FXR and TGR5 bile acid (BA)-derived backup compounds / Intercept - LARVOL DELTA

Positive results from REGENERATE: A phase 3 international, randomized, placebo-controlled study evaluating obeticholic acid treatment for NASH (EASL-ILC 2019) - "Background and Aims: Obeticholic acid (OCA), an FXR agonist, improved both fibrosis and histologic features of nonalcoholic steatohepatitis (NASH) in the Ph2 FLINT study. Treatment with OCA 25mg improved liver fibrosis, key histologic features of steatohepatitis and liver biochemistry, demonstrating consistent efficacy with an overall AE profile similar to previous studies."

Clinical • P3 data

Long-term obeticholic acid treatment is associated with improvements in collagen morphometry in patients with primary biliary cholangitis (EASL-ILC 2019) - "Background and aims: Obeticholic acid (OCA) is a potent, selective FXR agonist approved for the treatment of PBC based upon biochemical improvements predicted to improve transplant-free survival. In this analysis, 3 years of OCA treatment resulted in a reduction in CAR, CFD and CRI, supporting the overall trend of improvement or no progression in the histologic components of PBC Figure:"

Clinical

FXR Effect on Severe Alcohol-Associated Hepatitis (FRESH) Study (clinicaltrials.gov) - P2a | N=50 | Not yet recruiting | Sponsor: Intercept Pharmaceuticals

New P2a trial • Hepatology • Inflammation

THE NOVEL FXR AGONIST INT-787 SHOWS HIGHER EFFICACY AS WELL AS GREATER HEPATIC AND ILEAL GENE MODULATION THAN OBETICHOLIC ACID IN THE GUBRA-AMLN MOUSE MODEL OF DIET-INDUCED AND BIOPSY-CONFIRMED NON-ALCOHOLIC STEATOHEPATITIS (AASLD 2022) - "OCA has demonstrated clinical efficacy to improve histological NASH in multiple trials. INT-787 treatment for 8 weeks was superior to OCA in improving liver histology and liver injury-related plasma markers in a mouse model of NASH. Efficacy of INT-787 was dose-dependent and plateaued at 30 mg/kg/day; higher doses up to 120 mg/kg/day were well tolerated but further improvements in NASH biomarkers were minimal."

Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Liver Failure • Metabolic Disorders • Non-alcoholic Steatohepatitis

ALTERED ETHANOL METABOLISM AND INCREASED OXIDATIVE STRESS ENHANCE ALCOHOL-ASSOCIATED LIVER INJURY IN FARNESOID X RECEPTOR-DEFICIENT MICE (AASLD 2022) - "Ethanol-induced liver injury (serum ALT), liver inflammation (Ccl2, Tnf-α, IL1β), and neutrophil infiltration were higher in FXR-/- compared to WT mice. WT and FXR -/- mice consumed the same amount of alcohol. However, FXR-/- mice showed reduced blood alcohol levels post-binge."

Preclinical • Hepatology • Immunology • Inflammation • Liver Failure • ALDH1A1 • CCL2 • CYP2E1 • IL1B • MPO • TNFA

SAFETY, TOLERABILITY AND PHARMACOKINETICS OF ORAL INT-787, A NOVEL MODIFIED BILE ACID FXR AGONIST, IN HEALTHY VOLUNTEERS (AASLD 2022) - "INT-787 is generally safe and well-tolerated at single doses of 2.5 to 50 mg and after multiple doses for 14 days with INT-787 5 mg. Additional SAD and MAD cohorts at higher doses are being enrolled to confirm the safety and exposure profile."

Clinical • PK/PD data • CNS Disorders • Dermatology • Fatigue • Fibrosis • Hepatology • Migraine • Pain • Pruritus

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

Farnesoid X receptor activation by the novel agonist TC-100 (3α, 7α, 11β-Trihydroxy-6α-ethyl-5β-cholan-24-oic Acid) preserves the intestinal barrier integrity and promotes intestinal microbial reshaping in a mouse model of obstructed bile acid flow. (PubMed, Biomed Pharmacother) - "Intriguingly, Amuc abundance was also negatively associated to cholic acid levels. Collectively, these data indicate that intestinal FXR activation by TC-100 prevents early signs of intestinal mucosal damage by modulating BA homeostasis and GM composition."

Journal • Preclinical

Altered ethanol metabolism and increased oxidative stress enhance alcohol-associated liver injury in farnesoid X receptor deficient mice. (PubMed, Liver Int) - "ALD pathogenesis in FXR KO mice correlates with altered ethanol metabolism and increased oxidative stress, providing new insights on the protective function of FXR in ALD."

