Research Article Details

Article ID: A09983
PMID: 31536725
Source: Eur J Pharmacol
Title: Farnesoid X nuclear receptor agonists for the treatment of nonalcoholic steatohepatitis.
Abstract: Nonalcoholic fatty liver disease (NAFLD) affects 20-40% of the general population. Despite significant disease burden and mortality associated with advanced disease, i.e., nonalcoholic steatohepatitis (NASH), there is currently no approved medication for NASH. Farnesoid X receptor agonists have been investigated as candidates for the treatment of NASH. Obeticholic acid, approved for the treatment of primary biliary cholangitis, has gained significant attention after showing promising results in patients with NASH and fibrosis. Three trials investigating the effect of obeticholic acid in patients with NASH have been completed and the preliminary results of an ongoing one have also been made public. Generally, treatment with obeticholic acid improved hepatic histology, including inflammation and fibrosis, the latter being the main histological predictor of advanced disease. Nonetheless, there were adverse effects, the most common being pruritus and unfavorable changes in the lipid profile. Pruritus led to discontinuation of treatment in some patients. Obeticholic acid, however, is not the only farnesoid X receptor agonist currently investigated for the treatment of NASH. Another farnesoid X receptor agonist, cilofexor, in combination with firsocostat, an acetyl-CoA carboxylase inhibitor, improved hepatic steatosis, liver stiffness, liver function tests and serum fibrosis markers, without causing pruritus after 12 weeks of treatment. In conclusion, current evidence regarding the effect of farnesoid X receptor agonists on hepatic histology in patients with NASH is promising, but several safety issues need further evaluation.
DOI: 10.1016/j.ejphar.2019.172661

Strategy ID Therapy Strategy Synonyms Therapy Targets Therapy Drugs
S01 Improve insulin resistance insulin sensitizer; insulin resistance; glucose tolerance Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide Details
S03 Anti-fibrosis fibrosis Angiotensin Receptor Blocker (ARB); CCR2/CCR5 antagonist; Thyroid receptor β agonist; PEGylated human FGF21 analogue; Monoclonal antibody to lysyl oxidase-like 2 (LOXL2); Galectin-3 inhibitor; FGF19 variant Losartan; Cenicriviroc; VK-2809; MGL-3196; Pegbelfermin; Simtuzumab; GR-MD-02; NGM282 Details

Target ID Target Name GENE Action Class UniProtKB ID Entry Name

Diseases ID DO ID Disease Name Definition Class
I05 9352 Type 2 diabetes mellitus A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus Details

Drug ID Drug Name Type DrugBank ID Targets Category Latest Progress
D136 Firsocostat Chemical drug DB16166 ACC inhibitor Enhance lipid metabolism Under clinical trials Details
D328 Serine Chemical drug DB00133 SRR Improve insulin resistance Under clinical trials Details
D078 Cilofexor Chemical drug DB15168 FXR agonist Enhance lipid metabolism Under clinical trials Details
D182 Insulin Biological drug DB00030 INSR agonist; CPE modulator&product of -- Under clinical trials Details
D248 Obeticholic Acid Chemical drug DB05990 NR1H4 activator; NR1H4 agonist; FXR agonist Enhance lipid metabolism Approval rejected Details