Cell metabolism · 2022
MGAT2 inhibitor decreases liver fibrosis and inflammation in murine NASH models and reduces body weight in human adults with obesity.
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Cheng Dong, Zinker Bradley A, Luo Yi, Shipkova Petia, De Oliveira Claudia H, Krishna Gopal, Brown Elizabeth A, Boehm Stephanie L, Tirucherai Giridhar S, Gu Huidong, Ma Zhengping, Chu Ching-Hsuen, Onorato Joelle M, Kopcho Lisa M, Ammar Ron, Smith Julia, Devasthale Pratik, Lawrence R Michael, Stryker Steven A, Dierks Elizabeth A, Azzara Anthony V, Carayannopoulos Leon, Charles Edgar D, Lentz Kimberley A, Gordon David A
Аннотация
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.