Volixibat in adults with non-alcoholic steatohepatitis: 24-week interim analysis from a randomized, phase II study

Newsome, Philip N.; Palmer, Melissa; Freilich, Bradley; Sheikh, Muhammad Y.; Sheikh, Aasim; Sarles, H; Herring, Robert; Mantry, Parvez S.; Kayali, Zeid; Hassanein, Tarek; Lee, Hak-Myung; Aithal, Guruprasad P.

doi:10.1016/j.jhep.2020.03.024

Cited by 54 publications

(36 citation statements)

References 40 publications

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“…Another pathway involving bile acid biology in NASH is the chemical inhibition of the apical sodium-dependent bile acid transporter (ASBT), which blocks bile acid reuptake and stimulates hepatic bile acid production. The ASBT inhibitor volixibat increased bile acid synthesis and decreased cholesterol in NASH patients, but did not show clear signals of histological benefits in a phase 2 clinical trial (42).…”

Section: Inflammation Fibrosismentioning

confidence: 88%

Non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH)-related liver fibrosis: mechanisms, treatment and prevention

Tacke

Weiskirchen

2021

Ann Transl Med

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Liver fibrosis is the excessive expression and accumulation of extracellular matrix proteins in the liver. Fibrotic scarring occurs as the consequence of chronic injury and inflammation. While the successful treatment of hepatitis B and C reduced the burden of liver disease related to viral hepatitis, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) are nowadays the leading causes of hepatic fibrosis worldwide. Although basic research activities have significantly advanced our understanding of the molecular disease pathogenesis, the present therapeutic options for fibrosis are still limited. In advanced disease stages, liver transplantation often remains the only curative treatment. This highlights the necessity of preventive strategies to avoid complications of fibrosis, particularly cirrhosis, portal hypertension and liver cancer. Lifestyle modifications (weight loss, exercise, healthy diet) are the basis for prevention and treatment of NAFLD-associated fibrosis. In the present review, we discuss recent advances in antifibrotic prevention and therapy. In particular, we review the current concepts for antifibrotic drug candidates in the treatment of NAFLD and NASH. While some compounds aim at reverting pathogenic liver metabolism, an alternative approach is to disconnect the injury (e.g., NAFLD) from inflammation and/or fibrosis. Investigational drugs typically target metabolic pathways, insulin resistance, hepatocyte death, inflammatory cell recruitment or activation, the gut-liver axis, matrix expression or matrix turnover. While several promising drug candidates failed in phase 2 or 3 clinical trials (including elafibranor, emricasan and selonsertib), promising results with the farnesoid X receptor agonist obeticholic acid, the pan-PPAR agonist lanifibranor and the chemokine receptor CCR2/CCR5 inhibitor cenicriviroc support the expectation of an effective pharmacological therapy for liver fibrosis in the near future. Tackling NAFLD-associated fibrosis from different directions by combinatorial drug treatment and effective lifestyle changes hold the greatest prospects.

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Section: Inflammation Fibrosismentioning

confidence: 88%

Non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH)-related liver fibrosis: mechanisms, treatment and prevention

Tacke

Weiskirchen

2021

Ann Transl Med

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“…Volixibat (an intestinal ASBT inhibitor that prevents reabsorption of bile acids) decreased plasma total cholesterol and LDL-C but did not improve NASH in an interim analysis from a phase 2 trial ( ClinicalTrials.gov identifier: NCT02787304) [ 150 ]. Bile acid sequestrants, such as colesevelam and cholestyramine, improve glucose metabolism in T2D and lower CV risk (WHO trial) without improving liver histology ( ClinicalTrials.gov identifier: NCT01066364) [ 151 ].…”

Section: Therapeutic Strategies and Their Potential Impact On Cvd Rismentioning

confidence: 99%

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

Deprince

Haas

Staels

2020

Molecular Metabolism

273

161

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Background Non-alcoholic fatty liver disease (NAFLD) is rapidly becoming a global health problem. Cardiovascular diseases (CVD) are the most common cause of mortality in NAFLD patients. NAFLD and CVD share several common risk factors including obesity, insulin resistance, and type 2 diabetes (T2D). Atherogenic dyslipidemia, characterized by plasma hypertriglyceridemia, increased small dense low-density lipoprotein (LDL) particles, and decreased high-density lipoprotein cholesterol (HDL-C) levels, is often observed in NAFLD patients. Scope of review In this review, we highlight recent epidemiological studies evaluating the link between NAFLD and CVD risk. We further focus on recent mechanistic insights into the links between NAFLD and altered lipoprotein metabolism. We also discuss current therapeutic strategies for NAFLD and their potential impact on NAFLD-associated CVD risk. Major conclusions Alterations in hepatic lipid and lipoprotein metabolism are major contributing factors to the increased CVD risk in NAFLD patients, and many promising NASH therapies in development also improve dyslipidemia in clinical trials.

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“…Additional studies using the ASBT inhibitor volixibat in LDLr leiden knockout mice supported that conclusion and demonstrated a significant decrease in diet-induced Non-alcoholic fatty liver disease activity score by the inhibition of ASBT ( 55 ). In humans however, a phase 2 clinical trial to assess the effects of 48 weeks treatment with the ASBT inhibitor, volixibat, was terminated after mid-term assessment due to lack of improvement in NASH score as judged by MRI-PDFF imaging ( 56 ). It should be noted that the histological evaluations including the scores for ballooning and inflammation in this clinical trial were lacking.…”

Section: Cholesterol Lowering Drugs In the Management Of Nafld/nashmentioning

confidence: 99%

Disturbances in Cholesterol Homeostasis and Non-alcoholic Fatty Liver Diseases

et al. 2020

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Non-alcoholic fatty liver disease (NAFLD) is a major health problem associated with obesity and other features of the metabolic syndrome including insulin resistance and dyslipidemia. The accumulation of lipids in hepatocytes causes liver damage and triggers inflammation, fibrosis, and cirrhosis. Beside fatty acids and triglycerides, evidence showed an increased accumulation of free cholesterol in the liver with subsequent toxic effects contributing to liver damage. The maintenance of cholesterol homeostasis in the body requires a balance between several pathways responsible for cholesterol synthesis, transport and conversion into bile acids. Intestinal absorption is also one of the major determinants of cholesterol homeostasis. The nature of changes in cholesterol homeostasis associated with NAFLD has been a subject of extensive investigations. In this article, we will attempt to provide a brief overview of the current knowledge about the disturbances in cholesterol metabolism associated with NAFLD and discuss how certain molecular targets of these pathways could be exploited for the treatment of this multifactorial disease.

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Volixibat in adults with non-alcoholic steatohepatitis: 24-week interim analysis from a randomized, phase II study

Cited by 54 publications

References 40 publications

Non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH)-related liver fibrosis: mechanisms, treatment and prevention

Non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH)-related liver fibrosis: mechanisms, treatment and prevention

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

Disturbances in Cholesterol Homeostasis and Non-alcoholic Fatty Liver Diseases

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