Lancet.\u00a02021 Oct 30;398(10311):1581-1592.\u00a0doi: 10.1016\/S0140-6736(21)01256-3.Epub 2021 Oct 28.<\/p>\n\n\n\n
Emmanuel Gonzales<\/a> 1<\/a><\/sup>, Winita Hardikar<\/a> 2<\/a><\/sup>, Michael Stormon<\/a> 3<\/a><\/sup>, Alastair Baker<\/a> 4<\/a><\/sup>, Loreto Hierro<\/a> 5<\/a><\/sup>, Dorota Gliwicz<\/a> 6<\/a><\/sup>, Florence Lacaille<\/a> 7<\/a><\/sup>, Alain Lachaux<\/a> 8<\/a><\/sup>, Ekkehard Sturm<\/a> 9<\/a><\/sup>, Kenneth D R Setchell<\/a> 10<\/a><\/sup>, Ciara Kennedy<\/a> 11<\/a><\/sup>, Alejandro Dorenbaum<\/a> 12<\/a><\/sup>, Jana Steinmetz<\/a> 13<\/a><\/sup>, Nirav K Desai<\/a> 14<\/a><\/sup>, Andrew J Wardle<\/a> 15<\/a><\/sup>, Will Garner<\/a> 15<\/a><\/sup>, Pamela Vig<\/a> 15<\/a><\/sup>, Thomas Jaecklin<\/a> 16<\/a><\/sup>, Etienne M Sokal<\/a> 17<\/a><\/sup>, Emmanuel Jacquemin<\/a> 18<\/a><\/sup>Affiliations expand<\/p>\n\n\n\n Background: <\/strong>Alagille syndrome is a rare genetic disease that often presents with severe cholestasis and pruritus. There are no approved drugs for management. Maralixibat, an apical, sodium-dependent, bile acid transport inhibitor, prevents enterohepatic bile acid recirculation. We evaluated the safety and efficacy of maralixibat for children with cholestasis in Alagille syndrome.<\/p>\n\n\n\n Methods: <\/strong>ICONIC was a placebo-controlled, randomised withdrawal period (RWD), phase 2b study with open-label extension in children (aged 1-18 years) with Alagille syndrome (NCT02160782<\/a>). Eligible participants had more than three times the normal serum bile acid (sBA) levels and intractable pruritus. After 18 weeks of maralixibat 380 \u03bcg\/kg once per day, participants were randomly assigned (1:1) to continue maralixibat or receive placebo for 4 weeks. Subsequently, all participants received open-label maralixibat until week 48. During the long-term extension (204 weeks reported), doses were increased up to 380 \u03bcg\/kg twice per day. The primary endpoint was the mean sBA change during the RWD in participants with at least 50% sBA reduction by week 18. Cholestastic pruritus was assessed using observer-rated, patient-rated, and clinician-rated 0-4 scales. The safety population was defined as all participants who had received at least one dose of maralixibat. This trial was registered with ClinicalTrials.gov, NCT02160782<\/a>, and is closed to recruitment.<\/p>\n\n\n\n Findings: <\/strong>Between Oct 28, 2014, and Aug 14, 2015, 31 participants (mean age 5\u00b74 years [SD 4\u00b725]) were enrolled and 28 analysed at week 48. Of the 29 participants who entered the randomised drug withdrawal period, ten (34%) were female and 19 (66%) were male. In the RWD, participants switched to placebo had significant increases in sBA (94 \u03bcmol\/L, 95% CI 23 to 164) and pruritus (1\u00b77 points, 95% CI 1\u00b72 to 2\u00b72), whereas participants who continued maralixibat maintained treatment effect. This study met the primary endpoint (least square mean difference -117 \u03bcmol\/L, 95% CI -232 to -2). From baseline to week 48, sBA (-96 \u03bcmol\/L, -162 to -31) and pruritus (-1\u00b76 pts, -2\u00b71 to -1\u00b71) improved. In participants who continued to week 204 (n=15) all improvements were maintained. Maralixibat was generally safe and well tolerated throughout. The most frequent adverse events were gastrointestinal related. Most adverse events were self-limiting in nature and mild-to-moderate in severity.<\/p>\n\n\n\n Interpretation: <\/strong>In children with Alagille syndrome, maralixibat is, to our knowledge, the first agent to show durable and clinically meaningful improvements in cholestasis. Maralixibat might represent a new treatment paradigm for chronic cholestasis in Alagille syndrome.<\/p>\n\n\n\n Funding: <\/strong>Mirum Pharmaceuticals.<\/p>\n\n\n\n Copyright \u00a9 2021 Elsevier Ltd. All rights reserved.<\/p>\n\n\n\n Lancet.\u00a02021 Oct 30;398(10311):1581-1592.\u00a0doi: 10.1016\/S0140-6736(21)01256-3.Epub 2021 Oct 28. Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study Emmanuel Gonzales 1, Winita Hardikar 2, Michael Stormon 3, Alastair Baker 4, Loreto Hierro 5, Dorota Gliwicz 6, Florence Lacaille 7, Alain Lachaux 8, Ekkehard Sturm 9, Kenneth D R Setchell 10, Ciara Kennedy 11, Alejandro Dorenbaum 12, Jana Steinmetz 13, Nirav K Desai 14, Andrew J Wardle 15, Will Garner 15, Pamela Vig 15, Thomas Jaecklin 16, Etienne M Sokal 17, Emmanuel Jacquemin 18Affiliations expand PMID: 34755627 DOI: 10.1016\/S0140-6736(21)01256-3 […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}}},"categories":[1],"tags":[],"_links":{"self":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/2415"}],"collection":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=2415"}],"version-history":[{"count":2,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/2415\/revisions"}],"predecessor-version":[{"id":2418,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/2415\/revisions\/2418"}],"wp:attachment":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=2415"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=2415"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=2415"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}Abstract<\/h2>\n\n\n\n