Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study.

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.

• Authors: Emmanuel Gonzales, Winita Hardikar, Michael Stormon, Alastair Baker, Loreto Hierro, Dorota Gliwicz, Florence Lacaille, Alain Lachaux, Ekkehard Sturm, Kenneth D R Setchell, Ciara Kennedy, Alejandro Dorenbaum, Jana Steinmetz, Nirav K Desai, Andrew J Wardle, Will Garner, Pamela Vig, Thomas Jaecklin, Etienne M Sokal, Emmanuel Jacquemin
• Journal: Lancet (London, England) (Lancet) Vol. 398 Issue 10311 Pg. 1581-1592 (10 30 2021) ISSN: 1474-547X [Electronic] England
• PMID: 34755627 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial)
• Copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.

Chemical References

• Carrier Proteins
• Membrane Glycoproteins
• bile acid binding proteins

Topics

• Adolescent
• Alagille Syndrome (drug therapy)
• Carrier Proteins (adverse effects, antagonists & inhibitors, therapeutic use)
• Child
• Child, Preschool
• Female
• Humans
• Infant
• Male
• Membrane Glycoproteins (adverse effects, antagonists & inhibitors, therapeutic use)
• Pruritus (drug therapy)
• Treatment Outcome