- |||||||||| Review, Journal: Evolving role for pharmacotherapy in NAFLD/NASH. (Pubmed Central) - Oct 27, 2021
Outcomes of promising phase 2 trials in adults with NASH are also available and those have investigated agents including the FGF19 analogue NGM282, the GLP1 agonist liraglutide, the FGF21 analogue Pegbelfermin, the SGLT2 inhibitor Empagliflozin, the ketohexokinase inhibitor PF-06835919, the acetyl-coenzyme A carboxylase inhibitor GS-0976 and the chemokine receptor antagonist Cenicriviroc. Completed and ongoing clinical trials emphasize the need for a more nuanced understanding of the phenotypes of subgroups within NAFLD that may respond to an individualized approach to pharmacotherapy.
- |||||||||| Ocaliva (obeticholic acid) / Intercept, aldafermin (NGM282) / NGM Biopharma
[VIRTUAL] RESISTANCE TO FGF19 SIGNALING PREDICTS THE SEVERITY OF HEPATIC STEATOSIS DURING CROHN’S DISEASE () - Oct 21, 2021 - Abstract #AASLD2021AASLD_1867; Although the direction of causality is unresolved, either suppression of FGF19 production or disrupting its receptor’s (FGFR4) signaling pathway are expected to both promote de novo lipogenesis and reduce fatty acid oxidation . Future directions will include unravelling the molecular mechanism of FGF19 resistance and determining if it predicts clinical response to FGF19 relevant therapeutics (e .g .
- |||||||||| Ocaliva (obeticholic acid) / Intercept, cilofexor (GS-9674) / Gilead
[VIRTUAL] FXR AGONISM ELEVATES CIRCULATING LEVELS OF THE PRURITOGENIC CYTOKINE IL-31 () - Oct 21, 2021 - Abstract #AASLD2021AASLD_1832; P2 FXR activation, through agonists or the natural ligands (BAs), is associated with increased levels of the pruritogenic cytokine IL-31, which appears to derive in part from increased hepatocyte expression. These findings have potential therapeutic implications for the pruritus associated with FXR agonists and in patients with cholestasis .
- |||||||||| bezafibrate / Generic mfg.
[VIRTUAL] THE EFFECTIVE USE OF BEZAFIBRATE AS A SECOND LINE THERAPY FOR PBC () - Oct 21, 2021 - Abstract #AASLD2021AASLD_1534; Background: Bezafibrate, a peroxisome proliferator-activated receptor with anti-cholestatic effects, is not often used in the UK in clinical practice for treatment of primary biliary cholangitis (PBC) in patients who don’t respond to ursodeoxycholic acid (UDCA) because it is an unlicensed therapy for this condition...Of the 3 who didn’t; 1 died from metastatic breast cancer; 1 was referred for liver transplantation due to hepatic decompensation and 1 has commenced obeticholic acid without a significant response yet. Our case series demonstrates that bezafibrate is a highly effective and safe second line therapy for PBC, in combination with UDCA, for patients who don’t have an adequate biochemical response with UDCA monotherapy.
- |||||||||| Ocaliva (obeticholic acid) / Intercept
[VIRTUAL] RATIONALE FOR MRGPRX4 ANTAGONISM AS A TREATMENT FOR CHOLESTATIC AND UREMIC PRURITIS. () - Oct 21, 2021 - Abstract #AASLD2021AASLD_1524; These findings confirm and expand upon prior reports that MRGPRX4 is activated by a broad range of bile acid and heme metabolites, including those that may be elevated in cholestatic and/or uremic states, and establish this receptor as a central and specific mechanism of pruritus in these two conditions . MRGPRX4 antagonism, aimed at blocking the full range of agonists, is thus an attractive therapeutic intervention in both cholestatic and uremic pruritus .
- |||||||||| INT-767 / Intercept
[VIRTUAL] INHIBITION OF HEPATITIS B VIRUS INFECTION BY BILE ACID DERIVATIVES () - Oct 21, 2021 - Abstract #AASLD2021AASLD_1064; INT-767 may be binding to the hydrophobic region of NTCP binding motif of the preS1 peptide to inhibit the interaction between INT-767 and PreS1 peptide . Clarifying the underlying mechanisms of INT-767 would facilitate the development of novel anti-HBV agents .
- |||||||||| budesonide / Generic mfg., bezafibrate / Generic mfg.
Journal: Primary biliary cholangitis: treatment. (Pubmed Central) - Oct 20, 2021 This supports a therapeutic role for a combination of n-3 PUFAs+OCA for PBC treatment and establish the basement for future in vivo studies and clinical trials to validate this hypothesis . Patients with PBC need to be evaluated at baseline, and on-treatment, for the risk of progressive disease and eventually treated with second-line therapies in addition to UDCA.
- |||||||||| INT-767 / Intercept
Journal: Discovery, optimization, and evaluation of non-bile acid FXR/TGR5 dual agonists. (Pubmed Central) - Oct 16, 2021 Although several potent bile acid Farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5, GPBAR1) dual agonists such as INT-767 have been reported, no non-bile acid FXR/TGR5 dual agonist has been investigated to date...Compound 20p significantly increased the plasma levels of GLP-1 as a TGR5 agonist, and a high concentration of GLP-1 lowered blood glucose levels. We confirmed that compound 20p was a non-bile acid FXR/TGR5 dual agonist.
