武田（Takeda）3月3日宣布，已向日本劳动卫生福利部（MHLW）提交了实验性胃酸分泌抑制剂TAK-438（通用名：vonoprazan富马酸）的新药申请（NDA），该药属于钾离子（K+）竞争性酸阻滞剂（P-CAB）的新一类抑制剂，具有强劲、持久的胃酸分泌抑制作用，同时，在胃壁细胞胃酸分泌的最后一步中，通过抑制K+对H+,K+—ATP酶（质子泵）的结合作用，对胃酸分泌也具有提前终止作用。
武田已在日本开展了数个III期临床试验，调查了TAK-438用于糜烂性食管炎、胃溃疡、十二指肠溃疡、幽门螺杆菌根除适应症的疗效。在临床试验中，TAK-438表现出了疗效，同时耐受性和安全性良好。TAK-438 NDA的提交，便是基于这些临床试验的良好数据。
目前，在日本，质子泵抑制剂（PPIs）已被广泛处方用于酸相关疾病的一线治疗。但PPI并不总是能够提供足够的疗效，同时，胃酸分泌抑制效果可能也会因人而异，这是由于参与PPI代谢的一种蛋白CYP-2C19，其编码基因在不同个体中具有基因多态性。
但TAK-438并不主要由CYP2C19代谢，同时TAK-438对质子泵的抑制作用，无需酸的激活，该药以高浓度进入胃中，在首次给药时，便能产生最大的抑制效应，而且该效应可持续24小时。
TAK-438在酸中稳定，而速效配方现成，无需优化配方设计（如肠溶包衣），药效起效剂量在不同患者中的差异并于不显著。基于这些优点，TAK-438有望成为一种新的治疗药物，解决当前酸相关疾病治疗中存在的问题。
Published 03 March 2014
Takeda Pharmaceutical (Takeda) has submitted a new drug application (NDA) to the Japanese Ministry of Health, Labour and Welfare for an acid secretion inhibitor, TAK-438 (generic name: Vonoprazan Fumarate).
Discovered by Takeda, TAK-438 belongs to a new class of inhibitors called potassium-competitive acid blockers (P-CABs) that show strong and sustainable acid secretion inhibitory effects as well as demonstrate efficacy in early termination by inhibiting the binding of potassium ion (K+) to H+, K+-ATPase (proton pump) in the final step of gastric acid secretion in gastric parietal cells.
The company has also carried out Phase III clinical trials for TAK-438 in Japan for indications such as erosive esophagitis, gastric ulcer, duodenal ulcer, and H. pylori eradication.
In the trial, TAK-438 showed efficacy and has a favorable profile for safety and tolerability.
The new drug application was based on favorable results obtained from these trials.
Currently, proton pump inhibitors (PPIs) are widely prescribed as first-line therapy for the treatment of acid-related diseases in Japan.
The company said that PPIs do not always provide sufficient therapeutic efficacy, and the acid secretion inhibitory effects of PPIs may differ among inpiduals, because of the protein CYP2C19, which has gene polymorphisms that are involved in me-tabolism.
TAK-438 inhibits proton pumps without the need for activation by acid and the compound is distributed at high concentrations into the stomach, the target organ, thereby exerting a nearly maximum inhibitory effect from the first dose and remaining effective for 24 hours.
Unlike PPIs, TAK-438 is not primarily me-tabolized by CYP2C19 which has gene polymorphisms, the company said.
Takeda general manager of Pharmaceutical Development Division Nancy Joseph-Ridge said the company is pleased to submit the NDA for TAK-438, which would represent a new treatment option for patients with acid-related diseases that require inhibition of acid secretion.
"Takeda aims to achieve better treatment outcomes in the field of gastrointestinal diseases and will work hard to meet the medical needs of more patients," Joseph-Ridge said.
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