Kukreja Anjli, Keller Sascha, Shatillo Yury, Bauer Andras, Sharma Ashish, Wojciekowski Stephan, Visvanathan Sudha, Aslanyan Stella
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA.
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
Clin Transl Sci. 2025 Sep;18(9):e70285. doi: 10.1111/cts.70285.
BI 1595043 is an oral vanin-1 and vanin-2 inhibitor, which demonstrated promising effects on epithelial cell protection and reduction of inflammatory mediators in preclinical studies, as well as an acceptable safety profile in a previous single-rising-dose trial. Here, we report the results of a double-blind, randomized, placebo-controlled, multiple rising dose study, which investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of BI 1595043 in healthy male volunteers following oral administration of single and multiple rising doses over 18 days in total. Thirty subjects were treated (18-50 years of age; body mass index: 18.5-29.9 kg/m); each dose group included 10 subjects, of which eight were administered BI 1595043 (15, 30, or 60 mg) and two were administered placebo after an overnight fast of ≥ 10 h. With multiple rising doses, BI 1595043 appeared to effectively inhibit the conversion of pantetheine to pantothenic acid. BI 1595043 achieved rapid absorption after administration (median time from dosing to maximum measured concentration of the analyte in plasma: ~1 h) and plasma concentrations generally increased in a dose-proportional manner, with the majority excreted in urine within the first 24 h after dosing. Most adverse events reported were of mild or moderate severity, e.g., headache, dizziness, and abdominal discomfort. However, this study was temporarily halted after ophthalmologic adverse events judged to be drug-related by the investigator were reported in six subjects treated with BI 1595043. The study was discontinued prematurely due to the sponsor's decision to terminate the development of BI 1595043 in all indications.
BI 1595043是一种口服的泛酰巯基乙胺酶-1和泛酰巯基乙胺酶-2抑制剂，在临床前研究中显示出对上皮细胞保护和减少炎症介质有良好效果，并且在之前的单次递增剂量试验中具有可接受的安全性。在此，我们报告一项双盲、随机、安慰剂对照、多次递增剂量研究的结果，该研究在健康男性志愿者中口服单次和多次递增剂量共18天，调查了BI 1595043的安全性、耐受性、药代动力学和药效学。30名受试者接受治疗（年龄18 - 50岁；体重指数：18.5 - 29.9kg/m²）；每个剂量组包括10名受试者，其中8名给予BI 1595043（15、30或60mg），2名在禁食≥10小时过夜后给予安慰剂。随着多次递增剂量给药，BI 1595043似乎能有效抑制泛酰巯基乙胺转化为泛酸。BI 1595043给药后吸收迅速（血浆中分析物从给药到最大测量浓度的中位时间：约1小时），血浆浓度一般呈剂量比例增加，大部分在给药后24小时内随尿液排出。报告的大多数不良事件为轻度或中度严重程度，如头痛、头晕和腹部不适。然而，在用BI 1595043治疗的6名受试者中报告了被研究者判定与药物相关的眼科不良事件后，该研究暂时停止。由于申办方决定终止BI 1595043在所有适应症的研发，该研究提前终止。
