[MUSIC] Hello, I'm Guruprasad Aithal from the University of Nottingham. Let's look at what current and future good treatments will be for non-alcoholic fatty liver disease. The substantial interest in the drug development for non-alcoholic fatty liver disease, is estimated that by 2025, the drug market for NASH will be worth about $20-35 billion per year. Over 190 drugs are in the pipeline, and over 300 clinical trials are ongoing at the moment. Let's pick up individual drugs based on their mechanism of action. First of all, let's focus on insulin sensitivity, which is the most common underlying potential pathogenic pathway, which has been demonstrated in multiple settings and studies. NAFLD pathogenesis involves metabolic inflammation in multiple organ systems that results in progress of accumulation of fat, injury and scar formation. NAFLD is both the driver and consequence of its many associations. However, the hierarchy of this different pathogenic pathway isn't clear. So it's challenging to develop effective therapy for non-alcoholic fatty liver disease, which means that one need to identify the key pathways involved, and this pathway should be key in the development and progression of non-alcoholic fatty liver disease. Molecules should get the target engagement and bring meaningful change in the natural history on clinical outcomes. Before considering emerging pharmacological interventions, it's worth highlighting the evidence base for repurposed drugs. Pioglitazone has been shown in multiple randomized controlled trials to be effective. Resolving NASH, improving fibrosis of any stage and an improvement even in advanced fibrosis stage. It's been shown to be cost-effective, and it's now being recommended in clinical practice guidelines in Europe, America, as well as British organizations. When used in broader group of people with and without NASH, pioglitazone has been shown to reduce all-cause mortality, even when considered that there is an excess risk of heart failure related mortality. If you look at database research, there is data to show that it reduces all-cause mortality and cardiovascular outcomes, cerebrovascular outcomes. It also reduces incident diabetes, but its adverse effects such as fracture are still a concern. When used in a large population of type 2 diabetes, it reduced development of hepatocellular carcinoma and colorectal cancer. Its risk related to the bladder cancer has now been discounted. Glucagon-like-peptide-1 analogues are another group of drugs which have been licensed for the treatment of type 2 diabetes. Liraglutide in a multicenter double-blind placebo-controlled trial did demonstrate its efficacy in resolving NASH. It also brought about reduction in body mass index, as well as improvement in HbA1c, which are additional benefits from this drug. In a recent interimanalysis of ongoing double-blind randomized controlled trial, substantially more patients who were treated with semaglutide had resolution of NASH without progression of fibrosis compared to placebo. Focusing on lipotoxicity now, farnesoid receptor agonists have been the most promising group of drugs which have been investigated. Just to go through the mechanism of action CYP7A1 initiates the conversion of cholesterol in primary bile acids. In the IM, bile salts are reabsorbed via the apical sodium-dependent bile salt transporter. Then they bind and activate FXR within the enterocyte. Generate FGF19, fibroblast growth factor, which reaches the liver to portal circulation. Within the liver, FGF19 binds to its receptor FGFR4. This leads to inhibition of CYP7A1 thus down-regulating bile acid synthesis. Bile acids can also directly bind to FXR, which leads to reduced CYP7A1 action as well. So, FXR agonist affect FXR both in the liver as well as in the intestine. And this strongly down-regulates CYP7A1 or FGF19 dependent as well as independent manner. FGF19 in addition, affect lipogenesis, gluconeogenesis and liver regeneration. So FXR agonists have been under a randomized controlled trial. In contrast, volixibat, which is an inhibitor of apical sodium-dependent bile salt transporter, hypothesized as a good treatment for non-alcoholic steatohepatitis. By blocking bile acid reuptake, stimulating bile acid production, has been shown not to be beneficial in a randomized controlled trial. Obeticholic acid, one of the FXR receptor agonist in phase 3 study, demonstrated efficacy in reducing fibrosis without worsening NASH. 23% in the obeticholic acid, 24 milligrams group, improved fibrosis 18% in 10 milligram group, improved fibrosis compared to 12% in placebo group. However, obeticholic acid was not significantly efficacious in resolving NASH. Adverse of obeticholic acid, such as pruritis was seen 51% in 25 milligrams group, but overall less than 1% in 10 milligram group and less than 9% in 25 milligram group. we drew the medication because of adverse effect. Similarly, concerns of LDL cholesterol increased secondary treatment has been part of the investigation. And it appears as though the peak of LDL cholesterol occurs in week 4, and then subsequently it reverses back to the baseline by about week 18. Both the FGF-19 analogues as well as thyromimetics have been shown to reduce de novo lipogenesis, and enhance our target for investigation. Thyroxine and triiodothyronine both are master regulators of lipid metabolism. They activate through thyroid hormone receptor-beta within the hepatocytes, and there is inverse correlation between THR-Beta mRNA expression and NASH histologic severity. Thyroid hormone receptor increases cholesterol metabolism via CYP7A1 enhance reduces de novo lipogenesis. In a 36-week randomized-controlled trial, resmetirom, one of the thyromimetic acting on the liver, did demonstrate its efficacy in reducing liver fat. But its role on inflammation and fibrosis are unclear still. Coming to drugs targeting inflammation, cenicriviroc is a dual cytokine receptor 2 and 5 antagonist. Through its action it reduces recruitment, migration, and infiltration of pro-inflammatory monocytes and macrophages to the site of liver injury. From that, it reduces activation and proliferation of collagen-producing hepatic stellate cells. In a phase II randomized-controlled trial, the treatment was associated with substantial reduction in circulating biomarkers, implying its target engagement. There's a reduction in high sensitivity C-reactive protein. Interleukin-6, fibrinogen and interleukin-1beta levels. After one year treatment, twice as many patients who received treatment, demonstrated reduction in fibrosis by one grade. However, histologically there was no significant resolution of NASH, although one of the key end points, which is reduction in fibrosis without worsening of NASH has been met, the discordance between NASH and fibrosis conceptually and its impact on natural history of liver disease still remains. In summary, there are no license treatment at present for non-alcoholic steatohepatitis or NAFLD overall, but existing drugs may be used for the treatment in advanced fibrosis. Pioglitazone has been shown to be effective in reducing all histological changes in non-alcoholic fatty liver disease. It's been shown to be cost-effective when used in advanced fibrosis. Pioglitazone also has got beneficial effects on other important end points such as insulin, diabetes and cardiovascular and cerebrovascular outcomes. Obetocholic acid has been shown to be efficacious in reducing liver fibrosis in pivotal phase 3 studies, but its benefits are modest at present. Cenicriviroc has been shown to reduce liver fibrosis, but histologically non-alcoholic steatohepatitis resolution wasn't really reached. Phase II studies have shown potential benefits from the FGF-19 analogues and FGF-21 and acyl-CoA inhibitors have been shown to be potentially beneficial as well. Because of intricate and complex mechanistic pathway, non-alcoholic fatty liver disease treatment might need combination therapy. Thank you for listening. [MUSIC]
