Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA

Hansen BE 1 , Vandriel SM 2 , Vig P 3 , Garner W 3 , Mogul DB 3 , Loomes KM 4 Show all authors , Piccoli DA 4 , Rand EB 4 , Jankowska I 5 , Czubkowski P 5 , Gliwicz-Miedzińska D 5 , Gonzales EM 6 , Jacquemin E 6 , Bouligand J 7 , D'Antiga L 8 , Nicastro E 8 , Arnell H 9 , Fischler B 10 , Sokal É 11 , Demaret T 11 , Siew S 12 , Stormon M 12 , Karpen SJ 13 , Romero R 13 , Ebel NH 14 , Feinstein JA 15 , Roberts AJ 16 , Evans HM 16 , Sundaram SS 17 , Chaidez A 17 , Hardikar W 18 , Shankar S 19 , Fischer RT 20 , Lacaille F 21 , Debray D 22 , Lin HC 23 , Jensen MK 24 , Jaramillo C 24 , Karthikeyan P 25 , Indolfi G 26 , Verkade HJ 27 , Larson-Nath C 28 , Quiros-Tejeira RE 29 , Valentino PL 30 , Rogalidou M 31 , Dezsőfi A 32 , Squires JE 33 , Schwarz K 34 , Calvo PL 35 , Bernabeu JQ 36 , Zizzo AN 37 , Nebbia G 38 , Bulut P 39 , Santos-Silva E 40 , Fawaz R 41 , Nastasio S 42 , Karnsakul W 43 , Tamara ML 44 , Busoms CM 45 , Kelly DA 46 , Sandahl TD 47 , Jimenez-Rivera C 48 , Banales JM 49 , Mujawar Q 50 , Li LT 51 , She H 51 , Wang JS 51 , Kim KM 52 , Oh SH 52 , Sanchez MC 53 , Cavalieri ML 53 , Lee WS 54 , Hajinicolaou C 55 , Lertudomphonwanit C 56 , Waisbourd-Zinman O 57 , Arikan C 58 , Alam S 59 , Carvalho E 60 , Melere M 61 , Eshun J 62 , Önal Z 63 , Desai DM 64 , Wiecek S 65 , Pinto RB 66 , Wolters VM 67 , Garcia J 68 , Beretta M 69 , Kerkar N 70 , Brecelj J 71 , Rock N 72 , Lurz E 73 , Blondet N 30 , Shah U 74 , Thompson RJ 75 , Kamath BM 2 , Global ALagille Alliance (GALA) Study Group

