Taken together, the concept of combining PPARα, PPARβ/δ and PPARγ activation might represent a novel and potentially more efficacious therapeutic approach by targeting the large array of pathways that contribute to the development and progression of NASH. Lanifibranor is an indole sulfonamide PPAR agonist that activates all three subtypes, α, β/δ and γ, giving it the potential to address all the key features of NASH, namely inflammation, steatosis, ballooning and fibrosis. In in vitro and in vivo preclinical studies, lanifibranor prevented and induced the regression of pre-existing fibrotic damage in the liver and other organs, for example skin and lung, without the classic effects on body weight, fluid retention and increase in heart weight that are reported with TZDs. Lanifibranor also improved insulin sensitivity, diet-induced weight gain, adiposity index and lipid profile — all metabolic features relevant to NASH in diet-induced and genetic models. The effects of lanifibranor on liver histology, proinflammatory and profibrotic gene expression and macrophage accumulation and activation has been shown to be significantly superior to single and dual PPAR agonists in several models of NASH and fibrosis and is being investigated in a double-blind, randomized, placebo-controlled phase IIb trial, which is evaluating the efficacy and safety of 24-week lanifibranor treatment compared with placebo in 247 adult patients with NASH with liver steatosis and moderate-to-severe necroinflammation without cirrhosis. Highly significant positive results have been reported for reduction in the activity of steatohepatitis, resolution of NASH, regression of fibrosis and a combination of the latter two (in 31% of patients on the high dose of 1200 mg versus patients receiving placebo; P<0.001), along with improvement in glycaemic control and lipid profile and a good safety and tolerability profile.