A phase I study of TAS-205 in patients with Duchenne muscular dystrophy

Abstract

Objective: Currently, the only approved standard Duchenne muscular dystrophy (DMD) treatment in Japan is oral steroids, which have various disadvantages. Previous work has suggested that hematopoietic-type prostaglandin D synthase (HPGDS), involved in production of the inflammatory mediator prostaglandin D₂ (PGD₂), might have a role in DMD pathology. We therefore investigated the safety, pharmacokinetics (PK), and pharmacodynamics of a highly selective HPGDS inhibitor (TAS-205) in Japanese patients with genetically confirmed DMD.

Methods: This was a double-blind, randomized, placebo-controlled phase I study to evaluate the use of single or 7-day repeated doses of TAS-205 administered orally. The urinary excretion of PGD₂ metabolites was also assessed.

Results: The PK analysis set included 15 and 14 patients in the single- and repeated-dose periods, respectively; the pharmacodynamics set and the safety set included 21 and 19 patients in each period, respectively. The PK of TAS-205 were linear in the dose range studied (1.67-13.33 mg/kg/dose) and the plasma concentration of TAS-205 reached steady state by Day 4. TAS-205 dose-dependently decreased the urinary excretion of tetranor-prostaglandin D metabolite at each measurement time point and did not affect the urinary excretion of tetranor-prostaglandin E metabolite. No clinically significant adverse events were reported after TAS-205 single or repeated administration.

Interpretation: We confirmed the safety and tolerability of TAS-205 in this study. TAS-205 decreased the total urinary excretion of PGD₂ metabolites in a dose-dependent manner, suggesting that TAS-205 might be a therapeutic option to treat DMD patients.

Figure 1

Study flow. Disposition of patients in the single‐dose period included in PK evaluation. PK, pharmacokinetics.

Figure 2

Study flow. Disposition of patients in the single‐dose period included in PD evaluation. PD, pharmacodynamics.

Figure 3

Study flow. Disposition of patients in the repeated‐dose period included in PK evaluation. PK, pharmacokinetics.

Figure 4

Study flow. Disposition of patients in the repeated‐dose period included in PD evaluation. PD, pharmacodynamics.

Figure 5

Comparisons of (A) C _max/dose, (B) AUC_0‐48/dose, and (C) AUC_0‐inf/dose values of TAS‐205 among steps in the single‐dose period. N = 5. The solid line shows the median; the square shows the mean. Box ends represent 25th and 75th percentiles. Whiskers show the maximums and minimums. C _max, maximum plasma concentration; AUC_0‐48, area under the plasma concentration–time curve from time 0 to 48 h post‐dose, AUC_0‐inf, area under the plasma concentration–time curve from time 0 to infinity.

Figure 6

Time‐dependent changes in the ratio of (A) tetranor‐PGDM/Cre and (B) tetranor‐PGEM/Cre in pooled urine in the repeated‐dose period. Mean + standard deviation (n = 3–5). Day 0 = pre‐dose. PGDM, prostaglandin D metabolite; Cre, creatinine; PGEM, prostaglandin E metabolite.

Figure 7

Time‐dependent changes in the ratio of (A) Ex(tetranor‐PGDM) and (B) Ex(tetranor‐PGEM) in pooled urine in the repeated‐dose period. Mean + standard deviation (n = 3–5). Day 0 = pre‐dose. PGDM, prostaglandin D metabolite; PGEM, prostaglandin E metabolite.

Figure 8

Comparison of tetranor‐PGDM/Cre, Ex(tetranor‐PGDM), tetranor‐PGEM/Cre, and Ex(tetranor‐PGEM) ratios in pre‐dosing pooled urine between ambulatory and nonambulatory patients in (A) the single‐dose and (B) repeated‐dose periods. Ambulatory patients (A: n = 9, B: n = 8); nonambulatory patients (A: n = 12, B: n = 11). The solid line shows the median; the square shows the mean. Box ends represent 25th and 75th percentiles. Whiskers show the maximums and minimums. The open circle in (B) represents an outlier. PGDM, prostaglandin D metabolite; Cre, creatinine; PGEM, prostaglandin E metabolite.