Is it time for chronopharmacology in NASH?

Liver homeostasis is strongly influenced by the circadian clock, an evolutionarily conserved mechanism synchronizing physiology and behaviour across a 24-hour cycle. Disruption of the clock has been heavily implicated in the pathogenesis of metabolic dysfunction including non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). Furthermore, many of the current NASH drug candidates specifically target pathways known to be under circadian control including fatty acid synthesis and signalling via farnesoid X receptor (FXR), fibroblast growth factor (FGF) 19 and 21, peroxisome proliferator-activated receptor (PPAR) α and γ, glucagon like peptide 1 (GLP-1), and thyroid hormone receptor. Despite this, there has been little consideration of the application of chronopharmacology in NASH, a strategy whereby the timing of drug delivery is informed by biological rhythms in order to maximize efficacy and tolerability. Chronopharmacology has been shown to have significant clinical benefits in a variety of settings including cardiovascular disease and cancer therapy. The rationale for embedding clock-logic within the treatment of NASH is therefore compelling but is currently underutilized. Indeed, no clinical trials in NASH have specifically explored the impact of drug timing on disease progression and patient outcomes. This may contribute to the wide variability in reported outcomes of NASH trials and partly explain why even late-phase trials have stalled because of lack of efficacy or safety concerns. In this opinion piece, we describe the potential for chronopharmacology in NASH, discuss how the major NASH drug candidates are influenced by circadian biology, and encourage greater consideration of the timing of drug administration in the design of future clinical trials.