Early phase 2 trial of TAS-205 in patients with Duchenne muscular dystrophy

Hirofumi Komaki, Yoshihiro Maegaki, Tsuyoshi Matsumura, Kazuhiro Shiraishi, Hiroyuki Awano, Akinori Nakamura, Satoru Kinoshita, Katsuhisa Ogata, Keiko Ishigaki, Shinji Saitoh, Michinori Funato, Satoshi Kuru, Takahiro Nakayama, Yasuyuki Iwata, Hiroyuki Yajima, Shin'ichi Takeda, Hirofumi Komaki, Yoshihiro Maegaki, Tsuyoshi Matsumura, Kazuhiro Shiraishi, Hiroyuki Awano, Akinori Nakamura, Satoru Kinoshita, Katsuhisa Ogata, Keiko Ishigaki, Shinji Saitoh, Michinori Funato, Satoshi Kuru, Takahiro Nakayama, Yasuyuki Iwata, Hiroyuki Yajima, Shin'ichi Takeda

Abstract

Objective: Duchenne muscular dystrophy (DMD) is a progressive muscular disease characterized by chronic cycles of inflammatory and necrotic processes. Prostaglandin D2 (PGD2 ) is produced by hematopoietic PGD synthase (HPGDS), which is pathologically implicated in muscle necrosis. This randomized, double-blind, placebo-controlled early phase 2 study (NCT02752048) aimed to assess the efficacy and safety of the novel selective HPGDS inhibitor, TAS-205, with exploratory measures in male DMD patients aged ≥5 years.

Methods: Patients were randomized 1:1:1 to receive low-dose TAS-205 (6.67-13.33 mg/kg/dose), high-dose TAS-205 (13.33-26.67 mg/kg/dose), or placebo. The primary endpoint was the change from baseline in a 6-minute walk distance (6MWD) at Week 24.

Results: Thirty-six patients were enrolled, of whom 35 patients were analysed for safety. The mean (standard error) changes from baseline to Week 24 in 6MWD were -17.0 (17.6) m in the placebo group (n = 10), -3.5 (20.3) m in the TAS-205 low-dose group (n = 11), and -7.5 (11.2) m in the TAS-205 high-dose group (n = 11). The mean (95% confidence interval) difference from the placebo group was 13.5 (-43.3 to 70.2) m in the TAS-205 low-dose group and 9.5 (-33.3 to 52.4) m in the TAS-205 high-dose group. No obvious differences were observed in the incidences of adverse events between treatment groups. No adverse drug reactions specific to TAS-205 treatment were observed.

Interpretation: The HPGDS inhibitor TAS-205 showed a favorable safety profile in DMD patients. Further research is required to examine the effectiveness of TAS-205 in a larger trial.

Conflict of interest statement

HK reports grants from Taiho Pharmaceutical Co., Ltd. during the conduct of the study. TN reports grants from National Centre of Neurology and Psychiatry (NCNP) and Japan Agency for Medical Research and Development (AMED); and personal fees from Taiho Pharmaceutical Co., Ltd. during the conduct of the study. YM, HA, YI, HY, ST, TM, KS, AN, SK, KO, KI, SS, MF, and SK have nothing to disclose in relation to this manuscript.

© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

Figures

Figure 1
Figure 1
Patient disposition.
Figure 2
Figure 2
Change in 6‐minute walk distance from baseline to Week 24. Bars indicate standard error.
Figure 3
Figure 3
Percent change in pharmacodynamic endpoints from baseline to Week 24; (A) urinary tPGDM/Cre concentration ratio, (B) total urinary tPGDM excretion, (C) urinary tPGEM/Cre concentration ratio and (D) total urinary tPGEM excretion. Bars indicate standard error. Abbreviations: tPGDM, tetranor prostaglandin D2 metabolite; Cre, creatinine; tPGEM, tetranor prostaglandin E2 metabolite.

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