Volixibat in adults with non-alcoholic steatohepatitis: 24-week interim analysis from a randomized, phase II study
Open accessAbstract
BACKGROUND & AIMS: Volixibat is an inhibitor of the apical sodium-dependent bile acid transporter (ASBT) that has been hypothesized to improve non-alcoholic steatohepatitis (NASH) by blocking bile acid reuptake and stimulating hepatic bile acid production. We studied the safety, tolerability and efficacy of volixibat in patients with NASH. METHODS: In this double-blind, phase II dose-finding study, adults with ≥5% steatosis and NASH without cirrhosis (N = 197) were randomized to receive volixibat (5, 10 or 20 mg) or placebo once daily for 48 weeks. The endpoints of a predefined interim analysis (n = 80), at week 24, were: ≥5% reduction in MRI-proton density fat fraction and ≥20% reduction in serum alanine aminotransferase levels. The primary endpoint was a ≥2-point reduction in non-alcoholic fatty liver disease activity score without worsening fibrosis at week 48. RESULTS: Volixibat did not meet either interim endpoint; the study was terminated owing to lack of efficacy. In participants receiving any volixibat dose, mean serum 7-alpha-hydroxy-4-cholesten-3-one (C4; a biomarker of bile acid synthesis) increased from baseline to week 24 (+38.5 ng/ml [SD 53.18]), with concomitant decreases in serum total cholesterol (-14.5 mg/dl [SD 28.32]) and low-density lipoprotein cholesterol (-16.1 mg/dl [SD 25.31]). These changes were generally dose-dependent. On histological analysis, a greater proportion of participants receiving placebo (38.5%, n = 5/13) than volixibat (30.0%, n = 9/30) met the primary endpoint. Treatment-emergent adverse events (TEAEs) were mainly mild or moderate. No serious TEAEs were related to volixibat. Diarrhoea was the most common TEAE overall and the most common TEAE leading to discontinuation. CONCLUSIONS: Increased serum C4 and decreased serum cholesterol levels provide evidence of target engagement. However, inhibition of ASBT by volixibat did not elicit a liver-related therapeutic benefit in adults with NASH. LAY SUMMARY: A medicine called volixibat has previously been shown to reduce cholesterol levels in the blood. This study investigated whether volixibat could reduce the amount of fat in the liver and reduce liver injury in adults with an advanced form of non-alcoholic fatty liver disease. Volixibat did not reduce the amount of fat in the liver, nor did it have any other beneficial effect on liver injury. Participants in the study generally tolerated the side effects of volixibat and, as in previous studies, the main side effect was diarrhoea. These results show that volixibat is not an effective treatment for people with fatty liver disease. CLINICAL TRIAL IDENTIFIER: NCT02787304.
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Clinical studies in human NASH with resins and ASBT inhibitors have so far been disappointing.
“However, clinical studies in human NASH with resins and ASBT inhibitors have so far been disappointing.202”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [202]
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- IP, investigational product; m, number of events; n, number of participants experiencing the event; TEAE, treatment-emergent adverse event. a TEAEs occurring in at least 5% of the volixibat all doses group. 238 Journal of Hepatology 2020 vol. 73 j 231-240 References
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Targeting bile acid signaling for the treatment of liver diseases: From bench to bed
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Trauner, M. A., Karpen, S. J., & Dawson, P. A. (2025) · Hepatology · doi:10.1097/hep.0000000000001438 · Cited by 26 · see citing works
“[120] Although disappointing as monotherapy, the findings do not exclude a possible role for gut-restricted IBAT inhibitors in combination with other therapeutic approaches, particularly for metabolic liver diseases, which may have a (micro)cholestatic component (discussed above).”
