cilofexor (GS-9674) / Gilead - LARVOL DELTA

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

Cilofexor in non-cirrhotic primary sclerosing cholangitis (PRIMIS): a randomised, double-blind, multicentre, placebo-controlled, phase 3 trial. (PubMed, Lancet Gastroenterol Hepatol) - P3 | "Cilofexor did not significantly reduce the rate of fibrosis progression (vs placebo) in participants with non-cirrhotic PSC. A greater percentage of cilofexor-treated participants had pruritus than placebo-treated participants; this study provides valuable harms data for cilofexor and other drugs in its class."

Journal • P3 data • Dermatology • Fibrosis • Immunology • Infectious Disease • Liver Cirrhosis • Novel Coronavirus Disease • Pain • Pruritus

A RANDOMIZED, PLACEBO-CONTROLLED, PHASE 2 STUDY OF THE SAFETY AND EFFICACY OF COMBINATION TREATMENT WITH SEMAGLUTIDE, CILOFEXOR AND FIRSOCOSTAT IN PATIENTS WITH COMPENSATED CIRRHOSIS DUE TO METABOLIC DYSFUNCTION-ASSOCIATED STEATOHEPATITIS (WAYFIND) (AASLD 2025) - P2 | "SEMA+CILO/FIR did not achieve the primary endpoint of fibrosis improvement compared with PBO based on pathologist review. However, SEMA-containing regimens achieved MASH resolution and CILO/FIR achieved fibrosis improvement compared with PBO. Interestingly, PathAI showed clinical benefit with SEMA+CILO/FIR, suggesting that combination therapies should be explored for MASH."

Clinical • P2 data • Constipation • Fibrosis • Gastroenterology • Gastrointestinal Disorder • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

Recent Advances in Primary Sclerosing Cholangitis Pathogenesis and Targets for Therapeutic Intervention (AASLD 2025) - "Treatment with nor-ursodeoxycholic acid (norUDCA) and nonsteroidal farnesoid X receptor agonist (cilofexor) are being tested in phase 3 clinical trials to assess improvement of liver function in patients with PSC. Review current treatments for PSC. Discuss novel experimental approaches for the treatment of PSC."

Fibrosis • Hepatology • Immunology • Liver Failure

Acetyl-CoA Carboxylase Inhibitors for Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. (PubMed, Pharmaceuticals (Basel)) - "Interventions included firsocostat, clesacostat, and combined regimens with semaglutide, selonsertib, and cilofexor or ervogastat. Dual ACC 1/2 inhibitors reduce hepatic steatosis and ALT levels but do not improve fibrosis. Their consistent association with hypertriglyceridemia raises concerns regarding potential long-term cardiometabolic risks, particularly in NAFLD patients with metabolic dysfunction."

Journal • Retrospective data • Review • Dyslipidemia • Fibrosis • Hepatology • Hypertriglyceridemia • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease

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

Gilead culls Novo-partnered MASH candidate (FierceBiotech) - "The...dropped program was evaluating two Gilead assets, cilofexor and firsocostat, either alone or with Novo's semaglutide for the treatment of MASH, a serious liver disease that used be called nonalcoholic steatohepatitis (NASH). A phase 2 trial with 457 patients wrapped up in December 2024, but Gilead has yet to publicly disclose any data from the study...With the Novo collaboration dropped, Gilead’s fibrotic disease pipeline is now entirely empty."

Discontinued • Metabolic Dysfunction-Associated Steatohepatitis

Gilead culls Novo-partnered MASH candidate… (FierceBiotech) - "After the recent approval and launch of twice-yearly HIV prophylactic Yeztugo, Gilead is cleaning up its R&D pipeline. The Bay Area company has dropped...a Novo Nordisk-partnered combination treatment for metabolic dysfunction-associated steatohepatitis (MASH)....The...dropped program was evaluating two Gilead assets, cilofexor and firsocostat, either alone or with Novo's semaglutide for the treatment of MASH, a serious liver disease that used be called nonalcoholic steatohepatitis (NASH). A phase 2 trial with 457 patients wrapped up in December 2024, but Gilead has yet to publicly disclose any data from the study."

Pipeline update • Metabolic Dysfunction-Associated Steatohepatitis

Comparison of Pharmacological Therapies for Metabolic Dysfunction-Associated Steatohepatitis: Systematic Review and Network Meta-analysis (APASL 2025) - "For the co-primary endpoint of fibrosis improvement without MASH resolution, pegozafermin, cilofexor + firsocostat, survodutide, obeticholic acid, tirzepatide, and resmetirom were significantly better than placebo in improving ≥ 1 fibrosis stage without worsening MASH. Pegozafermin (SUCRA: 90.18), cilofexor plus firsocostat (SUCRA: 82.82), and cilofexor plus selonsertib (SUCRA: 79.62) were ranked the most effective interventions. For the co-primary endpoint of MASH resolution without worsening fibrosis, pegozafermin, survodutide, tirzepatide, efruxifermin, liraglutide, vitamin E + pioglitazone, resmetirom, semaglutide, pioglitazone, and lanifibranor were significantly better than placebo... This study provides updated rank-order efficacy of MASH pharmacological therapies for fibrosis regression and MASH resolution. These data are helpful to inform practice and clinical trial design."

