Evolving Models for NASH Drug Discovery: Tools for stemming a silent epidemic
Non-alcoholic fatty liver disease (NAFLD) has quietly become one of the most common causes of chronic liver disease in the modern world. If this prevalence is allowed to continue the economic and clinical burden will reach a staggering level.
Non-alcoholic fatty liver disease (NAFLD) consists of a complex combination of liver maladies, ranging from benign hepatic steatosis (fatty liver) to its more aggressive inflammatory manifestation, non-alcoholic steatohepatitis (NASH). In parallel to soaring rates of obesity and type 2 diabetes (T2D), the prevalence of NAFLD is rising rapidly. An estimated 25% of adults worldwide currently have NASH and ~30-59% of these patients will develop NASH.
NASH is a dynamic condition that can regress back to isolated steatosis, or cause progressive fibrosis that leads to irreversible cirrhosis (stage F4 fibrosis) and/or hepatocellular carcinoma (HCC) (2). Approximately 9% of patients with NASH will progress to these endstage liver diseases. Some experts believe the crisis is so significant in the United States that NASH will become the leading cause for liver transplantation by 2020 (3).
The looming global health crisis of NASH represents a substantial opportunity for pharmaceutical companies and market analysts estimate the peak drug market size for NASH therapeutics could be as high as $40 billion (4). There have already been more than 750 trials relating to NAFLD to date (5), yet despite the intense race to develop therapeutics, no approved treatments are available. Most clinical Phase III trial results have been disappointing, and even the most promising preclinical drugs have not performed as expected once tested in humans. In addition to lack of efficacy, significant safety concerns have been raised for some new drug candidates. These disappointing results are not only aggravating for companies funding trials, but also frustrating for patients waiting for a cure.
Why so many setbacks in this ‘golden age’ of medicine?
The R&D delays for efficacious therapies for NASH can be largely attributed to a lack of physiologically relevant and predictive preclinical models that translate to humans. Selecting and applying relevant disease models for drug discovery requires an understanding of clinical etiology, both in terms of the causes of the disease and its pathogenesis. Part of a systemic metabolic syndrome, NASH involves many complex mechanisms and there is not yet consensus in the field about disease initiation and progression. Some researchers propose a ‘dual-hit’ hypothesis (with steatosis from increased lipogenesis in hepatocytes as the first hit, proinflammatory mediators from macrophages the second); others favour a ‘multi-hit’ hypothesis (where free fatty acids (FFA) and their metabolites promote NASH through multiple toxic pathways), but most involve some form of FFA-mediated lipotoxicity.
Hepatic stellate cells, activated by sustained inflammation, are responsible for excessive extracellular matrix deposition, leading to fibrosis and eventually cirrhosis. Signalling interactions between hepatocytes, Kupffer cells and stellate cells are critical for NASH pathogenesis. Successfully modelling all the key physiological events (from steatosis to inflammation and fibrosis) evident in clinical NASH has been extremely challenging – in both in vivo animal models and in vitro cell-based ones. Meanwhile, researchers are realising it is unlikely that a single, ‘one-size-fitsall’ wonder drug will be discovered. Many pharmaceutical companies are shifting their R&D efforts toward combination therapies, making an extremely expensive bet that their preclinical models will accurately predict the best combinations to test in the clinic....
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