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      Seladelpar treatment reduces IL-31 and pruritus in patients with primary biliary cholangitis

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          Abstract

          Background and Aims:

          Pruritus is a debilitating symptom for many people living with primary biliary cholangitis (PBC). In studies with seladelpar, a selective peroxisome proliferator-activated receptor-delta agonist, patients with PBC experienced significant improvement in pruritus and reduction of serum bile acids. Interleukin-31 (IL-31) is a cytokine known to mediate pruritus, and blocking IL-31 signaling provides relief in pruritic skin diseases. This study examined the connection between seladelpar’s antipruritic effects and IL-31 and bile acid levels in patients with PBC.

          Approach and Results:

          IL-31 levels were quantified in serum samples from the ENHANCE study of patients with PBC receiving daily oral doses of placebo (n = 55), seladelpar 5 mg (n = 53) or 10 mg (n = 53) for 3 months, and for healthy volunteers (n = 55). IL-31 levels were compared with pruritus using a numerical rating scale (NRS, 0–10) and with bile acid levels. Baseline IL-31 levels closely correlated with pruritus NRS ( r = 0.54, p < 0.0001), and total ( r = 0.54, p < 0.0001) and conjugated bile acids (up to 0.64, p < 0.0001). Decreases in IL-31 were observed with seladelpar 5 mg (−30%, p = 0.0003) and 10 mg (−52%, p < 0.0001) versus placebo (+31%). Patients with clinically meaningful improvement in pruritus (NRS ≥ 2 decrease) demonstrated greater dose-dependent reductions in IL-31 compared to those without pruritus improvement (NRS < 2 decrease). Strong correlations were observed for the changes between levels of IL-31 and total bile acids ( r = 0.63, p < 0.0001) in the seladelpar 10 mg group.

          Conclusions:

          Seladelpar decreased serum IL-31 and bile acids in patients with PBC. The reductions of IL-31 and bile acids correlated closely with each other and pruritus improvement, suggesting a mechanism to explain seladelpar’s antipruritic effects.

          Abstract

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          Most cited references40

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          Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases

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            A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis

            Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease.
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              A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis

              Patients with primary biliary cholangitis who have an inadequate response to therapy with ursodeoxycholic acid are at high risk for disease progression. Fibrates, which are agonists of peroxisome proliferator-activated receptors, in combination with ursodeoxycholic acid, have shown potential benefit in patients with this condition.
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                Author and article information

                Contributors
                Journal
                Hepatology
                Hepatology
                HEP
                Hepatology (Baltimore, Md.)
                Lippincott Williams & Wilkins (Hagerstown, MD )
                0270-9139
                1527-3350
                July 2024
                20 December 2023
                : 80
                : 1
                : 27-37
                Affiliations
                [1 ]Department of Gastroenterology and Hepatology, University Hospital Zürich, University of Zürich, Zürich, Switzerland
                [2 ]Division of Digestive and Liver Diseases, University of Texas SW Medical Center, Dallas, Texas, USA
                [3 ]Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
                [4 ]Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
                [5 ]Schiff Center for Liver Diseases, University of Miami, Miami, Florida, USA
                [6 ]Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, California, USA
                [7 ]Clinical and Translation Research Institute, Newcastle University, Newcastle upon Tyne, UK
                [8 ]CymaBay Therapeutics, Inc., Fremont, California, USA
                Author notes
                Correspondence Andreas E. Kremer, Department of Gastroenterology and Hepatology, University Hospital Zürich, Rämistrasse 100, CH-8091, Zürich, Switzerland. Email: andreas.kremer@ 123456usz.ch Yun-Jung Choi, CymaBay Therapeutics, Inc, Fremont, California, USA. Email: ychoi@ 123456cymabay.com
                Author information
                https://orcid.org/0000-0002-9263-948X
                https://orcid.org/0000-0002-4874-7010
                https://orcid.org/0000-0002-6736-2255
                https://orcid.org/0000-0001-5498-6037
                https://orcid.org/0000-0002-3906-6811
                https://orcid.org/0009-0001-9384-9577
                https://orcid.org/0000-0002-7613-3008
                https://orcid.org/0000-0002-5153-9714
                Article
                HEP-23-1814 00009
                10.1097/HEP.0000000000000728
                11191048
                38117036
                ef22dbcf-b5f1-4da4-834d-d11d617e8217
                Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.

                This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/

                History
                : 25 September 2023
                : 1 December 2023
                Categories
                Original Articles: Immune-Mediated Diseases, DILI, and Biliary Tract Disease
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                Gastroenterology & Hepatology
                Gastroenterology & Hepatology

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