Emerging therapies for NASH - the future is now

Non-alcoholic fatty liver disease (NAFLD) represents an increasingly recognized disease entity with rising prevalence about 25% in the general population [1]. Given a substantial liver-related and cardiovascular mortality in affected individuals NAFLD causes an enormous socioeconomic impact in industrialized countries worldwide [2]. Surprisingly under these conditions, there are currently no drugs approved to treat patients with NAFLD. This situation reflects the fact that the ‘epidemic’ of obesity and related organ diseases has been neglected over long time not only by physicians but consequently also by the pharmaceutical industry. Surveys in Western countries like Germany just recently highlighted that an increasing amount of attention is paid to the fact that patients with metabolic syndrome and often type 2 diabetes are at a considerable risk for liver-related complications and mortality [3]. Current guidelines in Western countries recommend a multistep screening algorithm based on initial ultrasound and risk prediction tools like the NAFLD fibrosis score (http://nafldscore.com) followed by transient elastography stratification for the indication for liver biopsy. With increased awareness and implementation of screening algorithms in primary care more and more patients with Non-alcoholic steatohepatitis (NASH)-related fibrosis will be diagnosed in the near future. Epidemiological studies document an increased mortality with advanced fibrosis clearly highlighting the need for effective treatment options in these patients [4]. Different systems of histologic scoring/reporting are established. These include the NIDDK NASH CRN system which utilizes the NAFLD Activity Score (NAS) as a sum score consisting of the categories steatosis, lobular inflammation and ballooning as an activity score with fibrosis stage as a separate score [5]. A pattern of disease is reported with regard to the prognostically relevant zonation of NASH (zone 1 versus zone 3). It is important to note that the general pathological diagnosis ‘NAFL’ versus ‘NASH’ is based on the defined microscopic criteria (presence of steatosis, ballooning, inflammation) while the terms ‘borderline NASH’ and ‘definite NASH’ are solely based on the sum of the NAS. In contrast, diagnosis of ‘NASH’ in the European SAF/FLIP algorithm is entirely numeric, not pattern based and solely scores four features including steatosis >0, activity (ballooning >1 and lobular inflammation >1) >2 together with fibrosis [6]. In general, the principal therapeutic goal for NAFLD patients is the reduction of metabolic risk factors and the treatment of the metabolic syndrome as the underlying cause. The most effective treatment consists of weight reduction and lifestyle modification with an increase in physical activity, which has been confirmed to be able to improve histological results in NAFLD patients. However, these interventions are often difficult to realize in every-day practice. A medical therapy with long-term effectiveness that would beneficially affect the course of fibrosis does currently not exist. Over the past decade, different drugs licensed for diabetes therapy have been investigated in randomized, placebo controlled studies in NAFLD. Metformin has not been found to have any effect of significance on histology but it may have a positive effect in terms of the incidence of HCC. Pioglitazone improved the steatosis as well as the inflammation in several studies but no anti-fibrotic effect could be proven to date, data on the long-term effects and safety are lacking and a peripheral weight gain is observed as a typical adverse effect[7,8]. Given the epidemic increase of NAFLD as a serious threat without licensed medical treatment, regulatory agencies such as the FDA and the European Medicines Agency (EMA) have defined an unmet medical need and implemented several initiatives to expedite the development of drugs for NASH treatment. These emerging treatment options under clinical development will be reviewed in the following.