Phase I/II Trial of Brogidirsen: Dual-Targeting Antisense Oligonucleotides for Exon 44 Skipping in Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a severe muscle disorder caused by mutations in the DMD gene, resulting in dystrophin loss. Exon-skipping using antisense oligonucleotides (ASO) is a promising approach that partially restores dystrophin by correcting the frameshift during pre-mRNA splicing. However, a weakness of the current approach is that it is mutation-specific and has poor efficacy. To address these, we aim to develop brogidirsen, a new dual-targeting ASO that targets two sequences in exon 44 of the DMD using phosphorodiamidate morpholino oligomer. Here, we conducted an open-label, dose-escalation, Phase I/II trial to evaluate the safety, pharmacokinetics, and activity of brogidirsen, administered intravenously to six ambulant patients with DMD amenable to exon 44 skipping. The study consisted of a dose-escalation part to determine the optimal doses, followed by extended treatment with 40 mg/kg or 80 mg/kg weekly dose for 24 weeks. There were no serious adverse events related to brogidirsen. The results indicated a dose-dependent increase in dystrophin levels, reaching 10.27% and 15.79% of the normal level in the two cohorts. Motor functional tests suggested a trend toward maintaining or slightly improving motor function. There was a dose-dependent increase in Cmax and AUC0-t. High-throughput proteomic assays revealed that serum proteins such as PADI2, TTN, MYOM2, and MYLPF were observed to reduce, suggesting them as biomarkers for therapeutic effects. Notably, in vitro assays using urine-derived cells from patients with DMD support brogidirsens high efficacy in the first-in-human studies. These promising results warrant a subsequent multinational trial for DMD.