Author information
1Department of Hepatology, Toronto General Hospital University Health Network, Toronto, Ontario, Canada.
2Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada.
3Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
4Department of Paediatrics, Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada.
5Department of Scientific and Medical Affairs, Mirum Pharmaceuticals, Inc., Foster City, California, USA.
6Department of Pathology and Laboratory Medicine, Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
7Department of Gastroenterology, Hepatology, Nutrition Disturbances and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland.
8Department of Pediatric Hepatology and Liver Transplantation, Service d'Hépatologie et de Transplantation Hépatique Pédiatriques, Centre de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques (AVB-CG), FSMR FILFOIE, ERN RARE LIVER, Hôpital Bicêtre, AP-HP, Faculté de Médecine Paris-Saclay, Le Kremlin-Bicêtre, and Inserm U1193, Hépatinov, Université Paris-Saclay, Orsay, France.
9Department of Molecular Genetics, Pharmacogenetics and Hormonology, Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Hôpitaux Universitaires Paris-Saclay, Assistance PubliqueHôpitaux de Paris, Centre Hospitalier Universitaire de Bicêtre, Le Kremlin-Bicêtre, France.
10Department of Pediatric Hepatology, Gastroenterology, and Transplantation, Ospedale Papa Giovanni XXIII, Pediatric Hepatology, Gastroenterology and Transplantation, Bergamo, Italy.
11Department of Paediatric Gastroenterology, Hepatology and Nutrition, Astrid Lindgren Children's Hospital, Karolinska University Hospital and Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
12Department of Paediatric Gastroenterology, Hepatology and Nutrition, Astrid Lindgren Children's Hospital, Karolinska University Hospital and CLINTEC, Karolinska Institutet, Stockholm, Sweden.
13Department of Pediatric GI and Hepatology, Cliniques Universitaires Saint-Luc, Service De Gastroentérologie & Hépatologie Pédiatrique, Brussels, Belgium.
14Department of Gastroenterology, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
15Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology & Nutrition, Children's Healthcare of Atlanta & Emory University School of Medicine, Atlanta, Georgia, USA.
16Department of Pediatrics, Division of Gastroenterology, Stanford University School of Medicine, Palo Alto, California, USA.
17Department of Pediatrics (Cardiology), Stanford University School of Medicine, Lucile Packard Children's Hospital, Palo Alto, California, USA.
18Starship Child Health, Department of Paediatric Gastroenterology, Auckland, New Zealand.
19Section of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics and the Digestive Health Institute, Children's Hospital of Colorado and University of Colorado School of Medicine, Aurora, Colorado, USA.
20Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital, Melbourne, Victoria, Australia.
21Department of Pediatrics, Mazumdar Shaw Medical Center, Narayana Health, Bangalore, Karnataka, India.
22Department of Gastroenterology, Children's Mercy Kansas City, Section of Hepatology, Kansas City, Missouri, USA.
23Department of Pediatric Gastroenterology and Nutrition, Necker-Enfants Malades Hospital, University of Paris, Paris, France.
24Department of Pediatric Gastroenterology and Hepatology, Pediatric Liver Unit, National Reference Centre for Rare Pediatric Liver Diseases (Biliary Atresia and Genetic Cholestasis), FILFOIE, ERN RARE LIVER, Necker-Enfants Malades Hospital, University of Paris, Paris, France.
25Department of Pediatrics, Division of Pediatric Gastroenterology, Oregon Health and Science University, Portland, Oregon, USA.
26Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Primary Children's Hospital, University of Utah, Salt Lake City, Utah, USA.
27Department of Pediatrics, Leeds Teaching Hospitals NHS Trust, Leeds Children's Hospital, Leeds, UK.
28Department Neurofarba, University of Florence and Meyer Children's University Hospital, Paediatric and Liver Unit, Florence, Italy.
29Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, Groningen, The Netherlands.
30Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, Minnesota, USA.
31Department of Pediatrics, Children's Hospital & Medical Center and University of Nebraska Medical Center, Omaha, Nebraska, USA.
32Department of Pediatrics, Gastroenterology & Hepatology Division, University of Washington, Seattle Children's Hospital, Seattle, Washington, USA.
33First Department of Pediatrics, Division of Gastroenterology & Hepatology, "Agia Sofia" Children's Hospital, University of Athens, Athens, Greece.
34First Department of Paediatrics, Semmelweis University, Budapest, Hungary.
35Department of Pediatrics, Division of Pediatric Gastroenterology and Hepatology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
36Department of Pediatrics, Division of Pediatric Gastroenterology, Rady Children's Hospital San Diego, University of California San Diego, San Diego, California, USA.
37Department of Pediatrics, Pediatric Gastroenterology Unit, Regina Margherita Children's Hospital, Azienda Ospedaliera-Universitaria Citta' della Salute e della Scienza, Turin, Italy.
38Pediatric Hepatology and Liver Transplant Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
39Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute-Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
40Department of Paediatrics, Division of Paediatric Gastroenterology and Hepatology, London Health Sciences Centre, Children's Hospital, Western University, London, Ontario, Canada.
41Department of Pediatric Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Servizio di Epatologia Pediatrica, Milan, Italy.
42Department of Pediatrics, Division of Pediatric Gastroenterology and Hepatology, Phoenix Children's Hospital, Phoenix, Arizona, USA.
43Department of Pediatrics, Centro Hospitalar Universitário Do Porto, Pediatric Gastroenterology Unit, Porto, Portugal.
44Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA.
45Department of Pediatrics, Division of Gastroenterology, Hepatology, & Nutrition, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, US A.
46Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
47Department of Pediatrics, Paediatric Gastroenterology Unit, Cruces University Hospital, Bilbao, Spain.
48Department of Gastroenterology, Hepatology and Nutrition, Pediatric Gastroenterology Hepatology and Nutrition Unit, Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain.
49Department of Paediatric Hepatology, Liver Unit, Birmingham Women's & Children's Hospital NHS Trust and University of Birmingham, Birmingham, UK.
50Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
51Department of Paediatrics, Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
52Department of Hepatology and Gastroenterology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Biodonostia Health Research Institute-Donostia University Hospital, Universidad del País Vasco (UPV/EHU), San Sebastián, Spain.
53Section of Pediatric Gastroenterology, Department of Pediatrics, University of Manitoba, Winnipeg, Manitoba, Canada.
54Department of Pediatric Gastroenterology, Children's Hospital of Fudan University, The Center for Pediatric Liver Diseases, Shanghai, China.
55Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children's Hospital, Seoul, South Korea.
56Department of Pediatric Gastroenterology, Pediatric Gastroenterology and Hepatology Division, Hospital Italiano Buenos Aires, Buenos Aires, Argentina.
57Department of Paediatrics, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
58Department of Paediatrics and Child Health, Division of Paediatric Gastroenterology, Chris Hani Baragwanath Academic Hospital, University of the Witwatersrand, Johannesburg, South Africa.
59Department of Pediatrics, Division of Gastroenterology, Ramathibodi Hospital Mahidol University, Bangkok, Thailand.
60Department of Pediatrics, Schneider Children's Medical Center of Israel, Institute of Gastroenterology, Nutrition and Liver Diseases, Petah Tikva, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
61Department of Pediatric Gastroenterology and Organ Transplant, Koç University School of Medicine, Istanbul, Turkey.
62Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
63Pediatric Gastroenterology Department, Hospital de Base do Distrito Federal, Hospital da Criança de Brasília, Centro Universitário de Brasília, Brasília, DF, Brazil.
64Departamento de Gastroenterologia e Hepatologia Pediátrica, Pediatric Gastroenterology Service, Hospital da Criança Santo Antônio, Universidade Federal de Ciências da Saúde de Porto Alegre, Complexo Hospitalar Santa Casa, Porto Alegre, RS, Brazil.
65Department of Pediatric Gastroenterology, Le Bonheur Children's Hospital and The University of Tennessee Health Science Center, Memphis, Tennessee, USA.
66Pediatric Gastroenterology, Hepatology and Nutrition Department, Istanbul University Istanbul Medical Faculty, Istanbul, Turkey.
67Solid Organ Transplant Department, Children's Health-Children's Medical Center, Dallas, Texas, USA.
68Department of Pediatrics, Medical University of Silesia in Katowice, Katowice, Poland.
69Department of Pediatric Gastroenterology, Division of Pediatric Gastroenterology of Hospital da Criança Conceição do Grupo Hospitalar Conceição, Porto Alegre, RS, Brazil.
70Department of Pediatric Gastroenterology, University Medical Center Utrecht, Utrecht, The Netherlands.
71Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition/Miami Transplant Institute, University of Miami, Miami, Florida, USA.
72Department of Pediatric Intensive Care, Wits Donald Gordon Medical Centre, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
73Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Rochester Medical Center, Rochester, New York, USA.
74Pediatric Gastroenterology, Hepatology and Nutrition, and Department of Pediatrics, Faculty of Medicine, University Medical Center Ljubljana, Ljubljana, Slovenia.
75Department of Pediatrics, Gynecology, and Obstetrics, Division of Pediatric Specialties, Swiss Pediatric Liver Center, University Hospitals Geneva and University of Geneva, Geneva, Switzerland.
76Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany.
77Department of Pediatrics, Harvard Medical School, Massachusetts General Hospital for Children, Boston, Massachusetts, USA.
78Department of Inflammation Biology, Institute of Liver Studies, King's College London, London, UK.
Abstract
Background and aims: Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter inhibitor, is an approved pharmacologic therapy for cholestatic pruritus in ALGS. Since long-term placebo-controlled studies are not feasible or ethical in children with rare diseases, a novel approach was taken comparing 6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the G lobal AL agille A lliance (GALA) study.
Approach and results: Maralixibat trials comprise 84 patients with ALGS with up to 6 years of treatment. GALA contains retrospective data from 1438 participants. GALA was filtered to align with key maralixibat eligibility criteria, yielding 469 participants. Serum bile acids could not be included in the GALA filtering criteria as these are not routinely performed in clinical practice. Index time was determined through maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival, defined as the time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods. Sensitivity analyses and adjustments for covariates were applied. Age, total bilirubin, gamma-glutamyl transferase, and alanine aminotransferase were balanced between groups with no statistical differences. Event-free survival in the maralixibat cohort was significantly better than the GALA cohort (HR, 0.305; 95% CI, 0.189-0.491; p <0.0001). Multiple sensitivity and subgroup analyses (including serum bile acid availability) showed similar findings.
Conclusions: This study demonstrates a novel application of a robust statistical method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible, providing wide application for rare diseases. This comparison with real-world natural history data suggests that maralixibat improves event-free survival in patients with ALGS.