Gillard, J., & Leclercq, I. A. (2023) · Clinical Science · doi:10.1042/cs20220697 · Cited by 28 · see citing works
Matye, D. J., Li, Y., Chen, C., Chao, X., Wang, H., Ni, H., Ding, W., & Li, T. (2021) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.14619 · Cited by 26 · see citing works
Bile salt signaling and bile salt-based therapies in cardiometabolic disease
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“In addition, ASBT inhibitors have been shown to protect against the development of MASLD by restoring glucose tolerance and reducing TG levels in the liver in diet-induced MASLD in vivo models [165–167], while clinical trials showed no therapeutic impact [168].”
BackgroundMao, T., Sun, Y., Xu, X., & He, K. (2023) · Hepatology Communications · doi:10.1097/hc9.0000000000000234 · Cited by 24 · see citing works
“Nevertheless, 2 ileal BA transporter inhibitors, Elobixibat and Volixibat, both failed to improve ALT levels and steatosis in NASH patients, indicating that ileal BA transporter may not be the best choice for NAFLD/NASH therapy.[256] Compared with FGF19, FGF21 has attracted much more interest in terms of its multiple…”
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Bile acid signaling in MASLD: From pathogenesis to therapeutic applications
Simbrunner, B., Paternostro, R., Reiberger, T., & Trauner, M. (2025) · Hepatology · doi:10.1097/hep.0000000000001539 · Cited by 26 · see citing works
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“In humans, the opposite effect of ASBT inhibitor and FGF19 analogue treatment on hepatic bile acid synthesis rate has been confirmed by measurement of serum C4, a surrogate marker for de novo bile acid synthesis rate, but the actual magnitude of reduction in hepatic bile acid exposure and total bile acid pool by eithe…”
BackgroundCurrent status and challenges in the drug treatment for fibrotic nonalcoholic steatohepatitis
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“Volixibat, an inhibitor of the apical sodium-dependent bile acid transporter, has failed to show efficacy in improving the histological characteristics of NASH [84].”
BackgroundPaediatric research sets new standards for therapy in paediatric and adult cholestasis
Jeyaraj, R., Maher, E. R., & Kelly, D. A. (2023) · The Lancet Child & Adolescent Health · doi:10.1016/s2352-4642(23)00259-6 · Cited by 17 · see citing works
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van de Peppel, I. P., Rao, A., Dommerholt, M. B., Bongiovanni, L., Thomas, R., de Bruin, A., Karpen, S. J., Dawson, P. A., Verkade, H. J., & Jonker, J. W. (2020) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.202000750 · Cited by 10 · see citing works
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Breakthrough in the Treatment of Metabolic Associated Steatotic Liver Disease: Is it all over?
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“…primary outcome was a ≥ 2-point reduction in NAS without fibrosis worsening at week 48, but two predefined interim endpoints at week 24 ( ≥ 5% reduction in MRI-PDFF and ≥ 20% decrease in ALT) were not fulfilled; the study was terminated [ 30 ], but remained under development for cholestatic pruritus.”
Role of the Gut Microbiome in Metabolic Dysfunction-Associated Steatotic Liver Disease
Maher, S., Rajapakse, J., El-Omar, E. M., & Zekry, A. (2024) · Seminars in Liver Disease · doi:10.1055/a-2438-4383 · Cited by 12 · see citing works
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Laue, T., & Baumann, U. (2022) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2022.2151890 · Cited by 10 · see citing works
The Treatment of Primary Biliary Cholangitis: Time for Personalized Medicine
Men, X., Liu, Y., Zhao, H., Xie, B., Guo, C., Leung, P. S. C., Timilsina, S., Gershwin, M. E., Shang, Y., & Han, Y. (2025) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-025-09074-x · Cited by 8 · see citing works
MiR-203 is an anti-obese microRNA by targeting apical sodium-dependent bile acid transporter
Liu, X., Cheng, F., Bai, X., Zhao, T., Zhao, L., Wang, L., Li, M., Wu, X., Chen, X., Tang, P., et al. (2022) · iScience · doi:10.1016/j.isci.2022.104708 · Cited by 8 · see citing works
“Inhibition of ASBT expression or transport activity results in the blockage of enterohepatic circulation of BA with alterations in lipid and BA homeostasis (Newsome et al., 2020).”
