Pharmacodynamic effects of direct AMP kinase activation in humans with insulin resistance and non-alcoholic fatty liver disease: A phase 1b study.

AMPK is an energy sensor modulating metabolism, inflammation, and a target for metabolic disorders. Metabolic dysfunction results in lower AMPK activity. PXL770 is a direct AMPK activator, inhibiting de novo lipogenesis (DNL) and producing efficacy in preclinical models. We aimed to assess pharmacokinetics, safety, and pharmacodynamics of PXL770 in humans with metabolic syndrome-associated fatty liver disease. In a randomized, double-blind four-week trial, 12 overweight/obese patients with non-alcoholic fatty liver disease (NAFLD) and insulin resistance received PXL770 500 mg QD; 4 subjects received matching placebo. Endpoints included pharmacokinetics, hepatic fractional DNL, oral glucose tolerance testing, additional pharmacodynamic parameters, and safety. PK parameters show adequate plasma exposure in NAFLD patients for daily oral dosing. PXL770 decreases DNL-both peak and AUC are reduced versus baseline-and improves glycemic parameters and indices of insulin sensitivity versus baseline. Assessment of specific lipids reveals decrease in diacyglycerols/triacylglycerols. Safety/tolerability are similar to placebo. These results unveil initial human translation of AMPK activation and support this therapeutic strategy for metabolic disorders.
Competing Interests: C.C., D.E.M., F.M, J.D., P.G.-D., P.F., P.T., S.B., and S.H.-B. are employees of Poxel SA and have received stock options as a condition of employment. K.C. has served as a consultant for Allergan, Altimmune, Arrowhead, AstraZeneca, BMS, Boehringer Ingelheim, Coherus, Eli Lilly, Fractyl, Hanmi, Genentech, Gilead, Intercept, Janssen, Pfizer, Poxel, Prosciento, Madrigal, and Novo Nordisk. The study was funded and designed by the sponsor (Poxel SA) with the support of expert consultants in the NASH field. The corresponding author, all co-authors, and the sponsor had full responsibility for the decision to submit for publication. Patents WO2011080277A1 and WO2020099678A1, owned by Poxel SA, are related to this work.
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