tropifexor (LJN452) / Novartis - LARVOL DELTA

Clinical trial: A Phase 2 Randomised Platform Study to Assess Monotherapy and Combination Treatment Regimens in Metabolic Dysfunction-Associated Steatohepatitis. (PubMed, Aliment Pharmacol Ther) - P2 | "LYS006 20 mg bid monotherapy and LYS006 20 mg bid+tropifexor 200 μg qd therapy were well tolerated with the exception of a high frequency of pruritus in the combination arm, consistent with the now known pharmacologic effect of farnesoid X receptor agonists. The greater reductions in ALT and liver fat in the combination arm versus monotherapy arm were similar to those observed with tropifexor as monotherapy in a previously reported phase 2 clinical trial, and clear additional benefit was not observed in combination treatment with LYS006. This study design allowed for rapid screening of potentially high efficacy drug combinations in MASH."

Journal • Monotherapy • P2 data • Dermatology • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Pruritus

NLRP3 Inhibitor, NT-0796 Reduces MASH in Preclinical Models (OBESITY WEEK 2025) - "Reversal of High Fat Diet-Induced Obesity, Systemic Inflammation, and Astrogliosis by the NLRP3 Inflammasome Inhibitors NT-0249 and NT-0796...The Farnesoid X receptor agonist, Tropifexor, (0.5 mg, p.o. q.d.) was evaluated alongside... These findings indicate that NLRP3 inhibition with NT-0796 reduces key MASH-associated pathologies, including hepatic steatosis and fibrosis. Targeting hepatic NLRP3 may offer added therapeutic benefit for individuals at risk of MASH. Further translational studies are needed to explore the extent to which these mechanisms(s) may contribute to liver disease in patient cohorts."

Preclinical • Fibrosis • Genetic Disorders • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Obesity • NLRP3

FXR-targeted drug discovery: Recent advances and therapeutic perspectives. (PubMed, Eur J Med Chem) - "In 2016, obeticholic acid (OCA) received approval from FDA for marketing...Notable candidates include Tropifexor (for non-alcoholic steatohepatitis, NASH), Cilofexor (for PBC), and Nidufexor (for diabetic nephropathy). This review delineates the structural features and biological functions of FXR, analyzes molecular mechanisms underpinning its signal transduction pathways and disease pathogenesis, and highlights molecular design strategies and structure-activity relationship (SAR) advancements in FXR agonists. These insights aim to provide a theoretical foundation for rationally designing novel, potent FXR agonists."

Journal • Diabetic Nephropathy • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Nephrology • Primary Biliary Cholangitis • Renal Disease

Interaction between crizotinib and tropifexor through in vitro and in vivo studies. (PubMed, PeerJ) - "Our study developed this UPLC-MS/MS method for the accurate and sensitive quantitative determination of crizotinib and 2-Keto crizotinib concentrations, and elucidated the inhibitory effect of tropifexor on crizotinib metabolism and its inhibitory mechanism. The results of this study will support the necessity of monitoring crizotinib plasma concentrations when used in combination therapy."

Journal • Preclinical • Hepatology • Lung Cancer • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Farnesoid X Receptor Agonist Tropifexor Improves Intestinal Defense Response and Epithelial Barrier Function in Neonatal Piglets Receiving Parenteral Nutrition. (PubMed, FASEB J) - "Consequently, pharmacological activation of FXR by TXR substantially induced EPCAM expression and enhanced epithelial barrier integrity, particularly in the PDOs derived from pediatric patients receiving PN, while no significant changes were found in those derived from patients receiving oral feeding. In conclusion, this study suggested that TXR treatment could alleviate PN-induced impairment of defense responses and epithelial barrier dysfunction, potentially offering a preventive strategy for neonates receiving long-term PN therapy."

