Investigational Drug Details
| Drug ID: | D248 |
| Drug Name: | Obeticholic Acid |
| Synonyms: | (3α,5β,6α,7α)-6-ethyl-3,7-dihydroxycholan-24-oic acid; 6-ECDCA; 6-Ethyl-CDCA; 6-ethylchenodeoxycholic acid; 6alpha-Ethyl-chenodeoxycholic acid; 6α-ethylchenodeoxycholic acid; Obeticholic acid; OCA; INT-747 |
| Type: | Chemical drug |
| DrugBank ID: | DB05990 |
| DrugBank Description: | Primary biliary cirrhosis, or PBC, is a progressive and chronic condition that leads to hepatic injury often resulting in end-stage liver failure that requires liver transplantation. Obeticholic acid is a farnesoid-X receptor (FXR) agonist used to treat this condition, possibly allowing for increased survival. In 2016, it was granted approval to treat primary biliary cholangitis in combination with , which was previously the mainstay treatment for this condition. In May 2021, the FDA updated its prescribing information to contraindicate the use of obeticholic acid in patients with PBC and advanced cirrhosis (e.g. those with portal hypertension or hepatic decompensation) due to a risk of liver failure, in some cases requiring liver transplantation. Obeticholic acid is currently being considered for FDA approval to treat fibrosis caused by non-alcoholic liver steatohepatitis (NASH). The NDA from Intercept Pharmaceuticals was approved in November 2019 and obeticholic acid is expected to be granted full approval for this indication in 2020. |
| PubChem ID: | 447715 |
| CasNo: | 459789-99-2 |
| Repositioning for NAFLD: | Yes |
| SMILES: | C[C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)[C@H](CC4)[C@@H](CCC(=O)O)C)[C@@H]([C@@H]([C@@H]1C[C@@H](CC2)O)CC)O |
| Structure: |
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| InChiKey: | ZXERDUOLZKYMJM-ZWECCWDJSA-N |
| Molecular Weight: | 420.634 |
| DrugBank Targets: | Bile acid receptor agonist |
| DrugBank MoA: | Primary biliary cirrhosis is an autoimmune process by which the bile ducts and liver are damaged progressively, leading to fibrosis and cirrhosis. Bile acids increase the risk of damage and fibrosis to the damaged bile ducts. Obeticholic acid is a potent agonist of the farnesoid X receptor, which serves to regulate the hepatic metabolism of bile and cholesterol. This drug acts by binding to the farnesoid X receptor (FXR), found in the nucleus of liver and intestinal cells, which in turn increases liver bile flow, suppressing its production and decreasing hepatocyte exposure to excess levels of bile with cholestasis. Cholestasis is a process that normally causes inflammation and cirrhosis of the liver. |
| DrugBank Pharmacology: | The activation of the FXR by obeticholic acid acts to reduce the synthesis of bile acids, inflammation, and the resulting hepatic fibrosis. This may increase the survival of patients with PBC, but to date, an association between obeticholic acid and survival in PBC has not been established. |
| DrugBank Indication: | Obeticholic acid is indicated for the treatment of primary biliary cholangitis in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA. It is also used as a monotherapy in adults with PBC that are unable to tolerate UDCA. Obeticholic acid is currently being considered for FDA approval to treat fibrosis caused by non-alcoholic liver steatohepatitis (NASH), and is likely to be approved for this indication in 2020. |
| Targets: | NR1H4 activator; NR1H4 agonist; FXR agonist |
| Therapeutic Category: | Enhance lipid metabolism |
| Clinical Trial Progress: | Phase 3 active (NCT02548351: Based on the REGENERATE Month 18 interim analysis, rapid and sustained improvements in various NITs were observed with OCA treatment. Dynamic changes in selected NITs separated histologic responders from non-responders. These results suggest that NITs may be useful in assessing histologic response to OCA therapy.) |
| Latest Progress: | Approval rejected |
| Trial ID | Source ID | Phases | Status | Study Results | Start Date | Last Update Posted | |
|---|---|---|---|---|---|---|---|
| L0093 | NCT03836937 | Not applicable | Recruiting | No Results Available | March 5, 2019 | November 10, 2020 | Details |
| L0129 | NCT01265498 | Phase 2 | Completed | Has Results | March 2011 | April 6, 2018 | Details |
| L0169 | NCT02633956 | Phase 2 | Completed | Has Results | December 4, 2015 | June 4, 2018 | Details |
| L0256 | NCT02548351 | Phase 3 | Active, not recruiting | No Results Available | September 22, 2015 | March 9, 2022 | Details |
| L0334 | NCT03439254 | Phase 3 | Active, not recruiting | No Results Available | August 30, 2017 | March 9, 2022 | Details |
