Abstract

Non-alcoholic fatty liver disease (NAFLD) currently has few available treatment options. Bringing effective treatments rapidly to market is paramount. Quantitative systems pharmacology (QSP) modeling can accelerate clinical development by reducing the number of required experiments. One therapeutic target that holds promise is hepato-selective AMP Kinase activation (hAMPKa), with multiple steato-modulatory mechanisms. We used NAFLDsym, a novel QSP model of NAFLD originally derived from DILIsym, to predict the efficacy for hAMPKa. NAFLDsym mechanistically represents many of the key components of steatosis and lipotoxicity. A simulated cohort (SimCohorts) of 144 NAFLD patients, previously validated based on steatosis reductions due to weight loss, was used to predict changes in liver triglycerides (TG) and lipotoxicity (plasma ALT) with 12 weeks of mid or high hAMPKa. The simulations included hAMPKa-mediated effects on multiple enzymes that regulate de novo lipogenesis (DNL), fatty acid oxidation and TG synthesis. hAMPKa was predicted to reduce liver TG from 21±14% to 19±14% (mid) and 17±13% (high) after 12 weeks. However, maximal effects had not been achieved in 15% of the SimCohorts within 12 weeks. Plasma ALT was also reduced from 67±44 U/L to 60±39 U/L (mid) and 50±31 U/L (high). Normalization of plasma ALT was achieved in 30% of the SimCohorts. The NAFLDsym predictions suggest that hAMPKa holds potential for reducing steatosis and lipotoxicity in NAFLD patients. AMPK needs to be activated to a high degree to provide clinically meaningful efficacy. The simulations indicate that clinical trials need to extend for >12 weeks, as a significant proportion of the SimCohorts did not reach maximal liver TG reductions within this time frame.

American Society for Clinical Pharmacology & Therapeutics (ASCPT) 2017 Annual Meeting, March 15-18, 2017,  Washington, DC

By Grant Generaux, Theodore R. Rieger, Brett A Howell, Richard J. Allen, Cynthia J. Musante, Paul B Watkins, Scott Q Siler