Journal • Pediatrics • EPCAM • IFNG

Obeticholic Acid and Other Farnesoid-X-Receptor (FXR) Agonists in the Treatment of Liver Disorders. (PubMed, Pharmaceuticals (Basel)) - "Obeticholic acid (OCA), a semisynthetic derivative of chenodeoxycholic acid (CDCA), initially named 6-ethyl-CDCA or INT-747, is the first in a class of FXR ligands that have been approved for clinical use for the treatment of patients with primary biliary cholangitis (PBC) who are unresponsive or intolerant to ursodeoxycholic acid...Here, we review potential applications of OCA in PBC patients in the context of a highly competitive therapeutic landscape, generated by the approval for clinical use of safer and effective second-line therapies, including PPARs agonists such as elafibranor and seladelapar and increased off-label use of fibrates. The current status of development of second-generation FXR agonists such as cilofexor, tropifexor, and vonafexor and their potential in the treatment of liver fibrosis in MASH will be discussed and compared to recently approved therapies, resmetirom, and semaglutide, a GLP-1 agonist. Finally, since some of the novel candidates for..."

Journal • Review • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Primary Biliary Cholangitis

Targeting FXR in Hepatocytes: A Promising Approach to Enhance Fibrinolysis and Reduce Deep Vein Thrombosis Risk. (PubMed, Blood) - "Importantly, tropifexor treatment of obese mice lowered plasma PAI-1 levels and further alleviated fibrinolysis and the DVT load. These findings suggest that targeting FXR in hepatocytes may improve fibrinolysis and reduce DVT risk."

Journal • Cardiovascular • Genetic Disorders • Hematological Disorders • Obesity • Thrombosis • Venous Thromboembolism • SERPINE1

Subgroup definition and monitoring of liver fibrosis evolution in patients with MASH bridging fibrosis based on objective measurements of septa parameters using digital pathology with artificial intelligence analyses (EASL 2025) - P2 | " Paired liver biopsies from 57 patients, all with bridging fibrosis, part of the FLIGHT-FXR trial (NCT02855164): placebo (PLB, n=17), tropifexor (TXR, n=40) were included... SHG/TPEF microscopy with AI offers precise insights into fibrosis dynamics in MASH F3 patients, revealing details not detectable by conventional methods. Its use in clinical trials can optimise patients' selection and stratification, as well as dose-response analyses. These findings highlight the potential of digital pathology for an objective subgroup separation of F3 stage, informing future studies."

Clinical • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis

Bile Acids-Based Therapies for Primary Sclerosing Cholangitis: Current Landscape and Future Developments. (PubMed, Cells) - "The ursodeoxycholic acid (UDCA) has been widely used, although there is no evidence that the use of UDCA delays the time to liver transplant or increases survival...The largest group of these new agents is represented by FXR agonists, including obeticholic acid, cilofexor, and tropifexor...Additional agents under evaluation are PPARs (elafibranor and seladelpar), anti-itching agents such as MAS-related G-protein-coupled receptors antagonists, and anti-fibrotic and immunosuppressive agents. Drugs targeting gut bacteria and bile acid pathways are also under investigation, given the strong link between PSC and gut microbiota."

Journal • Review • Cholestasis • Fibrosis • Hepatology • Immunology • Transplantation • FGF19

Managing bile acid diarrhea: aspects of contention. (PubMed, Expert Rev Gastroenterol Hepatol) - "They are relatively inexpensive, and better-quality data is now available for colesevelam...The GLP-1 receptor agonist, liraglutide, is also effective, although mechanisms of action and whether this effect is common to other class members is unclear...The role of dietary factors in symptom development is a major patient concern, needing more formal studies. To build on recent findings, bile acid diarrhea needs further investment into causes, diagnosis and therapy to guide present and future patient care."

Journal • Review • Gastrointestinal Disorder • Inflammation

Digital quantitation of bridging fibrosis and septa reveals changes in natural history and treatment not seen with conventional histology. (PubMed, Liver Int) - "SHG/TPEF microscopy with AI provides greater granularity and precision in assessing fibrosis dynamics in patients with bridging fibrosis, thus advancing knowledge development of fibrosis evolution in natural history and in clinical trials."

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

Impaired intestinal FXR signaling is involved in aberrant stem cell function leading to intestinal failure-associated liver disease in pediatric patients with short bowel syndrome. (PubMed, FASEB J) - "Interestingly, however, treatment with Tropifexor in PDOs (an agonist for FXR) only enhanced FAO capacity, without improvement in ISC function and enterocyte proliferation. In conclusion, these findings suggested that impaired FXR may accelerate the depletion of LGR5 + ISC population through disrupted FAO processes, which may serve as a new potential target of preventive interventions against IFALD for SBS patients."

