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

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

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

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

Authors

Dong Cheng¹, Bradley A Zinker², Yi Luo³, Petia Shipkova⁴, Claudia H De Oliveira⁵, Gopal Krishna⁶, Elizabeth A Brown⁷, Stephanie L Boehm², Giridhar S Tirucherai⁸, Huidong Gu³, Zhengping Ma², Ching-Hsuen Chu², Joelle M Onorato⁴, Lisa M Kopcho⁹, Ron Ammar⁷, Julia Smith², Pratik Devasthale¹⁰, R Michael Lawrence¹⁰, Steven A Stryker⁴, Elizabeth A Dierks⁴, Anthony V Azzara², Leon Carayannopoulos⁶, Edgar D Charles⁵, Kimberley A Lentz⁴, David A Gordon²

Affiliations

¹ Departments of Discovery Biology Cardiovascular and Fibrosis, Bristol Myers Squibb, Princeton, NJ 08543, USA. Electronic address: dong.cheng@bms.com.
² Departments of Discovery Biology Cardiovascular and Fibrosis, Bristol Myers Squibb, Princeton, NJ 08543, USA.
³ Translational Medicine, Bristol Myers Squibb, Lawrenceville, NJ 08543, USA.
⁴ Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Princeton, NJ 08543, USA.
⁵ Global Drug Development, Bristol Myers Squibb, Lawrenceville, NJ 08543, USA.
⁶ ICF Early Clinical Development, Bristol Myers Squibb, Summit, NJ 07901, USA.
⁷ Translational Bioinformatics, Bristol Myers Squibb, Princeton, NJ 08543, USA.
⁸ Clinical Pharmacology, Bristol Myers Squibb, Lawrenceville, NJ 08543, USA.
⁹ Leads Discovery and Optimization, Bristol Myers Squibb, Princeton, NJ 08543, USA.
¹⁰ Small Molecule Drug Discovery, Bristol Myers Squibb, Princeton, NJ 08543, USA.

PMID: 36323235
DOI: 10.1016/j.cmet.2022.10.007

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.

MeSH terms

Adult
Animals
Body Weight
Clinical Trials, Phase I as Topic
Humans
Inflammation / drug therapy
Liver Cirrhosis / drug therapy
Mice
Non-alcoholic Fatty Liver Disease* / drug therapy
Obesity* / drug therapy

Substances

2-acylglycerol O-acyltransferase