Retrospective data • Review • Fibrosis • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

Comparison of pharmacological therapies in metabolic dysfunction-associated steatohepatitis for fibrosis regression and MASH resolution: Systematic review and network meta-analysis. (PubMed, Hepatology) - "This study provides updated rank-order efficacy of MASH pharmacological therapies for fibrosis regression and MASH resolution. These data are helpful to inform practice and clinical trial design."

Journal • Retrospective data • Fibrosis • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

Study of Semaglutide, and Cilofexor/Firsocostat, Alone and in Combination, in Adults With Cirrhosis Due to Nonalcoholic Steatohepatitis (NASH) (clinicaltrials.gov) - P2 | N=457 | Completed | Sponsor: Gilead Sciences | Active, not recruiting ➔ Completed

Trial completion • Fibrosis • Hepatology • Immunology • Metabolic Dysfunction-Associated Steatohepatitis

COMPARATIVE EFFICACY OF PHARMACOLOGIC THERAPIES FOR MASH IN REDUCING LIVER FAT CONTENT: SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS (AASLD 2024) - "By comparison of absolute MRI-PDFF decline at 24 weeks, aldafermin (SUCRA: 83.65), pegozafermin (SUCRA: 83.46), and pioglitazone (SUCRA: 71.67) were the most efficacious interventions. Efinopegdutide (SUCRA: 67.02), semaglutide + firsocostat (SUCRA: 62.43), and pegbelfermin (SUCRA: 61.68) were the most efficacious interventions for achieving ≥30% decline in MRI-PDFF at 24 weeks...Efruxifermin, aldafermin and pegozafermin were the most efficacious for MRI-PDFF decline at 12 weeks by both the absolute decline and achieving ≥30% decline in MRI-PDFF. At 48 weeks, Cilofexor + firsocostat, selonternib + firsocostat and cilofexor were most efficacious in absolute reduction in MRI-PDFF, while semglutide, tropifexor and tropifexor + cenicriviroc were most efficacious in achieving ≥30% decline in MRI-PDFF... This study provides an updated, relative rank-order efficacy of therapies for MASH in reducing hepatic fat as assessed by MRI-PDFF. These data may help inform the design and..."

Retrospective data • Review • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • FGF21

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

BIOMARKERS ASSOCIATE WITH FIBROSIS PROGRESSION IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS: AN AD-HOC ANALYSIS FROM THE PRIMIS STUDY (AASLD 2024) - " People with non-cirrhotic PSC were enrolled into PRIMIS study and randomized 2:1 to receive cilofexor 100 mg or placebo for 96 weeks... PSC patients with F3 fibrosis stage, higher ALP levels or IBD were at risk in fibrosis progression, which was consistent with previous reports. Our study also underscored the complexity of evaluating histological fibrosis progression. The risk factors for liver-related clinical outcomes need to be assessed in longer and larger studies for patients with non-cirrhotic PSC."

Biomarker • Clinical • Fibrosis • Gastroenterology • Gastrointestinal Disorder • Hepatology • Immunology • Inflammation • Inflammatory Bowel Disease • Liver Cirrhosis • TIMP1

ASSOCIATIONS BETWEEN BIOMARKERS AND MAGNETIC RESONANCE IMAGING-DERIVED ANALI SCORE IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS: ANALYSIS FROM THE PHASE 3 PRIMIS STUDY (AASLD 2024) - " 419 patients with large duct non-cirrhotic PSC were enrolled into PRIMIS study and randomized to receive cilofexor or placebo for 96 weeks... ANALI score correlates with BL liver fibrosis and cholestasis markers and cholangitis events over the course of the study. The association between ANALI score and other PSC related clinical events requires further exploration in future studies with longer follow up."

Biomarker • Clinical • MRI • P3 data • Cardiovascular • Cholestasis • Fibrosis • Hepatology • Immunology • Inflammatory Bowel Disease • Liver Cirrhosis • Portal Hypertension

Hepatic bile acid accretion correlates with cholestatic liver injury and therapeutic response in Cyp2c70 knockout mice with a humanized bile acid composition. (PubMed, Am J Physiol Gastrointest Liver Physiol) - "In this study, we investigated the potential of an ileal bile acid transporter (IBAT) inhibitor (SC-435) and steroidal FXR agonist (cilofexor) to modulate established hepatobiliary injury and the consequent relationship of intrahepatic bile acid content and hydrophobicity to the cholestatic liver injury phenotype...Biomarkers of liver injury increased linearly with similar hepatic thresholds for pathological accretion of hydrophobic bile acids in male and female Cyp2c70 KO mice. These findings further support targeting intrahepatic bile acid retention as a component of treatments for cholestatic liver disease."

