FDA Pauses U.S. Enrollment in Myotonic Dystrophy Trial After Serious Adverse Event
The FDA has placed a partial hold on U.S. enrollment in a Phase 2 trial of del-desiran for myotonic dystrophy type 1, citing preclinical mouse data showing blood pressure drops not seen in humans, following a serious adverse event in earlier testing.
The Food and Drug Administration has placed a partial hold on a Phase 2 trial of delpacibart etedesiran (del-desiran), halting U.S. patient enrollment after a serious adverse event occurred in an earlier study. The agency's action focuses on previously submitted preclinical data showing blood pressure drops in mice, concerns that have not been observed in human patients.
The hold comes as the company continues Phase 2 work internationally, having recently received permission to open the "Freedom2" study to patients in New Zealand, Australia and South Korea. The FDA has had the mouse data since mid-2024, and the timing of the hold appears related to the company's bid to open U.S. sites for Freedom2, which may have prompted reviewers to re-examine the preclinical findings.
Del-desiran is a monoclonal antibody-oligonucleotide conjugate designed to treat myotonic dystrophy type 1, a rare, dominantly inherited, progressive neuromuscular disease that leads to decreased life expectancy and has no approved therapies. The disease is caused by a trinucleotide repeat expansion in DMPK, which encodes myotonic dystrophy type 1 protein kinase and results in dysregulated alternative splicing. The antibody component targets transferrin receptor 1, and the oligonucleotide component targets DMPK mRNA in muscle tissue.
Results from the phase 1-2 MARINA trial showed that del-desiran reduced DMPK mRNA levels in muscle-biopsy samples by 46% in the 1-mg per kilogram group, 44% in the 2-mg group, and 37% in the 4-mg group, compared to 0.9% in the placebo group. Reductions in the mean composite missplicing score from baseline were 3%, 17%, 16%, and 7%, respectively, consistent with amelioration of missplicing in the 2-mg and 4-mg groups.
In the MARINA trial, six participants received del-desiran at a dose of 1 mg per kilogram, 9 at a dose of 2 mg per kilogram, and 13 at a dose of 4 mg per kilogram, while 10 participants received placebo. Mild or moderate adverse events occurred in 35 of the 38 participants who received an infusion. Two severe, serious adverse events occurred in 2 participants in the 2-mg and 4-mg groups. One event was a bilateral thalamic infarction attributed to del-desiran, which resulted in treatment discontinuation and prompted the FDA to pause new trial enrollment. The other severe, serious adverse event was respiratory failure deemed unrelated to the trial medication.
On tests of muscle function, participants receiving del-desiran experienced improvement in a dose-dependent manner. A timed measure of hand function saw a 0.55 second improvement in placebo, 1.49 seconds in the 2-mg group, and 3.45 seconds in the 4-mg group. Maximum plasma concentrations of small interfering RNA and the area under the curve increased proportionally with dose escalation, and a minor fraction of siRNA was recovered in urine.
The company faced an agency hold back in 2023 before beginning Phase 1 testing of its DM1 treatment. The FDA has a history of treading carefully with RNA medicines targeted at neuromuscular conditions, having issued similar pauses for other companies developing therapies in this space. The company also previously discontinued an experimental treatment for Duchenne muscular dystrophy for lack of efficacy.
The company is working with the FDA to address the concerns as quickly as possible. The MARINA trial involved adults aged 18 to 65 years with genetic diagnosis of myotonic dystrophy type 1, a DMPK CTG repeat length of 100 or more, and scores within certain thresholds on impairment rating tests. Participants in Part A received a single 1-mg per kilogram infusion dose, while Part B participants received three infusions of either 2 mg per kilogram or 4 mg per kilogram every six weeks.