INT-787 / Intercept, TES Pharma - LARVOL DELTA

Farnesoid X Receptor Agonist INT-787 Inhibits Hepatic Mitochondrial Dysfunction in a Diet-Induced ob/ob Mouse Model of MASH. (PubMed, Int J Mol Sci) - "TEM analysis showed that INT-787 reverted the mitochondrial alterations as documented by restored mitochondrial length, number of mitochondrial cristae junctions (CJs), and distance between endoplasmic reticulum (ER) and outer mitochondrial membrane (OMM) when compared with HFD groups. These results underline the involvement of the FXR pathway in the control of mitochondrial damage, thus revealing a previously undiscovered mechanism mediated by FXR activation: the upregulation of IMM protein MIC19, which is essential for maintaining cristae integrity and mitochondrial function."

Journal • Preclinical • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

FXR AGONIST INT-787 INHIBITS INFLAMMATION, FIBROSIS, SENESCENCE, AND APOPTOSIS ARREST IN HUMAN CHOLANGIOCYTES MODELING PSC (DDW 2025) - P2 | No abstract available

Fibrosis • Immunology • Inflammation

FARNESOID X RECEPTOR AGONIST INT-787 EXHIBITS HIGH INTESTINAL LOCALIZATION (DDW 2025) - "In vitro intestinal absorption of INT-787 in Caco-2 cells was low compared to FXR agonist obeticholic acid (OCA; P app(A-to-B) : 6.4 x 10 –6 cm/s vs 38.3 x 10 –6 cm/s, respectively; Figure 2 ) and even lower for tauro-INT-787 and glyco-INT-787 (P app(A-to-B) : 0.7 x 10 –6 cm/s and 0.3 x 10 –6 cm/s, respectively; Figure 2 ). Oral INT-787 is a unique FXR agonist with low intestinal absorption resulting in high gut localization, likely due to the inability of INT-787 and its metabolites to bind to IBABP. These findings further support clinical studies evaluating the therapeutic use of INT-787 in ALD, including sAH, in which the integrity of the intestinal barrier is critical."

Hepatology • Inflammation • Inflammatory Bowel Disease • FABP6

FARNESOID X RECEPTOR AGONIST INT-787 PROTECTS HUMAN LIVER ORGANOIDS FROM ALCOHOL-INDUCED INJURY (DDW 2025) - "Human liver organoids exposed to 0.5% EtOH demonstrated alcohol-induced liver injury, providing a reliable in vitro model to study ALD. INT-787 significantly reduced the effects of alcohol-induced liver injury via multiple protective mechanisms, including inhibition of steatosis, inflammation, fibrosis, oxidative stress, and apoptosis. Thus, INT-787 represents a promising molecule for clinical evaluation of ALD treatment."

Addiction (Opioid and Alcohol) • Fibrosis • Hepatocellular Cancer • Hepatology • Immunology • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Oncology • Primary Biliary Cholangitis • Solid Tumor • BAX • CYP2E1 • IL6 • PTGS2 • TGFB1 • TNFA

Intercept Announces Data to be Presented at Digestive Disease Week 2025 (GlobeNewswire) - "Intercept Pharmaceuticals...today announced 11 submitted abstracts have been accepted for presentation at Digestive Disease Week 2025, including oral presentations of data from a Phase 2 study evaluating the combination of obeticholic acid and bezafibrate in PBC, and investigational data for INT-787, a next-generation FXR agonist. The conference will be held from May 3-6 in San Diego."

Clinical data • Hepatology • Primary Biliary Cholangitis

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of INT-787, a Novel Farnesoid X Receptor Agonist, in Healthy Volunteers: A Phase 1 Trial. (PubMed, Clin Transl Sci) - "Single and multiple oral doses were generally well tolerated; 4 adverse events of mild, transient pruritus not requiring interventions were reported at higher doses. These results warrant further investigation of INT-787 in patients with liver-related disorders."

Clinical • Journal • P1 data • PK/PD data • Dermatology • Fibrosis • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Pruritus • FGF • FGF19

FXR Effect on Severe Alcohol-Associated Hepatitis (FRESH) Study (clinicaltrials.gov) - P2 | N=80 | Recruiting | Sponsor: Intercept Pharmaceuticals | N=50 ➔ 80 | Trial completion date: Mar 2025 ➔ Apr 2027 | Trial primary completion date: Dec 2024 ➔ Sep 2026

Enrollment change • Trial completion date • Trial primary completion date • Hepatology • Inflammation

FXR Effect on Severe Alcohol-Associated Hepatitis (FRESH) Study (clinicaltrials.gov) - P2 | N=50 | Recruiting | Sponsor: Intercept Pharmaceuticals | Trial completion date: Dec 2024 ➔ Mar 2025