BackgroundShi, R., Chai, K., Wang, H., Zhou, J., Yang, S., Li, J., Qiao, C., Sheng, X., Zhang, X., & Wu, J. (2025) · Journal of Evidence-Based Medicine · doi:10.1111/jebm.70002 · Cited by 9 · see citing works
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“Volixibat, a selective ASBT inhibitor, demonstrated a disconnect between pharmacodynamic activity and clinical efficacy in MASH treatment [38].”
Duan, X., Wu, J., Hu, J., Bai, W., & Hu, J. (2025) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.5c00225 · Cited by 5 · see citing works
Exome sequencing and analysis of 44,028 British South Asians enriched for high autozygosity
Kim, H. I., DeBoever, C., Walter, K., Kalantzis, G., Li, C., Mozaffari, S. V., Kundu, K., Jacobs, B. M., Mohammadi‐Shemirani, P., Musolf, A. M., et al. (2026) · Nature Genetics · doi:10.1038/s41588-026-02553-7 · Cited by 8 · see citing works
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Bile acids as therapeutic agents
Vu, B., Kawamoto, R., Villalba‐Davila, P., Dong, X., & Karnsakul, W. W. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1732854 · Cited by 4 · see citing works
Ileal Bile Acid Transporter Inhibitors in Cholestasis: Potential for More Than Just Paediatrics?
Krishna, M., & Boyer, J. L. (2026) · Liver International · doi:10.1111/liv.70524 · Cited by 4 · see citing works
Gairola, A., Wetten, A., & Dyson, J. K. (2024) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2024.2343789 · Cited by 4 · see citing works
“Volixibat was previously investigated in a phase 2 trial for steatotic liver disease, but this was terminated due to lack of efficacy at the interim analysis [118].”
BackgroundThe Role of Solute Carrier Family Transporters in Hepatic Steatosis and Hepatic Fibrosis
Zhang, C., Yang, X., Yi, X., Li, H., Zeng, C., & Chen, M. (2025) · Journal of Clinical and Translational Hepatology · doi:10.14218/jcth.2024.00348 · Cited by 4 · see citing works
“172 One possible explanation is that, while ASBT inhibitors reduce intrahepatic cholesterol levels, ASBT-mediated cholesterol catabolism leads to an increase in intrahepatic BAs.”
Ileal Bile Acid Transport Inhibitors for Cholestatic Pruritus: A Primer
Martins, A., & Levy, C. (2025) · Current Hepatology Reports · doi:10.1007/s11901-025-00699-2 · Cited by 3 · see citing works
“However, these effects did not translate into significant liver-related benefits, and the trial was terminated due to lack of efficacy [ 86]. subgroup analysis of adults with PFIC enrolled in PEDFIC 2, most patients experienced reductions in pruritus, sBA, and hepatic biomarkers, with a favorable…”
Park, S.-H., Ma, G., Park, S. J., Yang, S.-B., Seo, M., Lee, J.-H., Kweon, S., & Park, J. (2025) · Biomaterials · doi:10.1016/j.biomaterials.2025.123903 · Cited by 3 · see citing works
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Wang, Y., Yu, H., Cen, Z., Zhu, Y., & Wu, W. (2023) · Metabolism Open · doi:10.1016/j.metop.2023.100267 · Cited by 3 · see citing works
Targeting the ileal bile salt transporter in the treatment of non-alcoholic fatty liver disease
Jansen, P. L. M. (2021) · Hepatology International · doi:10.1007/s12072-021-10134-5 · Cited by 3 · see citing works
Exome sequencing and analysis of 44,028 British South Asians enriched for high autozygosityPreprint
Kim, H. I., DeBoever, C., Walter, K., Kalantzis, G., Li, C., Mozaffari, S. V., Kundu, K., Jacobs, B. M., Mohammadi‐Shemirani, P., Musolf, A. M., et al. (2025) · medRxiv · doi:10.1101/2025.06.05.25329068 · Cited by 3 · see citing works
Koutoukidis, D. A., Morris, E. M., Henry, J. A., Shammoon, Y., Zimmerman, M., Michalopoulou, M., Jebb, S. A., & Aveyard, P. N. (2021) · PLoS ONE · doi:10.1371/journal.pone.0250385 · Cited by 2 · see citing works
Pediatric Cholestatic Diseases in the Era of Ileal Bile Acid Transporter (IBAT) Inhibitors
Sciveres, M., Veraldi, S., Cirillo, F., & Maggiore, G. (2026) · Pediatric Reports · doi:10.3390/pediatric18010019 · Cited by 1 · see citing works
“Despite showing biochemical evidence of target engagement (increased bile acid synthesis and reduced cholesterol), it did not improve liver fat content on histology [95].”