Journal • Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Liver Failure • ALDH1A1 • CYP2E1

Enterohepatic Takeda G-Protein Coupled Receptor 5 Agonism in Metabolic Dysfunction-Associated Fatty Liver Disease and Related Glucose Dysmetabolism. (PubMed, Nutrients) - "Although described in the literature, treatment with fexaramine, an intestine-restricted FXR agonist, did not raise the concentrations of TGR5 ligands nor modulate TGR5 signaling and, accordingly, did not improve dysmetabolic status. In spite of the TGR5 activation capacity, INT-777, but not RO5527239, reduced liver disease severity. In conclusion, TGR5 activation in enterohepatic, rather than in peripheral, tissues has beneficial effects on glucose tolerance and MAFLD."

Journal • Hepatology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis

Obeticholic acid reduces hepatic matrix metalloproteinase activity in a diet-induced ob/ob mouse model of NASH (EASL-ILC 2022) - "Background and aims: Hepatic matrix metalloproteinases (MMPs) play a role in fibrogenesis of NASH contributing not only to the balance between formation and degradation of connective tissue components, but also to signal transduction for tissue repair.We have previously shown that the FXR agonist obeticholic acid (OCA) reduces hepatic MMP activity by restoring RECK, an MMP regulator tissue reversion-inducing cysteine rich protein with Kazal motifs, after ischemia/reperfusion injury (Ferrigno et al, 2020). Thus, OCA confers protection in a model of NASH, as shown by reduced serum bilirubin and cholesterol levels. This is the first study showing the positive effect of OCA on hepatic MMP-9 via restoration of RECK levels in a NASH model. These are intriguing findings considering a) the crucial role of MMPs in extracellular matrix homeostasis due to stellate cell activation into a profibrogenic phenotype occurring during inflammation and b) the emerging role of RECK in..."

Preclinical • Cardiovascular • Hepatology • Immunology • Inflammation • Non-alcoholic Steatohepatitis • Reperfusion Injury • MMP2 • MMP9

Obeticholic Acid Reduces Kidney Matrix Metalloproteinase Activation Following Partial Hepatic Ischemia/Reperfusion Injury in Rats. (PubMed, Pharmaceuticals (Basel)) - "We have previously demonstrated that the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) protects the liver via downregulation of hepatic matrix metalloproteinases (MMPs) after ischemia/reperfusion (I/R), which can lead to multiorgan dysfunction. The same trend occurred for tissue TNF-alpha and IL-6. Although the underlying mechanisms need further investigation, this is the first study showing, in the kidney, beneficial effects of OCA by reducing TNF-alpha-mediated expression of MMPs after liver I/R."

Journal • Preclinical • Reperfusion Injury • IL6 • MMP2 • MMP9 • TIMP1 • TIMP2 • TNFA

[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] THE NOVEL FARNESOID X RECEPTOR LIGAND TC-100 PROTECTS FROM LIVER INJURY VIA MODULATION OF THE INTESTINAL MICROBIOTA (UEGW 2021) - "Intestinal activation of FXR achieved by its novel ligand TC-100 modulates BA homeostasis and intestinal microbiota preventing early signs of cholestatic hepatic damage. Preliminary analysis performed on our data associated microbial changes to the modulation of FXR-dependent metabolic activities such as lipid and protein biosynthesis, glycolysis/gluconeogenesis, the biosynthesis of unsaturated fatty acids and the glycerophospholipid metabolism. Further analysis will aid in deepening our understanding of this hepatoprotection."

Cholestasis • Hepatology • Immunology • Liver Failure • Metabolic Disorders

"Too many FXR agonists for NASH! Which one is best in class? To be determined with emerging data! @VladRatziu @InterceptPharma @EnantaPharma @GileadSciences @NashTagConf @anitakohli @ann_MooreNP @Tomah_Hawk" (@AlkhouriNaim)

Hepatology • Non-alcoholic Steatohepatitis

[VIRTUAL] The FXR agonist obeticholic acid decreases matrix metalloproteinase activity via RECK and TIMP modulation in hepatic ischemia/reperfusion injury (EASL-ILC-I 2020) - "Our results demonstrate the ability of OCA to limit the hepatic activation of MMP-2 and MMP-9 that occurs during liver I/R damage, probably via timely recovery of RECK and TIMPs protein levels. This is supported by an inverse correlation between MMP activity versus RECK and a positive correlation between MMP activity versus iNOS. While further studies will clarify the sequence of alterations and cause-effect patterns, these results suggest that changes in RECK protein may have therapeutic potential in MMP modulation during hepatic I/R damage."

Reperfusion Injury • MMP2 • MMP9 • TIMP1

ENHANCED SUSCEPTIBILITY TO ALCOHOLIC LIVER DISEASE IN FXR DEFICIENT MICE IS LINKED TO ALTERED ETHANOL METABOLISM (AASLD 2019) - "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."

