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 et al.
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In 30 seconds
EXPLORE44 was a two-part, randomised, double-blind, placebo-controlled phase 1/2 trial at ten US sites, studying delpacibart zotadirsen (del-zota) in healthy adult men and in ambulatory and non-ambulatory males aged 7–27 years with Duchenne muscular dystrophy amenable to exon 44 skipping. In the DMD group, three doses of del-zota were compared with placebo. Mean exon 44 skipping increased by 36·6% with 5 mg/kg and 43·4% with 10 mg/kg, versus 1·6% with placebo; dystrophin levels also increased. Most adverse events were mild or moderate, although two participants discontinued treatment after reactions.
Key findings
- Mean exon 44 skipping increased by 36·6% (95% CI 20·8 to 52·4) at 5 mg/kg and 43·4% (32·8 to 54·0) at 10 mg/kg, versus 1·6% (-3·4 to 6·7) with placebo.
- Mean dystrophin levels increased by 25·0% (9·2 to 40·7) at 5 mg/kg and 25·6% (13·0 to 38·3) at 10 mg/kg, versus -0·7% (-4·8 to 3·3) with placebo.
- At least one adverse event was reported by 16 (84%) del-zota-treated participants and six (86%) placebo recipients; two participants in the 5 mg/kg group discontinued after adverse reactions.
Why it matters
DMD variants amenable to exon 44 skipping lack approved exon-skipping therapies, and this trial provides early human evidence that del-zota can engage its molecular target and increase dystrophin levels. These biomarker findings are relevant to development of a targeted approach, but do not establish clinical benefit; efficacy and longer-term safety remain to be assessed.
What to keep in mind
The DMD cohorts were small, follow-up for the reported biomarker endpoints was limited to month 4 or month 5, and the trial was not designed to establish clinical efficacy or long-term safety.