Applications of Quantitative Systems Pharmacology (QSP) in Drug Development for NAFLD and NASH and Its Regulatory Application.

Nonalcoholic steatohepatitis (NASH) is a widely prevalent disease, but approved pharmaceutical treatments are not available. As such, there is great activity within the pharmaceutical industry to accelerate drug development in this area and improve the quality of life and reduce mortality for NASH patients. The use of quantitative systems pharmacology (QSP) can help make this overall process more efficient. This mechanism-based mathematical modeling approach describes both the pathophysiology of a disease and how pharmacological interventions can modify pathophysiologic mechanisms. Multiple capabilities are provided by QSP modeling, including the use of model predictions to optimize clinical studies. The use of this approach has grown over the last 20 years, motivating discussions between modelers and regulators to agree upon methodologic standards. These include model transparency, documentation, and inclusion of clinical pharmacodynamic biomarkers. Several QSP models have been developed that describe NASH pathophysiology to varying extents. One specific application of NAFLDsym, a QSP model of NASH, is described in this manuscript. Simulations were performed to help understand if patient behaviors could help explain the relatively high rate of fibrosis stage reductions in placebo cohorts. Simulated food intake and body weight fluctuated periodically over time. The relatively slow turnover of liver collagen allowed persistent reductions in predicted fibrosis stage despite return to baseline for liver fat, plasma ALT, and the NAFLD activity score. Mechanistic insights such as this that have been derived from QSP models can help expedite the development of safe and effective treatments for NASH patients.