tropifexor (LJN452) / Novartis - LARVOL DELTA

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

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=235 | Completed | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Completed | N=380 ➔ 235 | Trial completion date: Mar 2024 ➔ Oct 2022 | Trial primary completion date: Apr 2023 ➔ Oct 2022

Combination therapy • Enrollment change • Monotherapy • Trial completion • Trial completion date • Trial primary completion date • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Non-alcoholic Steatohepatitis

A deep exploration of bridging fibrosis evolution and individual septa parameters in NASH using quantitative second harmonic generation imaging reveals fibrosis changes in natural history and treatment-induced not seen with conventional histology (EASL-ILC 2023) - P2 | " Paired liver biopsies from 57 patients [placebo, n=17) or tropifexor (TXR) [n=40], all with bridging fibrosis (F3 stage) according to the CRN scoring system at baseline (BL), who participated in the FLIGHT- FXR clinical trial (NCT02855164), were included in this study... SHG/TPEF microscopy with AI provides greater granularity and precision in assessing fibrosis dynamics in NASH patients with bridging fibrosis and reveal worsening or improvement undetectable by conventional microscopy, enhancing the understanding of pathogenesis and treatment response. These results support the use of digital approaches for quantitative fibrosis assessment, in the natural history and treatment of NASH and other liver diseases."

Clinical • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Non-alcoholic Steatohepatitis

A deep exploration of bridging fibrosis evolution and individual septa parameters in NASH using quantitative second harmonic generation imaging reveals fibrosis changes in natural history and treatment-induced not seen with conventional histology (EASL-ILC 2023) - P2 | " Paired liver biopsies from 57 patients [placebo, n=17) or tropifexor (TXR) [n=40], all with bridging fibrosis (F3 stage) according to the CRN scoring system at baseline (BL), who participated in the FLIGHT- FXR clinical trial (NCT02855164), were included in this study... SHG/TPEF microscopy with AI provides greater granularity and precision in assessing fibrosis dynamics in NASH patients with bridging fibrosis and reveal worsening or improvement undetectable by conventional microscopy, enhancing the understanding of pathogenesis and treatment response. These results support the use of digital approaches for quantitative fibrosis assessment, in the natural history and treatment of NASH and other liver diseases."

Clinical • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Non-alcoholic Steatohepatitis

HistoIndex SHG/TPE imaging and AI-based technology reveals dose-dependent effectiveness of Tropifexor for NASH patients in Nature Medicine (PRNewswire) - "Says Professor Arun J. Sanyal...'The findings highlight the potential of AI-based SHG/TPE digital pathology that might transform how liver biopsies are assessed and evaluated to determine treatment efficiency and provide more precise and personalized diagnostics for individuals with liver disease. I am hopeful that these findings will encourage greater adoption of SHG/TPE digital pathology with AI analyses in liver biopsy evaluation, ultimately leading to improved patient outcomes.'"

Media quote

Tropifexor plus cenicriviroc combination versus monotherapy in non-alcoholic steatohepatitis: Results from the Phase 2b TANDEM study. (PubMed, Hepatology) - "The safety profile of TXR + CVC combination was similar to respective monotherapies, with no new signals. TXR monotherapy showed sustained ALT and body weight decreases. No substantial incremental efficacy was observed with TXR + CVC combination on ALT, body weight, or in histological endpoints compared with monotherapy."

Journal • Monotherapy • P2b data • Dermatology • Fibrosis • Hepatology • Immunology • Non-alcoholic Steatohepatitis • Pruritus

Recombinant Porcine FGF19 Decreases Bile Acid Synthesis in Preterm Pigs (PAS 2023) - "Pigs that received rpFGF19 had significantly higher plasma FGF19, peaking at 780 ng/mL at 5 min post infusion but remaining high (40 ng/mL) in the first 12 hours of the pharmacokinetic study compared to control pigs (0.80 ng/mL). TRO5 and TRO25 treatment yielded similar levels of FGF19 12 hours after administration (7.0 ng/mL) while control pigs remained low (0.78 pg/mL). FGF19, TRO5, and TRO25 treatments resulted in lower relative expression of hepatic CYP7A1 and lower plasma levels of bile acid precursor C4."

Preclinical • Prematurity • CYP1A1 • FGF19

[VIRTUAL] Digital pathology with artificial intelligence analyses reveal new dynamics of treatment-induced fibrosis regression in nonalcoholic steatohepatitis (EASL-ILC 2021) - P2 | "The aim of this exploratory analysis was to understand the fibrosis dynamics and its relation to steatosis reduction after treatment with tropifexor (TXR), a non-bile acid farnesoid X receptor (FXR) agonist, in patients with NASH partici- pating in FLIGHT-FXR study (NCT02855164)... Following therapies that reduce hepatic lipid load and lipotoxicity, fibrosis regression is initially seen in the perisinusoidal regions, around areas of steatosis reduction. Digital pathology provides new insights in the dynamics of fibrosis regression, which are not captured by conventional staging systems."

Addiction (Opioid and Alcohol) • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Non-alcoholic Steatohepatitis • MRI