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

Pascale Fouqueray, Sebastien Bolze, Julie Dubourg, Sophie Hallakou-Bozec, Pierre Theurey, Jean-Marie Grouin, Clémence Chevalier, Pascale Gluais-Dagorn, David E Moller, Kenneth Cusi, Pascale Fouqueray, Sebastien Bolze, Julie Dubourg, Sophie Hallakou-Bozec, Pierre Theurey, Jean-Marie Grouin, Clémence Chevalier, Pascale Gluais-Dagorn, David E Moller, Kenneth Cusi

Abstract

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.

Trial registration: ClinicalTrials.gov NCT03950882.

Keywords: AMPK activation; DNL; MAFLD; NAFLD; NASH; PXL770; de novo lipogenesis; insulin resistance; metabolic syndrome-associated fatty liver disease; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; pharmacodynamics; pharmacokinetics; plasma lipids.

Conflict of interest statement

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.

© 2021 Poxel SA.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Study design and patient disposition
Figure 2
Figure 2
Mean plasma levels of PXL770 Steady-state plasma samples were obtained from subjects (n = 12 patients) receiving daily oral doses of 500 mg PXL770 on two occasions during the study, day 14 and day 26 (Figure 1), under fasted and fed conditions, respectively. Samples were analyzed to determine drug concentrations using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method.
Figure 3
Figure 3
PXL770 inhibits de novo lipogenesis (DNL) and improves glucose metabolism and insulin sensitivity DNL was measured as described in StarMethods by labeling of body water via D20 enrichment during the day prior to testing followed by oral fructose loading during the test days −1 and 28 (Figure 1). Fractional DNL (% of triglyceride-palmitate) was calculated based on measurements obtained at the indicated time points. Oral glucose tolerance tests were performed after an overnight fast at baseline and on day 27 during treatment. (A) Time course of mean (+SEM) DNL values for PXL770 (left panel; n = 12, p = 0.0045 for peak DNL, defined as average of last 3 time points) or placebo (right panel; n = 4, NS) treated subjects at baseline (dashed line) versus end of treatment on day 28 (solid line). (B) Individual patient results for DNL tests performed at baseline versus after 28 days of daily exposure to PXL770 (n = 12 patients). (C) Mean and individual values for incremental glucose AUC during the oral glucose tolerance test, OGTT (n = 4 placebo, n = 12 PXL770), and for the Matsuda insulin sensitivity index, data derived from the OGTT (n = 4 placebo, n = 10 PXL770), in subjects treated with placebo or PXL770 at baseline versus day 27. Matsuda values were calculated based on data obtained during OGTT tests as described in StarMethods. ∗p = 0.031; ∗∗p = 0.014.
Figure 4
Figure 4
PXL770 acutely decreases diacylglycerides and triacylglycerols Plasma samples were assayed using liquid chromatography coupled to mass spectrometry to detect and quantitate a range of selected circulating lipids. Day 14 samples were collected from both placebo and PXL770 treated subjects at pre-dose (trough) and 2 h post-dose (Cmax) time points; both under fasted conditions. Plasma total DG and TG are expressed as relative intensity (sum of the normalized peak areas of all detected DG and TG species) pre-dose and 2 h post-dose at day 14 for placebo (n = 4 patients) and PXL770 (n = 12 patients); mean ± SD, ∗p 

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