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.

What was studied

EXPLORE44 tested delpacibart zotadirsen (del-zota). Del-zota is an antibody-oligonucleotide conjugate. It aims to restore dystrophin in Duchenne muscular dystrophy. This applies to variants that allow skipping exon 44 (DMD44). No approved exon skipping therapies exist for DMD44. The trial was randomised, double-blind and placebo-controlled. It covered safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy. Part A had healthy adult men aged 18 to 55. Part B had male participants with DMD44 aged 7 to 27. It ran at 10 sites in the USA. In part B, participants were assigned 3 to 1 to del-zota or placebo. Some got 5 mg/kg every 6 weeks. Others got 10 mg/kg every 8 weeks. The main aim was safety and tolerability.

What they found

45 healthy volunteers and 26 males with DMD44 were enrolled. In part A, 21 of 34 on del-zota had an adverse event. So did 3 of 10 on placebo. Severe or serious events did not occur. Most events in part B were mild or moderate. One person on del-zota at 5 mg/kg stopped after an anaphylactic reaction. Another person at that dose stopped after an infusion-related reaction. At 5 mg/kg, exon 44 skipping rose by 36·6. At 10 mg/kg it rose by 43·4. With placebo it rose by 1·6. Dystrophin rose by 25·0 at 5 mg/kg. It rose by 25·6 at 10 mg/kg. With placebo it fell by 0·7.

What it means for patients

The authors say del-zota had an acceptable safety profile. They say it raised exon 44 skipping and dystrophin expression. They say it also lowered biomarkers of muscle damage. They say the findings support more study in a phase 3 study.

Why it is not certain yet

Part B had 26 participants. The authors say a phase 3 study is needed to assess efficacy and long-term safety. The trial was funded by Avidity Biosciences. A single trial can only show so much.

Source

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.

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