NASH’s prevalence is rising in parallel with that of obesity and type 2 diabetes mellitus. In light of this, the development of effective therapies to manage it is a pressing clinical priority. Clinical trials for developed drugs are currently underway, with phase 3 studies primarily focusing on NASH and fibrosis stage 2 and higher due to affected patients’ increased mortality risk.
This review aimed to expose the current clinical trial landscape for NASH. It further discussed the challenges impeding the development of effective NASH therapies.
NASH therapies which are currently in phase 3 include the farnesoid X Receptor agonist obeticholic acid, the thyroid hormone receptor-β agonist resmetirom, the glucagon-like peptide 1 receptor agonist semaglutide, and the pan-peroxisome proliferator-activated receptor agonist lanifibranor. The latter remains the only phase 3 drug with demonstrated efficacy on both its primary endpoints (fibrosis improvement and NASH resolution). These promising trial results mean lanifibranor may become one of the first NASH drugs to be approved. Despite these strides, however, several endpoint-related challenges to NASH trials remain unresolved. Invasive liver histology, for instance, is intrinsically unreliable, despite being a common primary surrogate endpoint. Moreover, recent imaging endpoints, e.g. relative decrease in liver fat content measured by MRI-PDFF, do not always translate into meaningful histological NASH resolution. In this vein, improving the reliability of trial endpoints is essential to developing comprehensive and effective NASH therapies.