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The gut microbiota-bile acid-FXR axis in NAFLD: from progression to therapeutic applications
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“…investigations for NAFLD and show potential therapeutic effects, such as EDP-305 (Ratziu et al., 2022), tropifexor (Sanyal et al., 2023), cilofexor (Alkhouri et al., 2022), INT-767 (Wang et al., 2022), fexaramine, and OCA, and BA transporter-targeting agents-volixibat (Newsome et al., 2020).”
Bile acid metabolism and signaling in human and animal health: A One Health perspective
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“Although volixibat increased C4 and reduced cholesterol levels, confirming adequate target engagement, it failed to improve MRI ‐ PDFF, ALT, or histology, and diarrhea was common, ultimately leading to termination for lack of efficacy [155].”
Navigating the liver landscape: upcoming pharmacotherapies for primary sclerosing cholangitis
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“A phase II study involving 197 MASH patients without cirrhosis showed that 48-week volixibat therapy did not provide liver-related therapeutic benefits compared to placebo, and the effects of volixibat are undefined in cholestatic liver injury [111].”
BackgroundSpezifische Therapie – neue Medikamente
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MiR-203 is an Anti-Obese miRNA by Targeting ASBTPreprint
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- Authors
- Newsome, P. N., Palmer, M., Freilich, B., Sheikh, M. Y., Sheikh, A., Sarles, H., Herring, R., Mantry, P., Kayali, Z., Hassanein, T., Lee, H.-M., & Aithal, G. P.
- Affiliations
- University Hospitals Birmingham NHS Foundation Trust (GB)
- Takeda (United States) (US)
- Kansas City Research Institute (US)
- GI Specialists of Georgia (United States) (US)
- Digestive Health Associates of Texas (US)
- Inland Empire Liver Foundation (US)
- Nottingham University Hospitals NHS Trust (GB)
- Corresponding author
- Newsome, Philip N.
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2020-08
- Volume
- 73
- Issue
- 2
- Pages
- 231-240
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W3013169226
- Cited by
- 80
- References
- 43
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 12 · 2023: 11 · 2022: 14 · 2021: 13 · 2020: 7
- FWCI
- 8.06
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Hepatology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by-nc-nd)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by-nc-nd)
- Funders
- Shire International GmBH
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- nonalcoholic steatohepatitis, ASBT, hepatic bile acid synthesis, steatosis, alanine aminotransferase, LDL cholesterol, target engagement
- MeSH terms
- Alanine Transaminase, Benzothiepins, Cholestenones, Cholesterol, Double-Blind Method, Female, Glycosides, Humans, Liver, Magnetic Resonance Imaging, Male, Middle Aged, Biomarkers, Treatment Outcome, Symporters, Organic Anion Transporters, Sodium-Dependent, Lipid Regulating Agents, Patient Acuity, Non-alcoholic Fatty Liver Disease
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