An Antibody-Oligonucleotide Conjugate for Myotonic Dystrophy Type 1

Myotonic dystrophy type 1 is a rare, dominantly inherited, progressive, disabling, 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 imparts a toxic gain of function to the transcribed messenger RNA (mRNA), resulting in dysregulated alternative splicing (missplicing). Delpacibart etedesiran (del-desiran [AOC 1001]) is a monoclonal antibody-oligonucleotide conjugate. The antibody component targets transferrin receptor 1, and the oligonucleotide component targets DMPK mRNA.

In this phase 1-2, multicenter, double-blind, randomized, placebo-controlled trial, we assigned participants with myotonic dystrophy type 1 to receive del-desiran intravenously in a single dose (1 mg per kilogram of body weight) or three doses (2 mg or 4 mg per kilogram) or placebo. The primary end point was safety, and secondary end points were the pharmacokinetic and pharmacodynamic profiles of del-desiran and changes in downstream aberrant splicing patterns at 43 days in the 1-mg group and at 92 days (49 days after the second dose) in the 2-mg and 4-mg groups.

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; 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; 1 of these participants discontinued participation in the trial. The percent change in DMPK mRNA levels in muscle-biopsy samples was -46% in the 1-mg group, -44% in the 2-mg group, -37% in the 4-mg group, and 0.9% in the placebo group. Maximum plasma concentrations of small interfering RNA (siRNA) and the area under the curve increased proportionally with dose escalation, and a minor fraction of siRNA was recovered in urine. 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.

Our results are consistent with delivery of del-desiran to muscle and amelioration of aberrant alternative splicing in some patients with myotonic dystrophy type 1; two serious adverse events occurred. These data support further clinical investigation. (Funded by Avidity Biosciences; ClinicalTrials.gov number, NCT05027269.).