cardiac problems, severe gastrointestinal complications, and cognitive and behavioral impairment—resulting in significant decline in quality of life and large caregiver burden. The disease is highly variable from patient to patient and with respect to disease severity, presentation, and age of onset.

DM1 is caused by an increase in the number of CUG triplet repeats found in the myotonic dystrophy protein kinase (DMPK) gene. In a healthy individual the number of repeats is approximately 35 but in someone with DM1 there can be thousands. When there are too many CUG repeats, large hairpin loops form trapping DMPK mRNA in the nucleus, effectively sequestering muscleblind-like protein (MBNL) and reducing its activity. Specifically, mutated DMPK mRNA binds to MBNL, a critical CUG-binding protein, forming nuclear foci and preventing MBNL from performing its normal function of processing the mRNAs for many other genes. As a result, multiple mRNAs that encode key proteins are misprocessed, resulting in atypical proteins that ultimately are the cause of DM1. Avidity’s AOC 1001 is designed to reduce DMPK and CUG levels thereby reducing nuclear foci and relieving the sequestration of MBNL so that MBNL can perform its normal function.

Avidity remains on track to conduct a preliminary assessment of safety, tolerability and key biomarkers in approximately half of the study participants in the MARINA trial in the fourth quarter of 2022.

Author: Rare Daily Staff

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