Drugs for Non-alcoholic Steatohepatitis (NASH): Quest for the Holy Grail

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a global epidemic that is likely to become the most common cause of chronic liver disease in the next decade, worldwide. Though numerous drugs have been evaluated in clinical trials, most of them have returned inconclusive results and shown poorly-tolerated adverse effects. None of the drugs have been approved by the Food and Drug Administration for treating biopsy-proven non-alcoholic steatohepatitis (NASH). Vitamin E and pioglitazone have been extensively used in treatment of biopsy-proven nondiabetic NASH patients. Although some amelioration of inflammation has been seen, these drugs did not improve the fibrosis component of NASH. Therefore, dietary modification and weight reduction have remained the cornerstone of treatment of NASH; moreover, they have shown to improve histological activity as well as fibrosis. The search for an ideal drug or ‘Holy Grail’ within this landscape of possible agents continues, as weight reduction is achieved only in less than 10% of patients. In this current review, we summarize the drugs for NASH which are under investigation, and we provide a critical analysis of their up-to-date results and outcomes.

Beneficial Activities of Alisma orientale Extract in a Western Diet-Induced Murine Non-Alcoholic Steatohepatitis and Related Fibrosis Model via Regulation of the Hepatic Adiponectin and Farnesoid X Receptor Pathways

“…The increasing clinical need for the development of NAFLD drugs and attractive commercial opportunities has led to a large number of pipeline drug profiles [ 4 ]. Although a growing number of candidate drugs have been steadily investigated to halt or resolve NAFLD, to date, no US FDA-approved drugs have been found, mainly due to the complex pathogenesis of NAFLD, unsatisfactory effects not covering all aspects of the disease, and side effects [ 1 ].…”

“…Due to incompletely known mechanisms, clinicians frequently prescribe NAFLD patients with antioxidants such as vitamin E and omega-3 fatty acids, hepatoprotective agents including ursodeoxycholic acid, or metabolic agents such as insulin sensitizers or lipid-lowering drugs to regulate simple steatosis and NASH [ 5 , 6 , 7 ]. However, the use of these therapeutic options, though considered easily accessible by physicians, has some limitations, such as unsatisfactory effects at resolving NASH, unfavorable side effects, and inability to decrease the risk of comorbidities [ 1 , 4 ]. Hence, lifestyle modification via calorie restriction and exercise are the most routinely recommended and highlighted methods in NAFLD management.…”

Dimerization of kringle 1 domain from hepatocyte growth factor/scatter factor provides a potent minimal MET receptor agonist

“…Activation of the MET pathway has been known to ameliorate alcoholic steatohepatitis as well as liver fibrosis or cirrhosis in pre-clinical models of liver disease (Matsuda, 1997;Matsuda et al, 1995;Tahara et al, 1999;Taı̈eb et al, 2002) and, conversely, deletion of the MET gene in postnatal mice causes hyperlipidemia, severe steatosis, and progressive liver disease (Kroy et al, 2014). No specific drug has been approved as yet for the treatment of alcoholic and non-alcoholic liver disease (Sharma et al, 2020) but we submit that the K1K1 protein data presented here may emerge as a strong candidate for clinical development owing to its favourable physical chemistry and its strong activity in a well-established clinical mouse model of alcoholic steatohepatitis (Fig. 7 and S7A).…”

Machine learning using longitudinal prescription and medical claims for the detection of non-alcoholic steatohepatitis (NASH)

“… 4 11 Finally, despite ongoing clinical trials, there are currently no approved pharmacological treatments for NASH outside of India. 12 Thus, detection of NASH remains a challenge and reliable diagnostic tools, including minimal or even non-invasive techniques, are warranted.…”