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. 2022 Nov 1;34(11):1732-1748.e5.
doi: 10.1016/j.cmet.2022.10.007.

MGAT2 inhibitor decreases liver fibrosis and inflammation in murine NASH models and reduces body weight in human adults with obesity

Dong Cheng  1 , Bradley A Zinker  2 , Yi Luo  3 , Petia Shipkova  4 , Claudia H De Oliveira  5 , Gopal Krishna  6 , Elizabeth A Brown  7 , Stephanie L Boehm  2 , Giridhar S Tirucherai  8 , Huidong Gu  3 , Zhengping Ma  2 , Ching-Hsuen Chu  2 , Joelle M Onorato  4 , Lisa M Kopcho  9 , Ron Ammar  7 , Julia Smith  2 , Pratik Devasthale  10 , R Michael Lawrence  10 , Steven A Stryker  4 , Elizabeth A Dierks  4 , Anthony V Azzara  2 , Leon Carayannopoulos  6 , Edgar D Charles  5 , Kimberley A Lentz  4 , David A Gordon  2
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Free article

MGAT2 inhibitor decreases liver fibrosis and inflammation in murine NASH models and reduces body weight in human adults with obesity

Dong Cheng et al. Cell Metab. .
Free article

Abstract

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.

Keywords: DCA; DGAT; GLP-1; MGAT2; NAFLD; NASH; PYY; dicarboxylic acid; liver fibrosis; steatosis; weight loss.

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Conflict of interest statement

Declaration of interests A.V.A., R.A., and S.A.S. were employees of Bristol Myers Squibb when the studies were conducted. All other authors are current employees of Bristol Myers Squibb and have Bristol Myers Squibb stock.

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