Trial completion date • Hepatology • Inflammation

FXR AGONIST INT-787 INHIBITS INFLAMMATION, FIBROSIS, SENESCENCE, AND APOPTOSIS ARREST IN HUMAN CHOLANGIOCYTES MODELING PSC (AASLD 2024) - P2 | "Activation of the farnesoid X receptor (FXR), a ligand-activated nuclear hormone receptor that is a key regulator of bile acid homeostasis, has demonstrated clinical benefit in patients with PSC, as shown by the sustained reduction in serum alkaline phosphatase levels induced by multiple FXR agonists, including obeticholic acid in a phase 2 trial (NCT02177136). Human immortalized H69 cholangiocyte cells treated with GCDCA or LPS successfully mimicked the in vivo PSC phenotype. Treatment with INT-787 reduces cellular senescence, apoptosis resistance, inflammation, and fibrosis. INT-787 represents a promising candidate for the clinical treatment of PSC."

Cholestasis • Fibrosis • Hepatology • Immunology • Inflammation • BCL2L1 • CDKN1A • TGFB1 • VCAM1

Farnesoid X receptor agonist INT-787 protects human liver organoids from alcohol-induced injury (EASL-ILC 2024) - "Human liver organoids exposed to 0.5% EtOH demonstrated alcohol-induced liver injury, providing a reliable in vitro model to study ALD. INT-787 significantly reduced the effects of alcohol-induced liver injury via multiple protective mechanisms, including inhibition of steatosis, inflammation, fibrosis, oxidative stress, and apoptosis. Thus, INT-787 represents a promising molecule for clinical evaluation of ALD treatment."

Addiction (Opioid and Alcohol) • Fibrosis • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Oncology • Primary Biliary Cholangitis • Solid Tumor • BAX • CYP2E1 • IL6 • TGFB1 • TNFA

Farnesoid X receptor agonist INT-787 exhibits high intestinal localization (EASL-ILC 2024) - "In vitro intestinal absorption of INT-787 in Caco-2 cells was low compared to FXR agonist obeticholic acid (OCA; P app(A-to-B) : 6.4 x 10–6 cm/s vs 38.3 x 10–6 cm/s, respectively) and even lower for tauro-INT-787 and glyco-INT-787 (P app(A-to- B): 0.7 x 10–6 cm/s and 0.3 x 10–6 cm/s, respectively). Oral INT-787 is a unique FXR agonist with low intestinal absorption resulting in high gut localization, likely due to the inability of INT-787 and its metabolites to bind to IBABP. These findings further support clinical studies evaluating the therapeutic use of INT-787 in alcohol-associated liver disease, including sAH, in which the integrity of the intestinal barrier is critical."

Hepatology • Inflammation • Inflammatory Bowel Disease • FABP6

Increased hepatoprotective effects of the novel farnesoid X receptor agonist INT-787 versus obeticholic acid in a mouse model of nonalcoholic steatohepatitis. (PubMed, PLoS One) - "INT-787 modulated a substantially greater number of genes associated with FXR signaling, lipid metabolism, and stellate cell activation relative to OCA in hepatic tissue. These findings demonstrate greater efficacy of INT-787 treatment compared with OCA in improving liver histopathology, decreasing liver enzyme levels, and enhancing gene regulation, suggesting superior clinical potential of INT-787 for the treatment of NASH and other chronic liver diseases."

Journal • Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • COL1A1

FXR Effect on Severe Alcohol-Associated Hepatitis (FRESH) Study (clinicaltrials.gov) - P2 | N=50 | Recruiting | Sponsor: Intercept Pharmaceuticals | Phase classification: P2a ➔ P2 | Trial completion date: Dec 2023 ➔ Dec 2024 | Trial primary completion date: Dec 2023 ➔ Dec 2024

Phase classification • Trial completion date • Trial primary completion date • Hepatology • Inflammation

A PHASE 2a, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY EVALUATING THE SAFETY, TOLERABILITY, EFFICACY, AND PHARMACOKINETICS OF INT-787 IN SUBJECTS WITH SEVERE ALCOHOL-ASSOCIATED HEPATITIS: STUDY DESIGN, OBJECTIVES, AND NOVEL ASSESSMENTS (AASLD 2023) - "INT-787 is a promising FXR agonist with preclinical data supporting its exploration in the treatment of sAH."

Clinical • P2a data • PK/PD data • Fibrosis • Hepatology • Immunology • Inflammation • Systemic Inflammatory Response Syndrome • Transplantation

FXR agonists INT-787 and OCA increase RECK and inhibit liver steatosis and inflammation in diet-induced ob/ob mouse model of NASH. (PubMed, Liver Int) - "INT-787 is superior to OCA in controlling specific cell types and clinically relevant anti-inflammatory and antifibrotic molecular mechanisms in NASH."

Journal • Preclinical • Fibrosis • Hepatology • Inflammation • Non-alcoholic Steatohepatitis • Reperfusion Injury • ADAM10 • ADAM17 • IL1B • MMP2 • MMP9 • TGFB1

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

Enrollment open • Hepatology • Inflammation

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

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