P.123 A Phase I/II study of NS-089/NCNP-02, Exon 44 skipping drug, in patients with Duchenne muscular dystrophy

This is to report on the current status of Phase I/II study of NS-089/NCNP-02, which is a novel phosphorodiamidate morpholino oligomer that consists of a novel sequence design involving connected antisense oligonucleotides targeting different parts of exon 44 discovered by NCNP and Nippon Shinyaku Co., Ltd. NS-089/NCNP-02 targets exon 44, to serve as an effective treatment for DMD patients amenable to exon 44 skipping. The trial was designed in two parts. First-in-human part 1 is a stepwise dose-finding stage (4 weeks). Part 2 is a 24-week evaluation period based on the dosages determined during Part 1. In Part 1 of the study, Cohort 1 (three patients) will initially receive NS-089/NCNP-02 at dosing Level 1 (1.62 mg/kg QW) for two weeks and at dosing Level 3 thereafter (40 mg/kg QW) for two weeks. Cohort 2 (three patients) will initially receive NS-089/NCNP-02 at dosing Level 2 (10 mg/kg QW) for two weeks and at dosing Level 4 thereafter (80 mg/kg QW) for two weeks. In Part 2 of the study, two different doses of NS-089/NCNP-02 (40 mg/kg QW and 80 mg/kg QW) were intravenously administered for 24 weeks. Patients who have completed Part 1 are allowed to participate in Part 2, and total 6 subjects were assigned to this study. The primary endpoints are safety, and the secondary endpoints include expression of dystrophin, motor function assessments, exon 44 skipping efficiency, plasma and urinary NS-089/NCNP-02 concentrations, and changes in blood creatine kinase levels. NS-089/NCNP-02 were well tolerated, showed no sign of safety signals, and production of anti-dystrophin antibody. All participants showed significant increases from baseline in dystrophin protein expression in posttreatment biopsies as measured by Western blot; the increase in dystrophin expression on western blots to an average of 10.27% of normal in Cohort 1 (Dose: 40 mg/kg QW) and 15.79% of normal in Cohort 2 (Dose: 80 mg/kg QW). All motor function scales including NSAA consistently tend to decrease in part 1 stage, but their functions tend to improve in part 2 stage. Our first-in-human studies shall provide critical data of safety, potential efficacy and pharmacokinetics of NS-089/NCNP-02 for subsequent clinical development of NS-089/NCNP-02, with the ultimate aim of expanding treatment capacity for DMD and other neuromuscular conditions.