1Hépatologie et Transplantation Hépatique Pédiatriques, Centre de référence de l'atrésie des voies biliaires et des cholestases génétiques, FSMR FILFOIE, ERN RARE LIVER, Hôpital Bicêtre, AP-HP, Université Paris-Saclay, Hépatinov, Inserm U 1193, Le Kremlin-Bicêtre, France. Electronic address: firstname.lastname@example.org.
2Department of Gastroenterology, The Royal Children's Hospital Melbourne, Parkville, VIC, Australia.
3Department of Gastroenterology, The Children's Hospital at Westmead, Sydney, NSW, Australia.
4Department of Child Health, The Paediatric Liver Centre, King's College Hospital, London, UK.
5Servicio de Hepatologìa y Trasplante Pediátrico, Hospital Universitario La Paz, Madrid, Spain.
6Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, Children's Memorial Health Institute, Warsaw, Poland.
7Gastroenterology-Hepatology-Nutrition Unit, Hôpital Universitaire Necker-Enfants Malades, Paris, France.
8Service de Gastroentérologie, Hépatologie et Nutrition Pédiatriques, Centre de référence de la maladie de Wilson et autres maladies rares liées au cuivre, Centre de référence de l'atrésie des voies biliaires et cholestases génétiques, Hôpital Femme-Mère-Enfant, Lyon, France.
9Paediatric Gastroenterology/Hepatology, University Hospital for Children and Adolescents, Tübingen, Germany.
10Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
11Amplyx Pharmaceuticals, San Diego, CA, USA.
12Pediatrics - Immunology and Allergy, Stanford Medical School, Stanford University, Palo Alto, CA, USA.
13Biostatistics, Premier Research, Naperville, IL, USA.
14Takeda Pharmaceuticals, Cambridge, MA, USA.
15Mirum Pharmaceuticals, Foster City, CA, USA.
16Mirum Pharmaceuticals, Basel, Switzerland.
17UCLouvain, Cliniques Universitaires Saint Luc, Service de Gastroentérologie Hépatologie Pédiatrique, Brussels, Belgium.
18Hépatologie et Transplantation Hépatique Pédiatriques, Centre de référence de l'atrésie des voies biliaires et des cholestases génétiques, FSMR FILFOIE, ERN RARE LIVER, Hôpital Bicêtre, AP-HP, Université Paris-Saclay, Hépatinov, Inserm U 1193, Le Kremlin-Bicêtre, France.
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.