Saroglitazar for the Treatment of NASH: The Peroxisome Proliferator‐Activated Receptor Story Goes On!

Abstract

Despite intensive research, no drug to date has been approved for the management of NAFLD, and many clinical trials have failed, including some recent large phase 3 trials. This has in part to do with the complex disease pathophysiology, which is only partially unraveled.(1) Furthermore, the disease is embedded in a set of metabolic drivers, creating an environment of metabolic and inflammatory stress. As a result, NAFLD is not an isolated liver disease, and treatment needs to take into account the extrahepatic drivers of disease progression, of which the adipose tissue dysfunction is a pivotal one.(2) Peroxisome proliferatoractivated receptors (PPARs) are nuclear receptors that are key regulators of glucose and lipid homeostasis as well as inflammation and fibrogenesis.(3) This makes them interesting targets for pharmacotherapy. Three different PPAR isotypes (α, β/δ, γ) exist, and their expression and function differ according to the organ and cell type (Fig. 1). Drugs targeting PPARs have hence the potential to target both intrahepatic and extrahepatic sites, depending on their characteristics: PPAR drugs can substantially differ in target engagement, even if they belong to the same molecular class and/or target the same isotype. This is best documented for PPARα agonists, a phenomenon called selective PPAR modulators. This implies that every PPAR agonist needs to be evaluated individually on top of class effects. In the current issue, Gawrieh et al. present the results of saroglitazar, a dual PPARαγ agonist, on noninvasive markers of NAFLD disease severity after 16 weeks of treatment.(4) The concept of a dual, or even triple/pan, PPAR agonist is interesting, because tackling several mechanisms (metabolic/inflammatory/fibrogenic) at several sites (hepatic/extrahepatic) theoretically has the potential of resulting in superior efficacy compared with monoagonists. Preclinical evidence supports this concept,(5) although clinical headtohead comparisons are lacking and comparison across trials needs caution. Combination of targets might also, by allowing lower affinity for the individual isotypes and/or by counteracting side effects of single agonists, reduce side effects. Again, there are no headtohead comparisons to prove these conceptual considerations, but comparison of the data of different compounds can provide some insights. Beyond a substantial amount of preclinical data, hepatic PPARα expression has been shown to inversely correlate with disease severity and to improve on disease improvement.(6) PPARα monoagonists have been poorly studied, but the PPARαδ dual agonist elafibranor showed some favorable effects in phase 2.(7) This was not confirmed in phase 3, but these data are not fully released yet and merit an indepth analysis. PPARγ Received June 2, 2021; accepted June 8, 2021. © 2021 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.32024