INT-767 / Intercept - LARVOL DELTA

Molecular mechanisms of hepatitis B virus entry inhibition by a bile acid derivative INT-767 binding to the preS1 region. (PubMed, Antiviral Res) - "INT-767 binding to these residues effectively blocked preS1 interaction with NTCP, thereby inhibiting HBV infection. These findings highlight a novel antiviral mechanism by which INT-767 exerts its anti-HBV effects through direct interaction with preS1, providing a potential therapeutic strategy targeting HBV entry."

Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Aberrant basement membrane production by HSCs in MASLD is attenuated by the bile acid analog INT-767. (PubMed, Hepatol Commun) - "These findings highlight the importance of basement membrane remodeling in MASH pathobiology and as a source of circulating biomarkers. Basement membrane deposition by activated HSCs is abrogated by INT-767 treatment and measurement of basement membrane molecules should be included when determining the therapeutic efficacy of FXR agonists."

Journal • Fibrosis • Hepatology • Immunology • Leptin Receptor Deficiency Obesity • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Psychiatry • LEP

Prophylactic and therapeutic hepatoprotective effects of the dual FXR/TGR5 agonist INT-767 in the GAN diet-induced ob/ob mouse model of advanced MASH with progressive fibrosis (EASL-ILC 2024) - "The dual FXR/TGR5 agonist INT-767 improves hallmarks of MASH in the GAN ob/ob-MASH mouse model in settings of both prophylactic and therapeutic treatment, respectively. Greater anti-fibrotic effects of INT-767 were attained by prophylactic treatment. These findings suggest the potential utility of dual FXR/TGR5 activation as disease intervention strategy in MASH."

Metastases • Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Leptin Receptor Deficiency Obesity • Metabolic Dysfunction-Associated Steatohepatitis • Obesity • COL1A1 • LEP

Bile acid receptor agonist reverses TGF-β1-mediated fibrogenesis in human induced pluripotent stem cells (iPSC)-derived kidney organoids. (PubMed, Lab Invest) - "A dual bile acid receptors agonist (INT-767) increased Farnesoid X receptor and reduced p-SMAD3 and TAZ, attenuating TGF-β1-induced fibrosis in kidney organoids. Finally, we show that TAZ interacted with TEA-domain transcription factors and p-SMAD3 with TAZ and TEA-domain transcription factor 4 co-regulating collagen 1α1 gene transcription. In summary, we establish a novel, readily manipulable fibrogenesis model and posit a role for bile acid receptor agonism early in renal parenchymal fibrosis."

Journal • Chronic Kidney Disease • Fibrosis • Immunology • Nephrology • Renal Disease • SMAD3 • SMAD4 • TAFAZZIN • TCF4 • TEAD4 • TGFB1

INT-767-A Dual Farnesoid-X Receptor (FXR) and Takeda G Protein-Coupled Receptor-5 (TGR5) Agonist Improves Survival in Rats and Attenuates Intestinal Ischemia Reperfusion Injury. (PubMed, Int J Mol Sci) - "Previous work demonstrated that pre-treatment with obeticholic acid (OCA) protected against ischemia reperfusion injury (IRI). This study demonstrates that treatment with INT-767 15 min after onset of intestinal ischemia significantly decreases IRI and improves survival. The ability to administer INT-767 intravenously greatly enhances its clinical potential."

Journal • Preclinical • Cardiovascular • Infectious Disease • Inflammation • Reperfusion Injury • Septic Shock

Kidney and lipids: novel potential therapeutic targets for dyslipidemia in kidney disease? (PubMed, Expert Opin Ther Targets) - "Attractive alternatives, such as PCSK9-small interfering RNA (siRNA) molecules or evinacumab are available. Additionally, several promising agents, such as cyclodextrins and the FXR/TGR5 dual agonist, INT-767, can improve renal lipid metabolism disorders and delay CKD progression. Drugs targeting mitochondrial dysfunction could be an option for the treatment of dyslipidemia and lipotoxicity, particularly in renal diseases."

Journal • Cardiovascular • Chronic Kidney Disease • Dyslipidemia • Metabolic Disorders • Nephrology • Renal Disease • Transplantation

The Role of FXR and TGR5 in Reversing and Preventing Progression of Western Diet-induced Hepatic Steatosis, Inflammation, and Fibrosis in Mice. (PubMed, J Biol Chem) - "Interestingly, the effects of INT-767 in attenuating NASH were absent in FXR-null mice, but still present in TGR5-null mice. Our findings support treatment and prevention protocols with the dual FXR-TGR5 agonist INT-767 arrest progression of WD-induced NASH in mice mediated by FXR-dependent, TGR5-independent mechanisms."

