Peer-reviewed article

Safety and efficacy of delpacibart zotadirsen in Duchenne muscular dystrophy mutations amenable to exon 44 skipping in the USA (EXPLORE44): a randomised, placebo-controlled, double-blind, phase 1/2 trial.

Aravindhan Veerapandiyan, Jamie Eskuri, Chamindra G Laverty, Craig M McDonald, Han Phan et al. · 21 Oct 2026

Abstract

BACKGROUND: There are no approved exon skipping therapies to treat Duchenne muscular dystrophy due to 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 deliver an exon 44-skipping phosphorodiamidate morpholino oligomer to muscle to restore dystrophin expression for individuals with DMD44. EXPLORE44 was a first-in-human trial to evaluate del-zota's safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy. METHODS: EXPLORE44 was a two-part randomised, double-blind, placebo-controlled, phase 1/2 study in healthy adult men (aged 18-55 years; part A) and ambulatory and non-ambulatory male participants with DMD44 (aged 7-27 years; part B) at ten clinical research sites in the USA. Dosing in part B was informed by safety, pharmacokinetic, and pharmacodynamic data from part A. In part B, participants with DMD44 were randomised (3:1 del-zota:placebo) within two dose cohorts to receive three intravenous doses of del-zota (5 mg/kg every 6 weeks, or 10 mg/kg every 8 weeks) or matching placebo. A computer-generated permuted-block randomisation schedule was prepared by an independent statistician with no further role in the study. Infusions were prepared by an unmasked pharmacist under supervision of the masked investigator; other site staff, participants, and sponsor team members were masked to allocation. The primary objective was safety and tolerability measured by the incidence of treatment-emergent adverse events. Secondary endpoints assessing target engagement were change from baseline in exon skipping (ie, defined as the percentage of dystrophin mRNA transcripts in which exon 44 is excluded from the mature mRNA relative to total dystrophin mRNA transcripts) and dystrophin level to month 4 (5 mg/kg cohort) or month 5 (10 mg/kg cohort). The trial was registered with ClinicalTrials.gov (NCT05670730) and is complete. FINDINGS: Between Dec 5, 2022, and June 27, 2024, we enrolled and randomly assigned 45 healthy volunteers and 26 men and boys with DMD44. In part A, three (30%) of ten healthy volunteers who received placebo and 21 (62%) of 34 who received del-zota reported at least one adverse event, none of which were severe or serious. In part B, nine participants with DMD44 received del-zota at 5 mg/kg, ten at 10 mg/kg, and seven received placebo; mean age 13·3 years (SD 4·2). 16 (84%) participants with DMD44 treated with del-zota and six (86%) treated with placebo reported at least one adverse event, most of which were mild or moderate; two participants, both in the 5 mg/kg del-zota group, discontinued due to adverse events (anaphylactic reaction and infusion-related reaction). Mean increases from baseline in exon 44 skipping were 36·6% (95% CI 20·8 to 52·4, SD 17·1, nominal p=0·0013) at 5 mg/kg, 43·4% (32·8 to 54·0, 14·9, nominal p<0·0001) at 10 mg/kg, and 1·6% (-3·4 to 6·7, 4·8, nominal p=0·44) with placebo. Mean increases from baseline in dystrophin levels were 25·0% (9·2 to 40·7, 17·0, nominal p=0·0082) at 5 mg/kg, 25·6% (13·0 to 38·3, 17·7, nominal p=0·0013) at 10 mg/kg, and -0·7% (-4·8 to 3·3, 3·9, nominal p=0·66) with placebo. INTERPRETATION: Del-zota had an acceptable safety profile, produced increases in exon 44 skipping and dystrophin expression, and decreased biomarkers of muscle damage in participants with DMD44. Findings from this study support further investigation of del-zota in a phase 3 study to assess efficacy and long-term safety. FUNDING: Avidity Biosciences, A Novartis Company.