PMID- 31957953 OWN - NLM STAT- MEDLINE DCOM- 20211110 LR - 20211110 IS - 2328-9503 (Electronic) IS - 2328-9503 (Linking) VI - 7 IP - 2 DP - 2020 Feb TI - Early phase 2 trial of TAS-205 in patients with Duchenne muscular dystrophy. PG - 181-190 LID - 10.1002/acn3.50978 [doi] AB - OBJECTIVE: Duchenne muscular dystrophy (DMD) is a progressive muscular disease characterized by chronic cycles of inflammatory and necrotic processes. Prostaglandin D(2) (PGD(2) ) 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. CI - (c) 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. FAU - Komaki, Hirofumi AU - Komaki H AUID- ORCID: 0000-0002-0659-1417 AD - Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan. FAU - Maegaki, Yoshihiro AU - Maegaki Y AD - Division of Child Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Tottori, Japan. FAU - Matsumura, Tsuyoshi AU - Matsumura T AD - Department of Neurology, National Hospital Organization Osaka Toneyama Medical Center, Osaka, Japan. FAU - Shiraishi, Kazuhiro AU - Shiraishi K AD - Department of Pediatrics, National Hospital Organization Utano National Hospital, Kyoto, Japan. FAU - Awano, Hiroyuki AU - Awano H AD - Department of Pediatrics, Kobe University Graduate School of Medicine, Hyogo, Japan. FAU - Nakamura, Akinori AU - Nakamura A AD - Third Department of Medicine, Shinshu University School of Medicine, Nagano, Japan. FAU - Kinoshita, Satoru AU - Kinoshita S AD - Department of Pediatrics, National Hospital Organization Niigata National Hospital, Niigata, Japan. FAU - Ogata, Katsuhisa AU - Ogata K AD - Department of Neurology, National Hospital Organization Higashisaitama National Hospital, Saitama, Japan. FAU - Ishigaki, Keiko AU - Ishigaki K AD - Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan. FAU - Saitoh, Shinji AU - Saitoh S AD - Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan. FAU - Funato, Michinori AU - Funato M AD - Department of Pediatrics, National Hospital Organization Nagara Medical Center, Gifu, Japan. FAU - Kuru, Satoshi AU - Kuru S AD - Department of Neurology, National Hospital Organization Suzuka National Hospital, Mie, Japan. FAU - Nakayama, Takahiro AU - Nakayama T AD - Department of Neurology, Division of Neuromuscular diseases, Yokohama Rosai Hospital, Kanagawa, Japan. FAU - Iwata, Yasuyuki AU - Iwata Y AD - Department of Rehabilitation, National Center of Neurology and Psychiatry, Tokyo, Japan. FAU - Yajima, Hiroyuki AU - Yajima H AD - Department of Rehabilitation, National Center of Neurology and Psychiatry, Tokyo, Japan. FAU - Takeda, Shin'ichi AU - Takeda S AD - National Center of Neurology and Psychiatry, Tokyo, Japan. LA - eng SI - ClinicalTrials.gov/NCT02752048 GR - Taiho Pharmaceutical/International PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20200120 PL - United States TA - Ann Clin Transl Neurol JT - Annals of clinical and translational neurology JID - 101623278 RN - 0 (Enzyme Inhibitors) RN - 0 (Morpholines) RN - 0 (Piperidines) RN - 0 (Pyrroles) RN - 0 (TAS-205) RN - EC 5.3.- (Intramolecular Oxidoreductases) RN - EC 5.3.99.2 (HPGDS protein, human) SB - IM MH - Child MH - Child, Preschool MH - Enzyme Inhibitors/administration & dosage/adverse effects/*pharmacology MH - Humans MH - Intramolecular Oxidoreductases/antagonists & inhibitors MH - Male MH - Morpholines/administration & dosage/adverse effects/*pharmacology MH - Muscular Dystrophy, Duchenne/*drug therapy MH - Outcome Assessment, Health Care MH - Piperidines/administration & dosage/adverse effects/*pharmacology MH - Pyrroles/administration & dosage/adverse effects/*pharmacology PMC - PMC7034509 COIS- 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. EDAT- 2020/01/21 06:00 MHDA- 2021/11/11 06:00 PMCR- 2020/01/20 CRDT- 2020/01/21 06:00 PHST- 2019/10/18 00:00 [received] PHST- 2019/12/16 00:00 [revised] PHST- 2019/12/17 00:00 [accepted] PHST- 2020/01/21 06:00 [pubmed] PHST- 2021/11/11 06:00 [medline] PHST- 2020/01/21 06:00 [entrez] PHST- 2020/01/20 00:00 [pmc-release] AID - ACN350978 [pii] AID - 10.1002/acn3.50978 [doi] PST - ppublish SO - Ann Clin Transl Neurol. 2020 Feb;7(2):181-190. doi: 10.1002/acn3.50978. Epub 2020 Jan 20.