What it is
No exon-skipping therapy is approved for Duchenne muscular dystrophy caused by DMD variants amenable to exon 44 skipping (DMD44). Delpacibart zotadirsen (del-zota, also known as AOC 1044) is a first-in-class antibody-oligonucleotide conjugate designed to carry an exon 44-skipping morpholino oligomer into muscle and restore dystrophin expression in people with DMD44. EXPLORE44 was its first-in-human trial, a two-part randomised, double-blind, placebo-controlled phase 1/2 study at ten US sites, in healthy adult men aged 18-55 (part A) and in ambulatory and non-ambulatory male participants with DMD44 aged 7-27 (part B), with part B's dosing informed by part A. Between December 2022 and June 2024, 45 healthy volunteers and 26 men and boys with DMD44 were enrolled and randomly assigned; in part B, 9 received del-zota at 5 mg/kg every 6 weeks, 10 at 10 mg/kg every 8 weeks and 7 placebo, with a mean age of 13.3 years. The primary objective was safety and tolerability. 16 of the 19 participants given del-zota reported at least one adverse event, as did 6 of the 7 on placebo, most of them mild or moderate; 2 participants, both at 5 mg/kg, discontinued after an anaphylactic reaction and an infusion-related reaction. Exon 44 skipping rose from baseline by 36.6% at 5 mg/kg and 43.4% at 10 mg/kg against 1.6% with placebo, and dystrophin levels by 25.0% and 25.6% against -0.7%. The authors conclude that del-zota had an acceptable safety profile, produced increases in exon 44 skipping and dystrophin expression and decreased biomarkers of muscle damage, supporting a phase 3 study. The trial was funded by Avidity Biosciences, A Novartis Company.
Why it matters
In a trial of 26 men and boys with a form of Duchenne muscular dystrophy that has no approved exon-skipping therapy, a first-in-human drug raised dystrophin by about 25%. Duchenne is caused by variants in the dystrophin gene, and for the subset amenable to exon 44 skipping no exon-skipping therapy has been approved. Del-zota is an antibody-oligonucleotide conjugate meant to carry its oligomer into muscle; in this phase 1/2 trial exon 44 skipping rose 36.6% at the lower dose and 43.4% at the higher, against 1.6% on placebo, and the authors report an acceptable safety profile with most adverse events mild or moderate. They say the findings support a phase 3 study to assess efficacy and long-term safety.
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Filed underMuscle Physiology and Disorders, Neurogenetic and Muscular Disorders Research, Amyotrophic Lateral Sclerosis Research
