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

Topic:

Clinical Trials

Poster Number: Virtual

Author(s):

Hirofumi Komaki, MD, PhD, National Center of Neurology and Psychiatry, Tokyo, Japan, Eri Takeshita, MD, PhD, National Center of Neurology and Psychiatry, Tokyo, Japan, Katsuhiko Kunitake, MD, National Center of Neurology and Psychiatry, Tokyo, Japan, Takami Ishizuka, PhD, National Center of Neurology and Psychiatry, Tokyo, Japan, Yuko Shimizu-Motohashi, MD, National Center of Neurology and Psychiatry, Tokyo, Japan, Akihiko Ishiyama, MD, PhD, National Center of Neurology and Psychiatry, Tokyo, Japan, Masayuki Sasaki, MD, PhD, National Center of Neurology and Psychiatry, Tokyo, Japan, Chihiro Yonee, MD, Kagoshima University, Kagoshima City, Kagoshima, Japan, Shinsuke Maruyama, MD, Kagoshima University, Kagoshima City, Kagoshima, Japan, Eisuke Hida, PhD, Osaka University, Osaka, Japan, Yoshitsugu Aoki, MD, PhD, National Center of Neurology and Psychiatry, Tokyo, Japan

Recently, exon skipping therapy has been attracting attention for patients with Duchenne muscular dystrophy (DMD). This therapy uses a synthesized antisense oligonucleotide designed to skip the specific exon to change out-of-frame mutation to in-frame in the dystrophin mRNA, thereby inducing the expression of a shorter but functional dystrophin protein. NS-089/NCNP-02 is a novel phosphorodiamidate morpholino oligomer that consists of a novel sequence design that involves connected antisense oligonucleotides, which target different parts of exon 44 as discovered by NCNP and Nippon Shinyaku Co., Ltd. NS-089/NCNP-02 targets exon 44 as an effective treatment for patients with DMD amenable to exon 44 skipping. The trial was designed in two parts. The first-in-human Part 1 is a stepwise dose-finding stage (4 weeks). Part 2 is a 24-week evaluation period based on determined dosages in Part 1. In Part 1, Cohort 1 (three patients) will initially receive NS-089/NCNP-02 at Level 1 dosing (1.62 mg/kg once a week [QW]) for 2 weeks and Level 3 dosing (40 mg/kg QW) for 2 weeks, thereafter. Cohort 2 (three patients) will initially receive NS-089/NCNP-02 at Level 2 dosing (10 mg/kg QW) for 2 weeks and Level 4 dosing (80 mg/kg QW) for 2 weeks, thereafter. In Part 2, two different doses of NS-089/NCNP-02 (determined from the results of Part 1) will be intravenously administered QW for 24 weeks. Patients who have completed Part 1 are allowed to participate in Part 2, wherein a total of six subjects were assigned to this study. The primary endpoint is safety, whereas the secondary includes expression of dystrophin protein, motor function assessments, exon 44 skipping efficiency, plasma and urinary NS-089/NCNP-02 concentrations, and blood creatine kinase level changes. Herein, we report data of safety, efficacy, and pharmacokinetics of NS-089/NCNP-02 from this study.