Editorial: targeting aberrant hepatic inflammation for treatment of non‐alcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and nonalcoholic steatohepatitis (NASH) is the clinically aggressive variant of NAFLD with higher risk for fibrosis progression, cirrhosis and development of hepatocellular carcinoma. As there are no approved pharmacological options for the treatment of NASH, the development of novel therapeutics is an area active for intense investigation.13 Unfortunately, latephase clinical trials thus far have produced disappointing results and underscore the importance of developing novel therapeutic targets for the treatment of NASH.4 As metabolic comorbidities and cardiovascular disease are an important cause of morbidity and mortality among patients with NASH, medications with a favourable metabolic profile have the potential to further improve longterm clinical outcomes in patients with NAFLD.5 The A3 adenosine receptor (A3AR) is upregulated in inflammatory liver tissues compared to normal liver cells and induces a robust antiinflammatory effect in the liver via deregulation of the Wnt/βcatenin pathway.6 Namodenoson, an A3AR agonist, had beneficial effects on liver histology and hepatic inflammatory pathways in murine model of NAFLD.6 In a recent issue, Safadi et al present the findings of a phase 2 doubleblinded, placebocontrolled multicentre trial evaluating the safety and efficacy of namodenoson in patients with NAFLD.7 In this proofofconcept study, patients with metabolic comorbidities and nonhistological evidence of NASH (elastography, ALT) were randomised to namodenoson 12.5 mg, 25 mg or placebo for 12 weeks. Patients receiving higher dose of namodenoson were more likely to achieve ALT normalisation and improvement in fibroscanAST (FAST) scores; however, improvement in hepatic steatosis as measured by both MRIPDFF and CAP did not reach statistical significance. The antiinflammatory effects of namodenoson were further illustrated by serum adiponectin, a protective and beneficial adipokine, levels increased by end of study. While a numerical decrease in weight was noted, this did not reach statistical significance. In targeting A3AR, namodenoson aims to expand the potential therapeutic targets under investigation for treatment of NASH.3 While the study findings are promising, this early phase study by design used nonhistology– based criteria and the impact of namodenoson on histology needs to be evaluated further. Additionally, the decrease in serum adiponectin levels were not accompanied by significant weight loss and at this point it is unclear if this was due to shorter study duration, improvement in adipose tissue profile and what is the longterm effect of adiponectin improvement on metabolic health. As liver and systemic inflammation plays a central role in glucose and lipid metabolism, the impact of namodenoson on serum lipids and insulin resistance needs to be better defined. Finally, the improvement in the noninvasive fibrosis measures (ie FAST and FIB4) were largely driven by improvement in serum AST and the impact of namodenoson on fibrosis remains to be seen. However, the initial study findings are encouraging and should be evaluated further in wellconstructed randomised doubleblinded placebocontrolled trial using histology entry criteria and endpoints. As namodenoson modules hepatic inflammatory response, its effect on cardiometabolic risk profile should be better defined.