Journal • Preclinical • Addiction (Opioid and Alcohol) • Diabetes • Fibrosis • Genetic Disorders • Hepatology • Immunology • Inflammation • Metabolic Disorders • Non-alcoholic Steatohepatitis • Obesity • Type 2 Diabetes Mellitus • SIRT1 • SIRT3

Development of 3α,7α-dihydroxy-6α-ethyl-24-nor-5β-cholan-23-sulfate sodium salt (INT-767): Process optimization, synthesis and characterization of metabolites. (PubMed, Eur J Med Chem) - "The final synthetic route may be successfully employed to produce the amount of INT-767 required to support late-stage clinical development of the compound. Furthermore, potential metabolites have been synthesized, characterized and evaluated for their ability to modulate FXR and TGR5 receptors providing key reference standards for future drug investigations, as well as offering further insights into the structure-activity relationships of this class of compounds."

Journal • Hepatology

[VIRTUAL] DIGITAL PATHOLOGY IMAGE ANALYSIS ACCURATELY QUANTIFIES ANTI-FIBROTIC AND ANTI-STEATOTIC EFFECTS OF FXR AGONISTS USING MULTIPLE HISTOLOGICAL METHODS (AASLD 2021) - "Histological features impacted by FXR agonists INT-2228 and INT-767 can be accurately quantified by both digital pathology methods. Using FibroNest® as an image analysis platform, SHG and conventional staining both provide similar performance and data quality . However, SHG are quite costly and requires special technician and imaging machine that is not widely available ."

Fibrosis • Hepatology • Immunology • Inflammation • Leptin Receptor Deficiency Obesity • Non-alcoholic Steatohepatitis • LEP

[VIRTUAL] INHIBITION OF HEPATITIS B VIRUS INFECTION BY BILE ACID DERIVATIVES (AASLD 2021) - "Our results suggest that bile acid derivatives are prospective candidate for anti-HBV agents. 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 ."

Hepatitis B • Hepatology • Infectious Disease • Inflammation

Discovery, optimization, and evaluation of non-bile acid FXR/TGR5 dual agonists. (PubMed, Sci Rep) - "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."

Journal

Dual Agonist of Farnesoid X Receptor and G Protein-coupled Receptor TGR5 Inhibits Hepatitis B Virus Infection in Vitro and in Vivo. (PubMed, Hepatology) - "Our results suggest that BA derivatives, particularly INT-767, are prospective candidate anti-HBV agents. Clarifying the underlying mechanisms of BA derivatives would facilitate the development of novel anti-HBV agents."

Journal • Preclinical • Hepatitis B • Hepatology • Infectious Disease

Obeticholic acid and INT-767 modulate collagen deposition in a NASH in vitro model. (PubMed, Sci Rep) - "Collagen deposition and metalloproteinase 2 and 9 (MMP2-9) activity were compared to tropifexor and selonsertib. All tested compounds reduced collagen deposition. OCA exerted a more potent and long-lasting effect, mainly related to modulation of collagen turn-over and MMP2-9 activity."

Journal • Preclinical • Addiction (Opioid and Alcohol) • Fibrosis • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Liver Cancer • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Solid Tumor

[VIRTUAL] Composite targeting of nuclear receptors protects against diet-induced NAFLD (EASL-ILC-I 2020) - "In conclusion, either INT-767 or antagomiR-21 alone prevent NAFLD triggering and progression, with both treatments combined more effectively ameliorating the NAFLD phenotype at distinct disease stages. These effects are mediated insulin resistance-, mitochondrial function-, lipid and cholesterol metabolism-related genes, in overlapping and complementary signalling cascades. Hence, the multiple targeting of selected bile acid-activated receptors may embody a novel putative therapeutic approach PTDC/MED- PAT/31882/2017, EU H2020 Marie Sklodowska-Curie 722619."

Fibrosis • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Oncology • Solid Tumor • FGF • MIR21 • NRF1

[VIRTUAL] Composite targeting of nuclear receptors protects against diet-induced NAFLD (EASL-ILC-I 2020) - "In conclusion, either INT-767 or antagomiR-21 alone prevent NAFLD triggering and progression, with both treatments combined more effectively ameliorating the NAFLD phenotype at distinct disease stages. These effects are mediated through modulation of multiple inflammatory-, fibrogenic-, insulin resistance-, mitochondrial function-, lipid and cholesterol metabolism-related genes, in overlapping and complementary signalling cascades. Hence, the multiple targeting of selected bile acid-activated receptors may embody a novel putative therapeutic approach in preventing NAFLD."

Fibrosis • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Oncology • Solid Tumor • FGF • MIR21 • NRF1

[VIRTUAL] INT 767 – A novel dual farnesoid-X receptor (FXR) and takeda G-protein-coupled receptor-5 (TGR5) agonist attenuates intestinal ischemia reperfusion injury (TTS 2020) - " We demonstrated that intravenous treatment with a dual FXR/TGR5 agonist (INT-767) after onset of ischemia significantly decreased intestinal damage caused by IRI. These results show that FXR and TGR5 receptors are promising targets for intestinal graft protection.  The ability to administer this substance intravenously greatly enhances the potential applicability for the frequent pathology of intestinal infarction as well as for transplantation."

