- |||||||||| Ocaliva (obeticholic acid) / Intercept
Journal: Bile Acids and Farnesoid X Receptor: Novel Target for the Treatment of Diabetic Cardiomyopathy. (Pubmed Central) - Dec 6, 2019 FXR is activated by primary bile acids (BAs) such as chenodeoxycholic acid, cholic acid and synthetic agonists such as obeticholic acid...Due to the regulatory effect of FXR on glucose and lipid metabolism, oxidative stress and inflammation, the treatment of BAs and FXR agonists for metabolic syndrome and DCM have gained more attention. This review will focus on the pathogenesis of diabetic cardiomyopathy and the regulatory effect of BAs and FXR on DCM.
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Review, Journal: Primary biliary cholangitis. (Pubmed Central) - Nov 2, 2019 Ursodeoxycholic acid is the specific treatment with an excellent response in more than 60% of patients. When this optimal response is not observed, it can be combined with new agents, but those that have shown to be effective are those that improve cholestasis such as fibrates and obeticholic acid.
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Journal: Bile Acids and the Gut Microbiome as Potential Targets for NAFLD Treatment. (Pubmed Central) - Oct 25, 2019 Semisynthetic bile acid (BA) obeticholic acid, a potent farnesoid X receptor (FXR) agonist, exhibited beneficial effects on nonalcoholic fatty liver disease (NAFLD)...Lastly, it is not known how FXR mediated signaling interact with G protein-coupled bile acid receptor 1 mediated signaling. Answering these questions may lead to an improved pharmaceutical intervention for NAFLD targeting the FXR signaling pathway.
- |||||||||| Triglide (fenofibrate) / Vectura, Shionogi, Ocaliva (obeticholic acid) / Intercept, Lacromid (bezafibrate) / Remedica
ADDITIVE BENEFICIAL EFFECTS OF FIBRATES COMBINED WITH OBETICHOLIC ACID IN THE TREATMENT OF PATIENTS WITH PRIMARY BILIARY CHOLANGITIS AND INADEQUATE RESPONSE TO SECOND-LINE THERAPY (Hynes Convention Center, Hall B) - Oct 15, 2019 - Abstract #AASLD2019AASLD_3159; Patients with PBC treated for at least 12 weeks with, and with no intolerance to, a combination of OCA (5-10 mg/d), fibrates (bezafibrate 400 mg/d or fenofibrate 200 mg/d) and UDCA (13-15 mg/kg/d) because of a Paris-2 inadequate response to one second-line option were included in a multicenter retrospective cohort study. Triple therapy with fibrates, OCA, and UDCA improves biochemical liver tests and increases the rate of ALP normalization in patients with PBC and incomplete response to second-line therapy.
- |||||||||| INT-767 / Intercept
Identification of TAZ as a Regulator of TGF-β Mediated Fibrosis in iPSC-Derived Organoids (Exhibit Hall, Walter E. Washington Convention Center) - Oct 14, 2019 - Abstract #KIDNEYWEEK2019KIDNEY_WEEK_2637; Previously, we have shown that INT767, a dual TGR5/FXR bile acid receptor agonist, blocks TGF-β1-induced fibrogenesis...We demonstrated a mechanism downstream of TGF-β1, involving TAZ and TEAD1 transcription factors, with translational therapeutic potential. Funding NIDDK Support
- |||||||||| Review, Journal: Current and future pharmacological therapies for NAFLD/NASH. (Pubmed Central) - Oct 9, 2019
Among a variety of medications in development, four agents such as OCA, elafibranor, ASK1 inhibitor, and CVC are currently being evaluated in an international phase 3 trial for the treatment of NASH. Within the next few years, the availability of therapeutic options for NASH will hopefully curb the rising trend of NASH-related diseases.
