br Clinical development of anti NASH drug

Clinical development of anti-NASH drug therapies The current understanding of NASH pathogenesis has led to broad efforts to target several features of the disease, alone or in combination, even in the absence of liver-guided therapies. Therefore, drug development in NASH is a rapidly changing field. A considerable number of single modality therapies are in various stages of clinical development, and it is expected that combination therapies will also soon be targeted. Most investigational new drugs have a hepatic metabolic target, engineered to reduce hepatic fat accumulation, inflammation, insulin resistance, or mitochondrial dysfunction. In addition, several emerging medical therapies are directly interfering with fibrosis pathways aiming to decrease hepatic fibrosis progression [25]. It is advantageous that drug therapies in NASH also induce weight loss, because successful weight management (≥5–10% weight loss) per se improves liver histology in NASH [26]. Current drug targets under clinical investigation are summarized in Fig. 1. Given that there are no benchmark standard endpoints that can be followed in lieu of histology, liver histology remains the main outcome variable for clinical trials. Liver biopsy is applied to confirm (or exclude) the diagnosis and stage of NASH, which also provides a rational basis for evaluation of treatment efficacy upon completion of the trial [4]. Several histological scoring systems have been developed for monitoring histopathological changes in NASH, including the NAFLD activity score (NAS) and steatosis–activity–fibrosis (SAF) systems 27, 28. The NAS system is widely used in clinical trials and grades the severity of macrovesicular and/or microvesicular steatosis, hepatocellular ballooning, and lobular TH588 mg on liver biopsies. Fibrosis is not included in NAS because it is a sign of the disease stage rather than of the grade of injury; hence, a separate semiquantitative scoring system is utilized for fibrosis stage monitoring [27]. The disease scoring and staging systems are semiquantitative and only consider changes in hepatic tissue architecture, which could narrow the window of treatment efficacy. Consequently, there is an increasing consensus that quantitative histology is required to fully conclude on treatment outcome [29]. The extent of liver fibrosis, rather than of NASH, is the major driver for cardiovascular co-morbidity, malignancy, and mortality in NASH [30]. Therefore, antifibrotic therapeutics have gained considerable focus in NASH drug discovery. Current antifibrotic strategies include reducing the primary disease, improving hepatocyte integrity, suppressing hepatic inflammation, downregulating HSC activation, or promoting extracellular matrix degradation (reviewed in [23]). Several of these strategies are approached by emerging immunotherapies for NASH and other fibrotic liver diseases [31]. Although there are currently no universal regulatory approval pathways for drug development in NASH, there is an emerging consensus that NASH resolution with halted progression or improvement of liver fibrosis stage are tangible primary endpoints in most clinical trials 32, 33. From a regulatory perspective, current pivotal clinical trials for precirrhotic NASH will likely need to demonstrate a decreased rate of progression to cirrhosis, which will require long-term extension trials [32]. In summary, an ideal drug candidate for NASH should reduce key clinical endpoints (i.e., steatosis, hepatic inflammation, and liver cell injury) and have antifibrotic effects, while also correcting underlying metabolic derangements, such as hepatic insulin resistance and obesity (Fig. 1). In this regard, most advanced clinical trials in NASH have indicated improved NASH with no worsening (but not reversal) of hepatic fibrosis on liver biopsies, but not all compounds have shown additional beneficial effects on insulin resistance and body weight 34, 35, 36.