Monoacylglycerol acyltransferase 2 (MGAT2) is an important enzyme highly expressed in the human small intestine and liver for the regulation of triglyceride absorption and homeostasis. We report that treatment with BMS-963272, a potent and selective MGAT2 inhibitor, decreased inflammation and fibrosis in CDAHFD and STAM, two murine nonalcoholic steatohepatitis (NASH) models. In high-fat-diet-treated cynomolgus monkeys, in contrast to a selective diacylglycerol acyltransferase 1 (DGAT1) inhibitor, BMS-963272 did not cause diarrhea. In a Phase 1 multiple-dose trial of healthy human adults with obesity (NCT04116632), BMS-963272 was safe and well tolerated with no treatment discontinuations due to adverse events. Consistent with the findings in rodent models, BMS-963272 elevated plasma long-chain dicarboxylic acid, indicating robust pharmacodynamic biomarker modulation; increased gut hormones GLP-1 and PYY; and decreased body weight in human subjects. These data suggest MGAT2 inhibition is a promising therapeutic opportunity for NASH, a disease with high unmet medical needs.

单酰基甘油酰基转移酶 2 (MGAT2) 是一种在人体小肠和肝脏中高表达的重要酶，用于调节甘油三酯的吸收和稳态。我们报告说，用一种有效的选择性 MGAT2 抑制剂 BMS-963272 治疗可减少 CDAHFD 和 STAM 这两种小鼠非酒精性脂肪性肝炎 (NASH) 模型的炎症和纤维化。在高脂肪饮食处理的食蟹猴中，与选择性甘油二酯酰基转移酶 1 (DGAT1) 抑制剂相比，BMS-963272 不会引起腹泻。在针对患有肥胖症的健康成人的 1 期多剂量试验 (NCT04116632) 中，BMS-963272 安全且耐受性良好，没有因不良事件而中断治疗。与啮齿动物模型中的发现一致，BMS-963272 升高血浆长链二羧酸，表明稳健的药效学生物标志物调制；增加肠道激素 GLP-1 和 PYY；并减轻了人类受试者的体重。这些数据表明 MGAT2 抑制是 NASH 的一个有前途的治疗机会，NASH 是一种医疗需求未得到满足的疾病。