Journal • Gastrointestinal Disorder • Hepatology • Pediatrics • Short Bowel Syndrome • CPT1A

FARNESOID X RECEPTOR AGONIST TROPIFEXOR AMELIORATES INTESTINAL METABOLIC DISTURBANCE AND EPITHELIAL BARRIER DYSFUNCTION IN NEONATAL PIGLETS RECEIVING PARENTERAL NUTRITION (ESPGHAN 2024) - "TXR treatment could ameliorate PN-induced intestinal metabolic disturbance and epithelial barrier dysfunction, potentially providing preventative strategies against intestinal injury."

Metabolic Disorders • Pediatrics • CLDN2 • TGFBI

Investigational farnesoid X receptor agonists for the treatment of primary biliary cholangitis. (PubMed, Expert Opin Investig Drugs) - "Up to 40% of Primary biliary cholangitis (PBC) patients have a suboptimal response to Ursodeoxycholic acid (UDCA). Close to half of such patients show a remarkable improvement when additionally treated with Obeticholic acid (OCA) but have a dose-dependent increase of pruritus...However, as with OCA, pruritus remains a concern with the newer drugs despite targeted chemical modifications to increase FXR specificity. Directing future resources toward studying the molecular mechanisms behind pruritus may lead to better drug design and efficacious yet safer drugs."

Journal • Review • Dermatology • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus

Hammerhead-type FXR agonists induce an enhancer RNA Fincor that ameliorates nonalcoholic steatohepatitis in mice. (PubMed, Elife) - "We show that Fincor is specifically induced by the hammerhead-type FXR agonists, including GW4064 and tropifexor...Overall, our findings highlight that pharmacological activation of FXR by hammerhead-type agonists induces a novel eRNA, Fincor, contributing to the amelioration of NASH in mice. Fincor may represent a new drug target for addressing metabolic disorders, including NASH."

Journal • Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Primary Biliary Cholangitis

Evaluation of Alternative Treatment Strategies for Bile Acid Malabsorption in Inflammatory Bowel Disease Patients: A Network Meta-Analysis. (PubMed, J Clin Med Res) - "Compared to colesevelam and the placebo, liraglutide was more efficient in decreasing fecal bile acid concentration (liraglutide; MD = -19, 95% CI (-37.61, -0.39)). Tropifexor has been identified as the most successful medication in mitigating BAM symptoms. To ensure more accurate results, there is a need for randomized controlled clinical trials that involve a larger participant pool."

Clinical • Journal • Retrospective data • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • FGF19

Herb-drug interactions of silybinin and cilofexor in beagle dogs based on pharmacokinetics by UPLC-MS/MS. (PubMed, Front Pharmacol) - " The plasma sample protein of the beagles were rapidly sedimented with acetonitrile, and cilofexor and tropifexor (internal standard, ISTD) were separated by gradient elution using a 0.1% formic acid aqueous solution and acetonitrile as the mobile phase. The Cmax of cilofexor in group B was 49.62% higher than that in group A, whereas the AUC(0-t) and AUC(0-∞) of cilofexor in group B were 47.85% and 48.52% higher, respectively, than those in group A. Meanwhile, the t1/2 extended from 7.84 h to 9.45 h, CL and Vz decreased in Group B. A novel UPLC-MS/MS approach was successfully applied for the measurement of cilofexor in beagle dog plasma. Silybinin can alter the pharmacokinetics of cilofexor in beagle dogs, thereby increasing plasma exposure to cilofexor."

Journal • PK/PD data

Farnesoid X receptor agonist tropifexor detoxifies ammonia by regulating the glutamine metabolism and urea cycles in cholestatic livers. (PubMed, Eur J Pharmacol) - "Mechanically, TXR activating FXR to increase express enzymes that regulating ureagenesis and glutamine synthesis through a transcriptional approach. Together, these results suggest that TXR may have therapeutic implications for hyperammonemic conditions in cholestatic livers."

Journal • Cholestasis • Fibrosis • Gastroenterology • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Liver Failure • ASS1

ELIVATE: Efficacy, Safety and Tolerability of the Combination of Tropifexor & Licogliflozin and Each Monotherapy, Compared With Placebo in Adult Patients With NASH and Liver Fibrosis. (clinicaltrials.gov) - P2 | N=234 | Terminated | Sponsor: Novartis Pharmaceuticals | Completed ➔ Terminated; The sponsor made a business decision to stop development of the trial drugs. The decision to stop the trial early was not because of any safety concerns.