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Journal: The critical role of FXR is associated with the regulation of autophagy and apoptosis in the progression of AKI to CKD. (Pubmed Central) - Oct 15, 2021 FXR regulated genes that participate in renal autophagy under feeding and fasting conditions, such as hepatic autophagy, and the activation of FXR by agonists, such as GW4064 and INT-747, attenuated the increased autophagy and apoptosis of hypoxia-induced human renal proximal tubule epithelial (HK2) cells...At 28 days after I/R injury, the autophagy levels were still elevated in FXR KO mice, and the expression levels of fibrosis-related proteins and ROS deposits were higher than those in WT mice. In conclusion, the regulation of renal autophagy and apoptosis by FXR may be a therapeutic target for the early stages of kidney damage, and the progression of AKI to CKD.
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Journal: A new mechanism of obeticholic acid on NASH treatment by inhibiting NLRP3 inflammasome activation in macrophage. (Pubmed Central) - Oct 7, 2021 NAFLD is associated with CVD, which may have certain clinical and therapeutic implications. This finding brings up a new mechanism of OCA on NASH treatment, suggested by direct inhibition on NLRP3 inflammasome activation in macrophage, further suppression on inflammasome activation-elicited hepatic lipid accumulation, and contributing to the amelioration of NASH.
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Journal: Defective FXR-SHP Regulation in Obesity Aberrantly Increases miR-802 Expression, Promoting Insulin Resistance and Fatty Liver. (Pubmed Central) - Sep 26, 2021 In obese mice, activation of FXR by obeticholic acid treatment reduced miR-802 levels and improved insulin resistance and hepatosteatosis, but these beneficial effects were largely abolished by overexpression of miR-802...These results demonstrate that normal inhibition of miR-802 by FXR-SHP is defective in obesity, resulting in increased miR-802 levels, insulin resistance and fatty liver. This FXR-SHP-miR-802 pathway may present novel targets for treating type 2 diabetes and NAFLD.
- |||||||||| Clinical, Review, Journal: Efficacy and safety of drugs for nonalcoholic steatohepatitis. (Pubmed Central) - Sep 19, 2021
Vitamin E has been recommended for patients with NASH without type 2 diabetes mellitus (T2DM), whereas a combination of pioglitazone and vitamin E is recommended for patients with both NASH and T2DM...Some of the drugs are at phase III clinical trials, including obeticholic acid (OCA), Elafibranor, Cenicriviroc, Selonsertib, Resmetirom, Emricasan and Aramchol...Especially, due to the interim positive effect for the improvement of liver fibrosis, OCA has been filling to FDA and is waiting for the final approval for the treatment of NASH. Therefore, it is urgent to review the efficacy and safety of drugs for NASH in current clinical trials.
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Preclinical, Journal: Obeticholic Acid Decreases Intestinal Content of Enterococcus in Rats With Cirrhosis and Ascites. (Pubmed Central) - Sep 14, 2021 At end of treatment, rats on OCA had a significantly lower aspartate aminotransferase (AST) (266 vs. 369 IU/L; P < 0.01) and higher serum albumin (0.9 vs. 0.7 g/dL; P < 0.01) than rats on placebo. Although OCA did not appear to reduce BT by pathogenic bacteria, the reduction in intestinal content of Enterococcus, which has been associated with hepatocyte death, in OCA-treated animals is consistent with our observed improvements in AST and in liver function, as evidenced by higher serum albumin.
- |||||||||| Ocaliva (obeticholic acid) / Intercept, NN1213 / Novo Nordisk
Trial completion date, Trial primary completion date: Effect of Heavy Alcohol Consumption on Farnesoid X Receptor (FXR) Signaling (clinicaltrials.gov) - Sep 14, 2021 P=N/A, N=45, Recruiting, Although OCA did not appear to reduce BT by pathogenic bacteria, the reduction in intestinal content of Enterococcus, which has been associated with hepatocyte death, in OCA-treated animals is consistent with our observed improvements in AST and in liver function, as evidenced by higher serum albumin. Trial completion date: Dec 2021 --> Apr 2023 | Trial primary completion date: Aug 2021 --> Apr 2022
- |||||||||| Journal: Nonalcoholic Fatty Liver Disease: A Drug Revolution Is Coming. (Pubmed Central) - Sep 11, 2021
Five pharmacologic agents-obeticholic acid, elafibranor, cenicriviroc, resmetirom, and aramchol-are being evaluated in large, histology-based phase 3 trials...Based on the results of phase 2 and 3 trials, combination treatments are also being investigated. Future treatment strategies will comprise drug combinations and precision medicine based on the different phenotypes of NASH and treatment response of the individual patient.
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Journal: Functional Analysis of Induced Human Ballooned Hepatocytes in a Cell Sheet-Based Three Dimensional Model. (Pubmed Central) - Sep 1, 2021 We can suggest that 7-ELCA may be a prospective approach to the treatment of type II diabetes as the dual modulation of GPBAR1 and FXR has been supposed to be effective in the synergistic regulation of glucose homeostasis in the intestine. In summary, this study demonstrates the priority of iBHs in recapitulating not only histology but also clinically relevant hepatic dysfunctions in human NASH and suggests TGF-β and bile acid related signal pathway may play important roles in the formation of iBHs.
- |||||||||| Ocaliva (obeticholic acid) / Intercept
Journal: A scalable and sensitive steatosis chip with long-term perfusion of in situ differentiated HepaRG organoids. (Pubmed Central) - Aug 28, 2021 SteatoChip detects reduction of steatosis when cells are incubated with three different anti-steatosis compounds, 78.5% by metformin hydrochloride, 71.3% by pioglitazone hydrochloride and 66.6% by obeticholic acid, versus the control FFA-free media (38% reduction). The precision microenvironment control in SteatoChip enables improved formation, differentiation, and function of HepaRG organoids to serve as a scalable and sensitive drug testing platform, to potentially accelerate the NAFLD drug development.
|