Ishibashi Toru, Tanioka Hideki, Ikehara Tatsuya, Kezbor Safwan, Sonoyama Takuhiro
Project Management Department, Shionogi & Co., Ltd., 9F, Nissay Yodoyabashi East, 3-13, Imabashi 3-chome, Chuo-ku, Osaka, 541-0042, Japan.
Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka, Japan.
Clin Drug Investig. 2025 Feb;45(2):85-99. doi: 10.1007/s40261-024-01418-3. Epub 2025 Jan 20.
Anti-obesity medications are recommended for patients who do not achieve and maintain weight loss despite lifestyle interventions. S-309309 is a novel oral inhibitor of monoacylglycerol O-acyltransferase 2 being developed as a treatment for obesity.
The objective of the study was to investigate the safety, clinical pharmacology, pharmacokinetics and pharmacodynamic biomarker of S-309309.
A phase I, single-center, two-part, randomized, double-blind, placebo-controlled study of S-309309 following oral administration of a single-ascending dose (part 1) and a multiple dose (part 2) in healthy adults with or without obesity was conducted. We also assessed the effect of food on the pharmacokinetics of S-309309 and the effect of S-309309 on electrocardiogram parameters, the pharmacokinetics of midazolam (a cytochrome P450 3A substrate), and the pharmacodynamic biomarker of monoacylglycerol O-acyltransferase 2 inhibition.
In part 1 (N = 50), a single-ascending dose of S-309309 in healthy adults demonstrated dose proportionality and comparable exposure of S-309309 between the fasted and fed states. In part 2 (N = 24), no clinically meaningful difference was observed in the pharmacokinetics of multiple doses between healthy adults with or without obesity. S-309309 did not affect the pharmacokinetics of the cytochrome P450 3A substrate. The pharmacodynamic biomarker of monoacylglycerol O-acyltransferase 2 inhibition, dicarboxylic acid (18:1), was significantly increased after S-309309 administration in healthy adults with or without obesity. Overall, S-309309 demonstrated acceptable safety and tolerability without any serious adverse events or discontinuations because of adverse events, and did not have a clinically relevant effect on the heart rate or cardiac conduction. An effect on the placebo-corrected change-from-baseline corrected QT interval, corrected for heart rate using the Fridericia method, exceeding 10 ms can be excluded.
S-309309 was well tolerated as single-dose (up to 300 mg) and multiple-dose (50 mg once daily for 14 days) oral administration. The pharmacokinetic characteristics remained unaffected by obesity and food intake. S-309309 did not affect the pharmacokinetics of the cytochrome P450 3A substrate. Overall, S-309309 had an acceptable safety profile and favorable pharmacokinetic and pharmacodynamic characteristics.
NCT05247970, date of registration: 8 February, 2022.
对于尽管进行了生活方式干预但仍未实现并维持体重减轻的患者，推荐使用抗肥胖药物。S-309309是一种新型的单酰甘油O-酰基转移酶2口服抑制剂，正被开发用于治疗肥胖症。
本研究的目的是调查S-309309的安全性、临床药理学、药代动力学和药效学生物标志物。
进行了一项I期、单中心、两部分、随机、双盲、安慰剂对照研究，在有或无肥胖的健康成年人中口服给予单剂量递增（第1部分）和多剂量（第2部分）的S-309309。我们还评估了食物对S-309309药代动力学的影响，以及S-309309对心电图参数、咪达唑仑（一种细胞色素P450 3A底物）的药代动力学和单酰甘油O-酰基转移酶2抑制的药效学生物标志物的影响。
在第1部分（N = 50）中，健康成年人单剂量递增的S-309309显示出剂量比例性，且禁食和进食状态下S-309309的暴露量相当。在第2部分（N = 24）中，有或无肥胖的健康成年人多剂量药代动力学方面未观察到具有临床意义的差异。S-309309不影响细胞色素P450 3A底物的药代动力学。在有或无肥胖的健康成年人中，给予S-309309后，单酰甘油O-酰基转移酶2抑制的药效学生物标志物二羧酸（18:1）显著增加。总体而言，S-309309显示出可接受的安全性和耐受性，没有任何严重不良事件或因不良事件而停药的情况，并且对心率或心脏传导没有临床相关影响。可以排除对使用弗里德里西亚方法校正心率后的安慰剂校正基线校正QT间期的影响超过10毫秒。
S-309309作为单剂量（高达300毫克）和多剂量（每日一次50毫克，共14天）口服给药耐受性良好。药代动力学特征不受肥胖和食物摄入的影响。S-309309不影响细胞色素P450 3A底物的药代动力学。总体而言，S-309309具有可接受的安全性概况以及良好的药代动力学和药效学特征。
NCT05247970，注册日期：2022年2月8日。
