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.
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
Affiliations
  • 1. Departments of Discovery Biology Cardiovascular and Fibrosis, Bristol Myers Squibb, Princeton, NJ 08543, USA. Electronic address: [email protected].
  • 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.
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