140-LB: NGM313, a Novel Activator of b-Klotho/FGFR1c, Improves Insulin Resistance and Reduces Hepatic Fat in Obese, Nondiabetic Subjects

Background: NGM313 is a humanized monoclonal antibody activator of β-klotho/FGFR1c that has been shown to reduce HOMA-IR in obese subjects. This study compared the effects of a single dose of NGM313 vs. daily pioglitazone (PIO) on insulin sensitivity, liver fat content (LFC) and lipids in insulin resistant, obese subjects with increased liver fat. Methods: 25 subjects were randomized 2:1 to either a single dose of NGM313 240 mg SC (n=17) or PIO 45 mg PO QD (n=8) for 36 days. Whole-body insulin sensitivity was determined by a two-step hyperinsulinemic, euglycemic clamp and LFC by magnetic resonance imaging-proton density fat fraction (MRI-PDFF). Results: (Table 1) A single dose of NGM313 significantly increased glucose disposal rate and was comparable to PIO. Suppression of endogenous glucose production was enhanced by both NGM313 and PIO. Significant reductions in LFC, HbA1c, serum triglycerides and LDL-C, and an increase in HDL-C, were observed with NGM313. NGM313 produced a greater reduction in LFC vs. PIO at day 23. The safety and tolerability profile was favorable for both drugs. Conclusion: NGM313 is a potent insulin sensitizer, comparable to PIO. In addition, NGM313 is highly effective in reducing LFC in subjects with increased liver fat. As such, NGM313 has significant potential to be an effective treatment for nonalcoholic steatohepatitis and type 2 diabetes. Disclosure A. DePaoli: Employee; Self; NGM Biopharmaceuticals. V. Phung: Employee; Self; NGM Biopharmaceuticals. Stock/Shareholder; Self; NGM Biopharmaceuticals. M.R. Bashir: Consultant; Self; RadMD. Research Support; Self; Madrigal Pharmaceuticals, Metacrine Inc, NGM Biopharmaceuticals, Pinnacle Clinical Research, ProSciento, Siemens Corporation. L. Morrow: Employee; Spouse/Partner; Eli Lilly and Company. Employee; Self; ProSciento. C. Beysen: None. A. Yan: None. L. Ling: Employee; Self; NGM Biopharmaceuticals. Stock/Shareholder; Self; NGM Biopharmaceuticals. B. Baxter: Employee; Self; NGM Biopharmaceuticals. K.L. Luskey: Consultant; Self; NGM Biopharmaceuticals. J.M. Olefsky: None.