Gastrointestinal Disorder • Immunology • Reperfusion Injury • Transplantation • IL10 • IL13 • IL6 • TNFA

Validity of biopsy-based drug effects in a diet-induced obese mouse model of biopsy-confirmed NASH. (PubMed, BMC Gastroenterol) - "In conclusion, in-depth analyses of liver homogeneity demonstrated that drug-induced improvement in liver biopsy-assessed histopathology is representative for overall liver effects assessed using stereology. Importantly, these findings reveal how changes in whole-liver mass should be considered to provide a deeper understanding of apparent drug treatment efficacy in preclinical NASH studies."

Journal • Preclinical • Fibrosis • Hepatology • Immunology • Leptin Receptor Deficiency Obesity • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Obesity

T cell interactions with the biliary epithelium in primary biliary cholangitis (ILC 2017) - "...CD4+ T cells isolated from healthy volunteerswere cultured with senescent H69 for 72 h. Senescent H69 cellswere stimulated with selective BAR agonists for FXR (obeticholic acid; OCA), TGR5 (INT-777) and a dual FXR/TGR5 agonist (INT-767) or recombinant human fibroblast growth factor (FGF) 19... Senescent BEC have the potential to suppress induction of regulatory T cells in vitro. Furthermore, the release of FGF19 from cells such as enterocytes indicates a potential mechanism by which FXR agonists may be effective even in patients with reduced FXR expression within the liver."

Oncology

Intercept Pharmaceuticals reports 2015 financial results and provides business update (GlobeNewswire) - "Planned 2016 milestones: INT-767 Program: Completion of Phase 1 trial and planning of Phase 2 trial"

Anticipated new P2 trial • Anticipated trial completion date • Fibrosis

Fibrosis involves increased fibroblast and hepatocyte collagen species, reflecting the interstitial and basement membrane matrix: Restoration of the local tissue milieu with FXR agonism (ILC 2018) - "We demonstrated that fibrosis is not only associated with increased Col1 and Col3 of the fibroblasts, but also a significant thickening of the BM involving a completely different functional type of collagen, Col4. INT-767 treatment reduced Col4 and LAM, the major components of the BM which are likely contributors to improvements in endpoint fibrosis. For Col4, these changes were evident at the mRNA level and linked to circulating P4NP7S."

Biosimilar • Fibrosis • Immunology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis

Semisynthetic bile acids: a new therapeutic option for metabolic syndrome. (PubMed, Pharmacol Res) - "Obeticholic acid (INT-747) has achieved the biggest clinical success so far being in use for the treatment of primary biliary cholangitis. This review summarizes and critically evaluates the key chemical modifications of bile acids resulting in development of novel semisynthetic derivatives as well as the current status of their preclinical and clinical evaluation in metabolic syndrome treatment, so far lacking in the scientific literature. Taking into account the balance between therapeutic benefits and potential adverse effects associated with specific structure and mechanism of action, recommendations for future studies are proposed."

Journal • Review • Cardiovascular • Diabetes • Dyslipidemia • Gastroenterology • Hepatology • Immunology • Metabolic Disorders • Primary Biliary Cholangitis

Acarbose improves health and lifespan in aging HET3 mice. (PubMed, Aging Cell) - "Three other interventions were also tested: ursolic acid, 2-(2-hydroxyphenyl) benzothiazole (HBX), and INT-767; none of these affected lifespan at the doses tested. The acarbose results confirm and extend our original report, prompt further attention to the effects of transient periods of high blood glucose on aging and the diseases of aging, including cancer, and should motivate studies of acarbose and other glucose-control drugs in humans."

Journal • Preclinical • Diabetic Nephropathy • Lung Cancer • Oncology • Renal Disease • Solid Tumor • Thoracic Cancer

Identification of TAZ as a Regulator of TGF-β Mediated Fibrosis in iPSC-Derived Organoids (KIDNEY WEEK 2019) - "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"

Bile Acid G Protein-Coupled Membrane Receptor TGR5 Modulates Aquaporin 2-Mediated Water Homeostasis. (PubMed, J Am Soc Nephrol) - "TGR5 stimulation increases renal AQP2 expression and improves impaired urinary concentration in lithium-induced NDI. TGR5 is thus involved in regulating water metabolism in the kidney."

Journal

Simultaneous inhibition of FXR and TGR5 exacerbates atherosclerotic formation. (PubMed, J Lipid Res) - "We demonstrated that 1) FXR and TGR5 dual deficiency exacerbated the development of atherosclerosis and 2) the anti-atherogenic effect of INT-767 requires the anti-inflammatory effect but not the lipid-lowering effect through the simultaneous activation of FXR and TGR5. Our results indicate that dual activation of FXR and TGR5 is a promising strategy for treating atherosclerosis."

Journal