Background: Brogidirsen (NS-089/NCNP-02) is being studied for the treatment of Duchenne muscular dystrophy (DMD) in patients with a dystrophin gene mutation amenable to exon 44 skipping. Brogidirsen is a novel phosphorodiamidate morpholino oligomer (PMO) that contains two linked sequences targeting two separate binding sites within exon 44. In a previous Phase 1/2 study, skeletal muscle dystrophin levels increased significantly after 24 weeks of brogidirsen treatment (mean change from baseline: 13.1%, p = 0.03). This first-in-human data led to FDA orphan drug designation.
Objectives: We present the study design for a Phase 2, open-label, 2-part study (NCT05996003) assessing the efficacy, safety, tolerability, and pharmacokinetics of brogidirsen in ambulant boys with DMD. The primary objectives of Part 1 and Part 2 are to evaluate the safety, tolerability, and pharmacokinetics of brogidirsen. The primary objective of Part 2 also includes dystrophin protein induction in skeletal muscle of participants treated at the maximum tolerable dose (MTD) from Part 1.
Methods: Brogidirsen will be administered weekly by intravenous infusion to ambulant boys aged ≥4 to <15 years with DMD mutations amenable to exon 44 skipping. The study (N = 20) will consist of 2 cohorts. Cohort 1 (n = 6) will receive ascending doses consisting of a 4-week Treatment Phase at each of three dose levels (Part 1). These participants will continue into a 24-week Treatment Phase at the MTD from Part 1 (Part 2). Cohort 2 (n = 14) will go through a 24-week Treatment at the MTD of Part 1 (Part 2) and will undergo muscle biopsies at baseline and Week 25 to determine dystrophin induction. Secondary outcomes of muscle strength and motor function will be evaluated. Conclusions: The design of this 2-part Phase 2 study was informed by the results of the previous Phase 1/2 trial that showed brogidirsen induced significant dystrophin production. The Phase 2 study has begun recruitment.