Preclinical • CYP2E1 • IL1B • MMP9

BILIARY AND PLASMA BILE ACID PROFILING DURING OBETICHOLIC ACID TREATMENT IN PATIENTS WITH PRIMARY BILIARY CHOLANGITIS AND NON-ALCOHOLIC STEATOHEPATITIS AND IN HEALTHY VOLUNTEERS (AASLD 2019) - "Background: The nuclear farnesoid X receptor (FXR) agonist obeticholic acid (OCA) has shown promising anticholestatic and antifibrotic effects in primary biliary cholangitis (PBC) and non-alcoholic steatohepatitis (NASH), respectively, and is approved as 2nd line treatment in PBC. Our novel and therapeutically relevant findings indicate that OCA induces remarkable UDCA enrichment in bile of UDCA-treated PBC patients and a shift from glycine to less toxic taurine conjugates in NASH patients and HV. Plasma endogenous bile acids decreased during OCA treatment in PBC and HV and tended to decrease in NASH."

Clinical • Late-breaking abstract

SAFETY, PHARMACOKINETICS AND PHARMACODYNAMICS OF OBETICHOLIC ACID IN PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS AND FIBROSIS OR CIRRHOSIS (AASLD 2019) - "Both studies included extensive serial PK sampling performed on Day 1 and the last day of the respective study (Day 85 or Day 28) as well as, sampling for quantitation of PD markers of FXR activation (FGF-19 and C4). There were no SAEs in either study. Daily OCA at 10 mg and 25 mg was generally safe and well tolerated. Plasma exposure of total OCA was highest in F4 patients, however liver concentrations were similar or modestly higher with higher fibrosis score. Results are consistent with a disproportionate increase in plasma exposure of OCA in more advanced patients relative to the liver exposure (primary site of action for therapy)."

Clinical • PK/PD data

POSITIVE RESULTS FROM REGENERATE: A PHASE 3 INTERNATIONAL, RANDOMIZED, PLACEBO-CONTROLLED STUDY EVALUATING OBETICHOLIC ACID TREATMENT FOR NONALCOHOLIC STEATOHEPATITIS (UEGW 2019) - "Introduction: Obeticholic acid (OCA), an FXR agonist, improved both fibrosis and histologic features of nonalcoholic steatohepatitis (NASH) in the Ph2 FLINT study. Treatment with OCA 25 mg improved liver fibrosis, key histologic features of steatohepatitis and liver biochemistry, demonstrating consistent efficacy with an overall AE profile similar to previous studies."

Clinical • P3 data

Evaluation of anti-fibrotic properties of OCA and INT-767 in an in vitro system of NAFLD (EASL-ILC 2019) - "In this study, we assessed the anti-fibrotic effect of the FXR agonist obeticholic acid (OCA, INT-747) and the dual FXR/TGR5 agonist INT-767 in a well-established in vitro co-culture model reproducing NASH development. Human hepatoma (Huh7) and hepatic stellate (HSCs, LX2) cells were simultaneously co-cultured (SCC) at a 5:1 ratio and exposed to 1200 µM of free fatty acids (FFAs) without or with OCA or INT-767. All FXR agonists tested reduce collagen deposition. OCA exerts a more potent and long-lasting effect (-50% vs. FFAs) compared to INT-767 (-30%), tropifexor (-20%) and GS-9674 (-35%)."

Preclinical

Morphometric collagen analysis discerns anti-fibrotic effects of INT-767 and OCA in NASH mouse models using second harmonic generation imaging (EASL-ILC 2019) - "Here, we assess the anti-fibrotic efficacy of INT-767 (a dual FXR/TGR5 agonist) and obeticholic acid (OCA) (an FXR agonist) in a diet-induced NASH mouse model with a focus on the morphometric quantification of the fibrosis phenotype imaged by Second Harmonic Generation (SHG). These data confirm that morphometric analysis of SHG images is an effective label-free method to describe and quantify the severity and progression of liver fibrosis and may differentiate pharmacological agents. These data enrich previous findings obtained using conventional methods."

Obeticholic acid reduces matrix metalloproteinases activity via iNOS modulation in hepatic ischemia/reperfusion injury (EASL-ILC 2019) - "Background and aims: We have previously shown that the Farnesoid X Receptor (FXR) agonist obeticholic acid (OCA) decreases inducible NOS (iNOS) content in ischemia/reperfusion (I/R)-treated rats (Ferrigno A et al., 2018). In liver submitted to I/R a reduction in MMPs activity by OCA administration was found. For the first time, we have shown an MMPs biliary content that was modulated by the treatment with OCA. These data are also associated with lower levels of biliary markers of cholangiocyte injury and biliary reabsorption of glucose, this last index of cholangiocyte function (Tabibian JH et al., 2013)."

"Now we are looping for FXR intercept safety ?" (@ToledanoManu)

Clinical