844-P: Lanifibranor Improves Markers of Cardiometabolic Health in Patients with NASH and Type 2 Diabetes, Correlated with Responses in Adiponectin Levels

Background: Lanifibranor, a pan-PPAR agonist, has shown efficacy on liver histology and metabolic-immune markers of NASH in the phase 2b NATIVE study. PPAR signaling is involved in common pathways of NASH and type 2 diabetes (T2D). Adiponectin (ADP) is a pleiotropic adipokine which improves insulin resistance (IR), lipid metabolism, inflammation and fibrosis; low ADP levels are associated with risk for cardiovascular disease and NASH. Methods: NATIVE evaluated lanifibranor 800 and 1200 mg/d versus placebo in 247 patients with non-cirrhotic NASH for 24 weeks treatment. Of these 103 had T2D, 144 did not have T2D of whom 47 had prediabetes defined by fasting glucose levels (FGL) between 5.6 - 6.9 mmol/l. ADP serum levels, metabolic-immune and hepatic markers (glycemic control, IR, lipids, systemic inflammation) were measured at baseline (BL) and end of treatment (EOT). In each subgroup, we evaluated ADP at BL, ADP fold-change at EOT, and correlation between ADP change and response of markers. Results: ADP levels were lower in patients with T2D compared to those with pre-DM or normal glycemic control (NGC) (mean 4.6, 5.5, and 5.6 ug/ml, respectively). More patients with T2D had ADP below 5 mg/ml compared to pre-DM or NGC (65% vs 62/54%). In lanifibranor-treated group, ADP folds were similar in the 3 groups, with mean 4.3 fold increase by EOT, versus no increase in the placebo-treated group. In the pooled lanifibranor arms, increase in ADP correlated with improvements in glycemic control, IR, lipid metabolism, and systemic inflammation, consistently in the 3 groups, with higher improvements in patients with T2D and prediabetes compared to the NGC group. Conclusion: The pan-PPAR agonist lanifibranor significantly improves ADP levels and this improvement correlated with markers of cardiometabolic health in patients with T2D and prediabetes. Lanifibranor improves cardiovascular risk profile in patients with impaired glycemic control and NASH.