A Tough Challenge in the Development of NAFLD/NASH Treatments
Non-alcoholic fatty liver disease (NAFLD) / non-alcoholic steatohepatitis (NASH) clinical trial results have been confounded by unexpected positive results in the placebo-treated group. For example, some 10‑25% of placebo-treated patients were reported to have an improvement in fibrosis 1,2.
In November 2021, at the AASLD annual meeting, we presented simulation results demonstrating that yo-yo dieting, particularly leading to 1% loss of body weight over 4 weeks, followed by a return to baseline weight over the following 4 weeks, and repeated over one year, was sufficient to elicit reductions in fibrosis scores of simulated NASH patients. Behavioral considerations (e.g., periodic clinic visits) that lead patients to eat less are what drives yo-yo dieting. These simulation results show how the behavior can impact the standard liver biopsy-derived fibrosis score in these patients, inadvertently complicating the interpretation of clinical trial results.
A Partner for your NAFLD/NASH Programs
We can work together to prospectively evaluate multiple clinical trial designs, addressing your key questions. For example,
What is the additional benefit achieved by our treatment if 10% of the placebo‑control group experience reductions in fibrosis?
Can we achieve better efficacy if we alter the dosing paradigm?
What’s the best design to be able to conduct a post-hoc analysis of the relationship between weight fluctuations and fibrosis score?
Our Software Capabilities
Our quantitative systems pharmacology (QSP) software NAFLDsym represents NAFLD pathophysiology, including liver steatosis, inflammation, and fibrosis. Simulated patients reflect alternate NAFLD activity scores (NAS) and fibrosis scores. NAFLDsym can be customized to represent proprietary drugs and simulate treatment in patients with varying disease levels.
Our GastroPlus software builds custom PBBM and PBPK models to estimate liver concentrations of your compound.
Contact us if you are interested in learning more!
Harrison SA, Neff G, Guy CD, et al. Efficacy and Safety of Aldafermin, an Engineered FGF19 Analog, in a Randomized, Double-Blind, Placebo-Controlled Trial of Patients With Nonalcoholic Steatohepatitis. Gastroenterology. 2021;160(1):219-231.e1. doi:10.1053/j.gastro.2020.08.004
Ratziu V, Sanyal A, Harrison SA, et al. Cenicriviroc Treatment for Adults With Nonalcoholic Steatohepatitis and Fibrosis: Final Analysis of the Phase 2b CENTAUR Study. Hepatology. Published online January 13, 2020. doi:10.1002/hep.31108