- |||||||||| bile acid cholic acid (INT-777) / Intercept
Journal: Metabolite-Sensing G Protein Coupled Receptor TGR5 Protects Host From Viral Infection Through Amplifying Type I Interferon Responses. (Pubmed Central) - Oct 8, 2019 Most importantly, overexpression of TGR5 or treatment with the modified bile acid INT-777 broadly protected host cells from vesicular stomatitis virus (VSV), newcastle disease virus (NDV) and herpes simplex virus type 1 (HSV-1) infection...Mechanistically, TGR5 facilitates type I interferon (IFN-I) production through the AKT/IRF3-signaling pathway, which is crucial in promoting antiviral innate immunity. Taken together, our data reveal a positive feedback loop regulating IRF3 signaling and suggest a potential therapeutic role for metabolite-sensing GPCRs in controlling viral diseases.
- |||||||||| Ocaliva (obeticholic acid) / Intercept, INT-747 / Intercept
Journal, IO Biomarker: Activation of the Nuclear Receptor Fxr Improves Intestinal Cell Tolerance to Ischemia-reperfusion Injury. (Pubmed Central) - Oct 2, 2019 INT-747 enhanced Caco-2 cell viability and inhibited inflammatory response by blocking the NF-κB pathway after OGD/R injury, which was diminished by a CSE-specific inhibitor (PAG). Thus, we demonstrated that FXR activation enhances intestinal epithelial cell tolerance to I/R by suppressing the inflammatory response and NF-κB pathway via CSE mediation.
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Journal: The FXR agonist obeticholic acid inhibits the cancerogenic potential of human cholangiocarcinoma. (Pubmed Central) - Oct 2, 2019 The effects of OCA predominated in mixed iCCA cells, consistent with the lower aggressiveness and the higher FXR expression in this CCA subtype. These results, showing the FXR-mediated capacity of OCA to inhibit cholangiocarcinogenesis, represent the basis for testing OCA in clinical trials of CCA patients.
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CHANGES IN INTESTINAL MICROBIOME IN RATS WITH CIRRHOSIS AND ASCITES: COMPARISON BETWEEN OBETICHOLIC ACID (OCA) AND PLACEBO (Hynes Convention Center, Hall B) - Sep 29, 2019 - Abstract #AASLD2019AASLD_2771; Although overall there appeared to be no significant effect of OCA treatment on the relative abundances of the most common genera in the ileum or the cecum (stool), multiple specific bacterial genera were differentially expressed in the ileum and colon, notably Enterococcus which has been shown to secrete cytolysin, a bacteriocin that causes hepatocyte death and liver injury. These findings may explain the beneficial effects of OCA in this model of cirrhosis.This study was supported by a grant from Intercept Pharmaceuticals.
- |||||||||| elafibranor (GFT505) / Genfit, Ocaliva (obeticholic acid) / Intercept
COMPARING AN IN VITRO ORGAN-ON-CHIP MODEL OF NON-ALCOHOLIC STEATOHEPATITIS TO MURINE MODELS AND LIVER TISSUE FROM PATIENTS (Hynes Convention Center, Hall B) - Sep 29, 2019 - Abstract #AASLD2019AASLD_2648; Furthermore, major reductions in bile acids by fenofibrate occurred through taurine- and glycine-conjugated pathways, suggesting a role of PPARα in amidation. The phenotypic changes in the 3D in vitro NASH model support its clinical translatability potentially over traditional in vivo models and demonstrate its utility as a preclinical tool to probe the therapeutic efficacy of compounds in NASH drug development.
- |||||||||| CRV431 / ContraVir
CRV431 TARGETS THE LIVER AND DECREASES LIVER FIBROSIS IN THE CARBON TETRACHLORIDE MOUSE MODEL (Hynes Convention Center, Hall B) - Sep 29, 2019 - Abstract #AASLD2019AASLD_2607; The antifibrotic activity differentiates CRV431 from compounds such as OCA that mechanistically target earlier stages in NASH progression. CRV431 inhibition of multiple cyclophilin isoforms provides the advantage of neutralizing multiple pathologic mechanisms with a single liver-targeting pharmaceutical agent.
