Therapeutics
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.
N on-alcoholic fatty liver disease
(NAFLD) consists of a complex combi- nation of liver maladies, ranging from
benign hepatic steatosis (fatty liver) to its more aggressive inflammatory manifestation, non-alco- holic steatohepatitis (NASH). In parallel to soar- ing rates of obesity and type 2 diabetes (T2D), the prevalence of NAFLD is rising rapidly. An esti- mated 25% of adults worldwide currently have NASH and ~30-59% of these patients will devel- op NASH (see Figure 1)1. NASH is a dynamic condition that can regress back to isolated steato- sis, or cause progressive fibrosis that leads to irre- versible cirrhosis (stage F4 fibrosis) and/or hepa- tocellular carcinoma (HCC)2. Approximately 9% of patients with NASH will progress to these end- stage liver diseases. Some experts believe the crisis is so significant in the United States that NASH will become the leading cause for liver transplan- tation by 20203. The looming global health crisis of NASH repre-
sents a substantial opportunity for pharmaceutical companies and market analysts estimate the peak drug market size for NASH therapeutics could be as high as $40 billion4. There have already been more than 750 trials relating to NAFLD to date5, yet despite the intense race to develop therapeutics, no approved treatments are available. Most clini- cal Phase III trial results have been disappointing,
Drug Discovery World Fall 2019
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 can- didates. 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 physi- ologically relevant and predictive preclinical mod- els 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 initia- tion and progression. Some researchers propose a ‘dual-hit’ hypothesis (with steatosis from increased lipogenesis in hepatocytes as the first hit, proin- flammatory mediators from macrophages the sec- ond); others favour a ‘multi-hit’ hypothesis (where free fatty acids (FFA) and their metabolites pro- mote NASH through multiple toxic pathways), but most involve some form of FFA-mediated lipotox- icity. Hepatic stellate cells, activated by sustained
61
By Dr Sue Grepper, Dr Radina Kostadinova, Dr Eva Thoma and Professor Armin Wolf
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68