Combination therapy • Monotherapy • Trial termination • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Non-alcoholic Steatohepatitis

Rational design of FXR agonists: a computational approach for NASH therapy. (PubMed, Mol Divers) - "Utilizing tropifexor as a reference molecule, we generated a shape-based pharmacophore model with seven features, identifying key binding requirements within the FXR active site...To assess its dynamic stability, we subjected DB15416 to molecular dynamics simulations, confirming its suitability as a FXR agonist. These findings suggest that DB15416 holds promise as a FXR agonist for NASH treatment, which can be evaluated by experimental studies."

Journal • Cardiovascular • Hepatology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • FGF21 • PPARA

CLINICAL TRANSLATABILITY OF THE GAN DIET-INDUCED OBESE AND BIOPSY-CONFIRMED MOUSE MODEL OF NON-ALCOHOLIC STEATOHEPATITIS (AASLD 2023) - "GAN DIO-NASH mice (n=14-18 per group) were administered resmetirom (THR-β agonist, 3 mg/kg, QD, PO), semaglutide (GLP-1 receptor agonist, 30 nmol/kg, SC, QD), obeticholic acid (FXR agonist, 30 mg/kg, PO, QD), tropifexor (FXR agonist, 0.3 mg/kg, PO, QD), cilofexor (FXR agonist, 30 mg/kg, PO, QD), lanifibranor (pan-PPAR agonist, 30 mg/kg, PO, QD), elafibranor (PPAR-α/δ agonist, 30 mg/kg, PO, QD), seladelpar (PPAR-δ agonist, 10 mg/kg, PO, QD), firsocostat (ACC inhibitor, 5 mg/kg, PO, QD), cenicriviroc (CCR2/5 receptor antagonist, 100 mg/kg, PO, BID), or vehicle for 12 weeks. GAN DIO-NASH mice faithfully reproduce histological outcomes of several compounds profiled in clinical trials for NASH, highlighting clinical translatability and utility of the model in preclinical drug development."

Biopsy • Preclinical • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Obesity • CCR2

Tropifexor, a selective non-acid farnesoid X receptor agonist, improved nonalcoholic steatohepatitis in a phase 2 trial, but several issues remain to be resolved. (PubMed, Hepatobiliary Surg Nutr) - No abstract available

Journal • P2 data • Genetic Disorders • Hepatology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis

The Efficacy of Treatments for Bile Acid Diarrhea: A Systematic Review and Meta-Analysis (ACG 2023) - "BA therapies evaluated were cholestyramine, colesevelam, tropifexor, and aldafermin. Database search resulted in 1143 citations. 186 publications passed screening. Ultimately, 9 studies involving 232 patients were included in qualitative review and summarized in the Table ."

Retrospective data • Review • Gastrointestinal Disorder

COMPARATIVE EFFICACY OF PHARMACOLOGIC THERAPIES FOR LIVER STEATOSIS AND FIBROSIS IN PATIENT WITH NONALCOHOLIC FATTY LIVER DISEASE BASED ON MAGNETIC RESONANCE IMAGING BIOMARKERS: SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS (UEGW 2023) - "In terms of individual agents, efruxifermin, aldafermin, semaglutide, liraglutide, pioglitazone, vitamin E, tropifexor and resmetirom were superior to placebo with MDs ranging from -13.5% for efruxifermin to -4.0% for liraglutide. Pioglitazone and semaglutide are the most efficacious glucose-lowering agents for LFC reduction in patients with NALFD. Among non-glucose-lowering agents, efruxifermin, vitamin E and tropifexor can lead to significant steatosis reduction. Combination treatments, from different drugs classes seem promising for the management of NAFLD."

Biomarker • MRI • Retrospective data • Review • Fibrosis • Hepatology • Immunology • Non-alcoholic Fatty Liver Disease • FGF

Inhibiting Wnt signaling reduces cholestatic injury by disrupting the inflammatory axis. (PubMed, Cell Mol Gastroenterol Hepatol) - "Inhibiting Wnt signaling suppresses cholangiocyte activation and disrupts the NF-κB-dependent inflammatory axis, reducing cholestatic-induced injury."

Journal • Cholestasis • Fibrosis • Hepatology • Immunology • Inflammation • ABCB4