- |||||||||| Ocaliva (obeticholic acid) / Intercept, resmetirom (MGL-3196) / Madrigal
EC-18, A NOVEL IMMUNE RESOLUTION ACCELERATOR, IMPROVES NASH AND LIVER FIBROSIS (Hynes Convention Center, Hall B) - Sep 29, 2019 - Abstract #AASLD2019AASLD_2454; In various mice models, EC-18 ameliorated hepatic steatosis, NASH and liver fibrosis via regulating lipid metabolism in peripheral tissue and attenuating hepatocyte inflammation and cell damage caused by damage-associated molecular patterns (DAMPs). In conclusion, EC-18 can be a promising therapeutics to resolve NASH and to prevent progression to liver fibrosis.
- |||||||||| Cutasil (STP705) / Guangzhou Xiangxue Pharmaceutical, Sirnaomics
EFFECT ON LIVER FIBROSIS BY TGF-β1/COX-2 siRNA COMBINATION PRODUCT (STP705) IN A CCl4-INDUCED LIVER FIBROSIS MOUSE MODEL (Hynes Convention Center, Hall B) - Sep 29, 2019 - Abstract #AASLD2019AASLD_2439; The data suggests that STP705-treatment results in significant reduction of liver fibrosis and HKP delivery system successfully delivers STP705 to the liver post-intravenous administration. Overall, STP705 is an innovative siRNA-based treatment that results in significant suppression of liver fibrosis in a CCl4-induced liver fibrosis mouse model.
- |||||||||| Ocaliva (obeticholic acid) / Intercept
EFFECTS OF OBETICHOLIC ACID ON APRI AND GLOBE SCORE IN PATIENTS WITH PRIMARY BILIARY CHOLANGITIS (Hynes Convention Center, Hall B) - Sep 29, 2019 - Abstract #AASLD2019AASLD_2425; Overall, STP705 is an innovative siRNA-based treatment that results in significant suppression of liver fibrosis in a CCl4-induced liver fibrosis mouse model. Twelve month use of obeticholic acid is associated with improvements in the APRI and GLOBE score, consistent with a reduction in risk of liver related complications in patients with PBC.
- |||||||||| FXR and TGR5 bile acid (BA)-derived backup compounds / Intercept
ENHANCED SUSCEPTIBILITY TO ALCOHOLIC LIVER DISEASE IN FXR DEFICIENT MICE IS LINKED TO ALTERED ETHANOL METABOLISM (Hynes Convention Center, Hall B) - Sep 29, 2019 - Abstract #AASLD2019AASLD_2378; Beyond the choleretic effect of OCA in PBC, real world data revealed a significant improvement of ALT values in patients with PBC-AIH overlap with persistently abnormal transaminases despite long-term immunosuppression. Our data show for the first time that enhanced susceptibility to alcoholic liver disease in FXR KO mice is associated with altered ethanol metabolism and increased oxidative stress.
- |||||||||| Ocaliva (obeticholic acid) / Intercept
FARNESOID X RECEPTOR AND BILE ACIDS REGULATE VITAMIN A STORAGE (Hynes Convention Center, Hall B) - Sep 29, 2019 - Abstract #AASLD2019AASLD_2308; In conclusion, hepatic FXR is required for efficient vitamin A storage in mouse liver, while activation of FXR by OCA or CA also suppresses hepatic vitamin A storage. These data suggest that FXR-targeted therapies may be prone to cause vitamin A-related pathologies.
- |||||||||| PXL007 / Poxel SA, ENYO
IN VITRO AND IN VIVO CHARACTERIZATION OF EYP001 A NOVEL, POTENT AND SELECTIVE FXR AGONIST NOW IN A PHASE 2 CLINICAL TRIAL IN NASH (Hynes Convention Center, Hall B) - Sep 29, 2019 - Abstract #AASLD2019AASLD_1917; A close analogue of EYP001 significantly improved NASH parameters such as fibrosis, steatosis, ballooning, inflammation and NAS in a murine model of NASH. Based on these preclinical efficacy findings, and safety, tolerability, pharmacokinetics and pharmacodynamics data obtained in Phase 1 clinical trials, EYP001 has now entered a Phase 2 clinical trial examining benefit in NASH patients.
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