Journal • Preclinical • Cholestasis • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Liver Failure

Pharmacokinetics and Safety of Cilofexor and Firsocostat in Healthy Japanese and Non-Japanese Participants. (PubMed, J Clin Pharmacol) - P2 | "Both study drugs were well tolerated with no clear differences in adverse events or laboratory abnormalities between Japanese and non-Japanese participants. The approximate 2-fold exposure difference of firsocostat between Japanese and non-Japanese participants at the 20 mg dose does not warrant dose reduction given the previously established safety and tolerability of once-daily doses of firsocostat up to 200 mg."

Journal • PK/PD data • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

Cilofexor in Patients with Compensated Cirrhosis Due to Primary Sclerosing Cholangitis: an Open-label Phase 1B Study. (PubMed, Clin Transl Gastroenterol) - P1 | "Escalating doses of cilofexor over 12 weeks were well tolerated and improved cholestasis markers in patients with compensated cirrhosis due to PSC (NCT04060147)."

Journal • P1 data • Cholestasis • Dermatology • Fatigue • Fibrosis • Hepatology • Immunology • Infectious Disease • Pain • Pruritus • Respiratory Diseases • FGF19

Artificial intelligence-derived granular histological markers of fibrosis from hematoxylin and eosin-stained whole slide images associate with non-invasive tests of fibrosis and prognosis to cirrhosis in patients with metabolic dysfunction-associated steatohepatitis (EASL-ILC 2024) - " We deployed NASH Explore on 4454 H&E WSIs from 3 clinical datasets (STELLAR 3 and STELLAR 4, trials of selonsertib on MASH patients with F3 or F4 fibrosis, respectively, and ATLAS, a trial testing combinations of selonsertib, cilofexor, and firsocosat in F4 MASH patients). Using NASH Explore HIFs, we showed that relative areas of pathological and nodular fibrosis positively associate with non-invasive measurement of fibrosis severity and prognosis. Further research is required to validate the association between NITs and granular histological features, which may support the assessment of MASH disease progression or regression through non-invasive surrogates of liver histopathology."

Clinical • Fibrosis • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

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

Recent advances in medical treatment for PSC (APASL 2024) - "38 Ursodeoxycholic acid (UDCA) represents the most extensively studied pharmacotherapy, demonstrating reduction in hepatic and biliary enzymes in numerous randomized controlled trials...Bezafibrate, a medication for dyslipidemia, acts as an agonist for Peroxisome Proliferator-Activated Receptor alpha (PPARα) and has been reported to decrease hepatic and biliary enzymes in PSC...Other pharmacotherapies include a Phase II randomized trial showcasing improvement in hepatic and biliary enzymes with cilofexor, a farnesoid X (FXR) receptor ligand, followed by an ongoing Phase III trial...Biliary 8. Endoscopic management of hilar obstruction"

Dyslipidemia • Fibrosis • Gastroenterology • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Cirrhosis • Metabolic Disorders • Pneumonia • Transplantation • PPARA

Development of Cilofexor, an intestinally-biased Farnesoid X Receptor agonist, for the treatment of fatty liver disease. (PubMed, J Pharmacol Exp Ther) - "Here, we examined the preclinical and clinical effects of the first-generation FXR agonist, Px-102 (4-[2-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methoxy]phenyl]cyclopropyl] benzoic acid), to enable the selection of an analog, cilofexor, with unique properties that reduced side effects yet maintained efficacy. Cilofexor is one of few remaining FXR agonists in clinical development."

Journal • Fibrosis • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Metabolic Dysfunction-Associated Steatohepatitis • Solid Tumor

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

Evaluation of the Effects of Meal Type and Acid-Reducing Agents on the Pharmacokinetics of Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor Agonist. (PubMed, Clin Pharmacol Drug Dev) - "Cilofexor is a nonsteroidal farnesoid X receptor agonist being developed in combination with firsocostat/semaglutide for the treatment of nonalcoholic steatohepatitis...Cohort 3 (n = 30, 100 mg fasting) followed a 2-period, 2-sequence crossover design and evaluated the effects of a 40-mg single dose of famotidine...With a low-fat meal, omeprazole increased cilofexor exposure to a lesser extent (Cmax 2.5-fold, AUC 2.1-fold) than fasting conditions. This study suggests that caution should be exercised when cilofexor is administered with ARAs under fed conditions; coadministration of cilofexor (100 or 30 mg) with ARAs under fasting conditions is not recommended with the current clinical trial formulations."

Journal • PK/PD data • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis

Study of Semaglutide, and the Fixed-Dose Combination of Cilofexor and Firsocostat, Alone and in Combination, in Adults With Cirrhosis Due to Nonalcoholic Steatohepatitis (NASH) (clinicaltrials.gov) - P2 | N=457 | Active, not recruiting | Sponsor: Gilead Sciences

Trial completion date • Trial primary completion date • Fibrosis • Hepatology • Immunology • Metabolic Dysfunction-Associated Steatohepatitis