| L0553 | EUCTR2016-002965-67-NL | Phase 2 | Authorised | No Results Available | 29/03/2017 | 17 July 2017 | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T17 | Farnesoid X-activated receptor | NR1H4 | agonist | Nuclear hormone receptor | Q96RI1 | NR1H4_HUMAN | Details |
| T21 | Diacylglycerol O-acyltransferase 2 | DGAT2 | inhibitor | Enzyme | Q96PD7 | DGAT2_HUMAN | Details |
| T07 | Bile acid receptor | NR1H4 | agonist | Nuclear hormone receptor | Q96RI1 | NR1H4_HUMAN | Details |
| Strategy ID | Strategy | Synonyms | Related Targets | Related Drugs | |
|---|---|---|---|---|---|
| S10 | Liver transplantation | -- | -- | -- | Details |
| S02 | Enhance lipid metabolism | triglyceride-lowering; lipid tolerance; lipid metabolism | 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitor; Decreases intestinal cholesterol absorption; FXR agonist; ACC inhibitor; FAS inhibitor; DGAT2 inhibitor; SCD-1 inhibitor | Atorvastatin; Ezetimibe; Obeticholic Acid; GS-9674; GS-0976; TVB-2640; IONIS-DGAT2rx; Aramchol; | 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 |
| Article ID | PMID | Source | Title | |
|---|---|---|---|---|
| A00474 | 35068796 | J Clin Exp Hepatol | A Current Understanding of Bile Acids in Chronic Liver Disease. | Details |
| A00500 | 35060815 | Expert Opin Investig Drugs | Nonalcoholic steatohepatitis (NASH) cirrhosis: a snapshot of therapeutic agents in clinical development and the optimal design for clinical trials. | Details |
| A00700 | 34998040 | Eur J Med Chem | Discovery of a tricyclic farnesoid X receptor agonist HEC96719, a clinical candidate for treatment of non-alcoholic steatohepatitis. | Details |
| A00831 | 34954593 | Eur J Med Chem | Discovery of new and highly effective quadruple FFA1 and PPARα/γ/δ agonists as potential anti-fatty liver agents. | Details |
| A01068 | 34881283 | Front Nutr | Caffeine and EGCG Alleviate High-Trans Fatty Acid and High-Carbohydrate Diet-Induced NASH in Mice: Commonality and Specificity. | Details |
| A01124 | 34862975 | FASEB J | Atorvastatin protects against liver and vascular damage in a model of diet induced steatohepatitis by resetting FXR and GPBAR1 signaling. | Details |
| A01311 | 34793868 | J Hepatol | Non-invasive evaluation of response to obeticholic acid in patients with NASH: Results from the REGENERATE study. | Details |
| A01634 | 34675338 | Sci Rep | Repositioning of a novel GABA-B receptor agonist, AZD3355 (Lesogaberan), for the treatment of non-alcoholic steatohepatitis. | Details |
| A01853 | 34588764 | Drug Des Devel Ther | Non-Alcoholic Steatohepatitis (NASH) - A Review of a Crowded Clinical Landscape, Driven by a Complex Disease. | Details |
| A02030 | 34526653 | Commun Biol | Modelling human liver fibrosis in the context of non-alcoholic steatohepatitis using a microphysiological system. | Details |
| A02287 | 34435378 | Aliment Pharmacol Ther | Systematic review with network meta-analysis: comparative efficacy of pharmacologic therapies for fibrosis improvement and resolution of NASH. | Details |
| A02330 | 34416040 | Aliment Pharmacol Ther | Review article: non-alcoholic fatty liver disease and cardiovascular diseases: associations and treatment considerations. | Details |
| A02557 | 34328687 | Liver Int | Zonation in NASH - A key paradigm for understanding pathophysiology and clinical outcomes. | Details |
| A02909 | 34200685 | Metabolites | Metabolomic Study of High-Fat Diet-Induced Obese (DIO) and DIO Plus CCl4-Induced NASH Mice and the Effect of Obeticholic Acid. | Details |
| A03126 | 34119888 | Biomaterials | A scalable and sensitive steatosis chip with long-term perfusion of in situ differentiated HepaRG organoids. | Details |
| A03317 | 34047448 | Mol Nutr Food Res | Soyasaponin A2 Alleviates Steatohepatitis Possibly through Regulating Bile Acids and Gut Microbiota in the Methionine and Choline-Deficient (MCD) Diet-induced Nonalcoholic Steatohepatitis (NASH) Mice. | Details |
| A03482 | 33987427 | Ann Transl Med | Non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH)-related liver fibrosis: mechanisms, treatment and prevention. | Details |
| A03484 | 33987424 | Ann Transl Med | Non-alcoholic fatty liver diseases: current challenges and future directions. | Details |
| A03493 | 33984334 | Metabolism | A new mechanism of obeticholic acid on NASH treatment by inhibiting NLRP3 inflammasome activation in macrophage. | Details |
| A03845 | 33849361 | Expert Opin Drug Discov | The identification of farnesoid X receptor modulators as treatment options for nonalcoholic fatty liver disease. | Details |