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

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.

Figure 1

Patient disposition.

Figure 2

Change in 6‐minute walk distance from baseline to Week 24. Bars indicate standard error.

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.