1. Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study.
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Gonzales, Emmanuel, Hardikar, Winita, Stormon, Michael, Baker, Alastair, Hierro, Loreto, Gliwicz, Dorota, Lacaille, Florence, Lachaux, Alain, Sturm, Ekkehard, Setchell, Kenneth D R, Kennedy, Ciara, Dorenbaum, Alejandro, Steinmetz, Jana, Desai, Nirav K, Wardle, Andrew J, Garner, Will, Vig, Pamela, Jaecklin, Thomas, Sokal, Etienne M, and Jacquemin, Emmanuel
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GENETIC disorders , *BILE acids , *SYNDROMES , *ITCHING , *SYNDROMES in children , *LEAST squares , *RESEARCH , *CLINICAL trials , *RESEARCH methodology , *MEDICAL cooperation , *EVALUATION research , *MEMBRANE glycoproteins , *ALAGILLE syndrome , *TREATMENT effectiveness , *COMPARATIVE studies , *RANDOMIZED controlled trials , *CARRIER proteins , *CHEMICAL inhibitors - Abstract
Background: 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.Methods: 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). Eligible participants had more than three times the normal serum bile acid (sBA) levels and intractable pruritus. After 18 weeks of maralixibat 380 μg/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 μg/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, and is closed to recruitment.Findings: Between Oct 28, 2014, and Aug 14, 2015, 31 participants (mean age 5·4 years [SD 4·25]) 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 μmol/L, 95% CI 23 to 164) and pruritus (1·7 points, 95% CI 1·2 to 2·2), whereas participants who continued maralixibat maintained treatment effect. This study met the primary endpoint (least square mean difference -117 μmol/L, 95% CI -232 to -2). From baseline to week 48, sBA (-96 μmol/L, -162 to -31) and pruritus (-1·6 pts, -2·1 to -1·1) 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.Interpretation: 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.Funding: Mirum Pharmaceuticals. [ABSTRACT FROM AUTHOR]- Published
- 2021
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