Affiliations 

  • 1 Department of Hepatology, Toronto General Hospital University Health Network, Toronto, Ontario, Canada
  • 2 Department of Paediatrics, Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada
  • 3 Department of Scientific and Medical Affairs, Mirum Pharmaceuticals, Inc., Foster City, California, USA
  • 4 Department 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
  • 5 Department of Gastroenterology, Hepatology, Nutrition Disturbances and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
  • 6 Department 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
  • 7 Department 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
  • 8 Department of Pediatric Hepatology, Gastroenterology, and Transplantation, Ospedale Papa Giovanni XXIII, Pediatric Hepatology, Gastroenterology and Transplantation, Bergamo, Italy
  • 9 Department 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
  • 10 Department of Paediatric Gastroenterology, Hepatology and Nutrition, Astrid Lindgren Children's Hospital, Karolinska University Hospital and CLINTEC, Karolinska Institutet, Stockholm, Sweden
  • 11 Department of Pediatric GI and Hepatology, Cliniques Universitaires Saint-Luc, Service De Gastroentérologie & Hépatologie Pédiatrique, Brussels, Belgium
  • 12 Department of Gastroenterology, The Children's Hospital at Westmead, Sydney, New South Wales, Australia
  • 13 Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology & Nutrition, Children's Healthcare of Atlanta & Emory University School of Medicine, Atlanta, Georgia, USA
  • 14 Department of Pediatrics, Division of Gastroenterology, Stanford University School of Medicine, Palo Alto, California, USA
  • 15 Department of Pediatrics (Cardiology), Stanford University School of Medicine, Lucile Packard Children's Hospital, Palo Alto, California, USA
  • 16 Starship Child Health, Department of Paediatric Gastroenterology, Auckland, New Zealand
  • 17 Section 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
  • 18 Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital, Melbourne, Victoria, Australia
  • 19 Department of Pediatrics, Mazumdar Shaw Medical Center, Narayana Health, Bangalore, Karnataka, India
  • 20 Department of Gastroenterology, Children's Mercy Kansas City, Section of Hepatology, Kansas City, Missouri, USA
  • 21 Department of Pediatric Gastroenterology and Nutrition, Necker-Enfants Malades Hospital, University of Paris, Paris, France
  • 22 Department 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
  • 23 Department of Pediatrics, Division of Pediatric Gastroenterology, Oregon Health and Science University, Portland, Oregon, USA
  • 24 Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Primary Children's Hospital, University of Utah, Salt Lake City, Utah, USA
  • 25 Department of Pediatrics, Leeds Teaching Hospitals NHS Trust, Leeds Children's Hospital, Leeds, UK
  • 26 Department Neurofarba, University of Florence and Meyer Children's University Hospital, Paediatric and Liver Unit, Florence, Italy
  • 27 Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, Groningen, The Netherlands
  • 28 Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, Minnesota, USA
  • 29 Department of Pediatrics, Children's Hospital & Medical Center and University of Nebraska Medical Center, Omaha, Nebraska, USA
  • 30 Department of Pediatrics, Gastroenterology & Hepatology Division, University of Washington, Seattle Children's Hospital, Seattle, Washington, USA
  • 31 First Department of Pediatrics, Division of Gastroenterology & Hepatology, "Agia Sofia" Children's Hospital, University of Athens, Athens, Greece
  • 32 First Department of Paediatrics, Semmelweis University, Budapest, Hungary
  • 33 Department of Pediatrics, Division of Pediatric Gastroenterology and Hepatology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
  • 34 Department of Pediatrics, Division of Pediatric Gastroenterology, Rady Children's Hospital San Diego, University of California San Diego, San Diego, California, USA
  • 35 Department of Pediatrics, Pediatric Gastroenterology Unit, Regina Margherita Children's Hospital, Azienda Ospedaliera-Universitaria Citta' della Salute e della Scienza, Turin, Italy
  • 36 Pediatric Hepatology and Liver Transplant Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain
  • 37 Department of Paediatrics, Division of Paediatric Gastroenterology and Hepatology, London Health Sciences Centre, Children's Hospital, Western University, London, Ontario, Canada
  • 38 Department of Pediatric Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Servizio di Epatologia Pediatrica, Milan, Italy
  • 39 Department of Pediatrics, Division of Pediatric Gastroenterology and Hepatology, Phoenix Children's Hospital, Phoenix, Arizona, USA
  • 40 Department of Pediatrics, Centro Hospitalar Universitário Do Porto, Pediatric Gastroenterology Unit, Porto, Portugal
  • 41 Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
  • 42 Department of Pediatrics, Division of Gastroenterology, Hepatology, & Nutrition, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, US A
  • 43 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  • 44 Department of Pediatrics, Paediatric Gastroenterology Unit, Cruces University Hospital, Bilbao, Spain
  • 45 Department of Gastroenterology, Hepatology and Nutrition, Pediatric Gastroenterology Hepatology and Nutrition Unit, Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
  • 46 Department of Paediatric Hepatology, Liver Unit, Birmingham Women's & Children's Hospital NHS Trust and University of Birmingham, Birmingham, UK
  • 47 Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
  • 48 Department of Paediatrics, Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
  • 49 Department 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
  • 50 Section of Pediatric Gastroenterology, Department of Pediatrics, University of Manitoba, Winnipeg, Manitoba, Canada
  • 51 Department of Pediatric Gastroenterology, Children's Hospital of Fudan University, The Center for Pediatric Liver Diseases, Shanghai, China
  • 52 Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children's Hospital, Seoul, South Korea
  • 53 Department of Pediatric Gastroenterology, Pediatric Gastroenterology and Hepatology Division, Hospital Italiano Buenos Aires, Buenos Aires, Argentina
  • 54 Department of Paediatrics, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 55 Department of Paediatrics and Child Health, Division of Paediatric Gastroenterology, Chris Hani Baragwanath Academic Hospital, University of the Witwatersrand, Johannesburg, South Africa
  • 56 Department of Pediatrics, Division of Gastroenterology, Ramathibodi Hospital Mahidol University, Bangkok, Thailand
  • 57 Department 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
  • 58 Department of Pediatric Gastroenterology and Organ Transplant, Koç University School of Medicine, Istanbul, Turkey
  • 59 Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
  • 60 Pediatric Gastroenterology Department, Hospital de Base do Distrito Federal, Hospital da Criança de Brasília, Centro Universitário de Brasília, Brasília, DF, Brazil
  • 61 Departamento 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
  • 62 Department of Pediatric Gastroenterology, Le Bonheur Children's Hospital and The University of Tennessee Health Science Center, Memphis, Tennessee, USA
  • 63 Pediatric Gastroenterology, Hepatology and Nutrition Department, Istanbul University Istanbul Medical Faculty, Istanbul, Turkey
  • 64 Solid Organ Transplant Department, Children's Health-Children's Medical Center, Dallas, Texas, USA
  • 65 Department of Pediatrics, Medical University of Silesia in Katowice, Katowice, Poland
  • 66 Department of Pediatric Gastroenterology, Division of Pediatric Gastroenterology of Hospital da Criança Conceição do Grupo Hospitalar Conceição, Porto Alegre, RS, Brazil
  • 67 Department of Pediatric Gastroenterology, University Medical Center Utrecht, Utrecht, The Netherlands
  • 68 Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition/Miami Transplant Institute, University of Miami, Miami, Florida, USA
  • 69 Department of Pediatric Intensive Care, Wits Donald Gordon Medical Centre, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
  • 70 Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Rochester Medical Center, Rochester, New York, USA
  • 71 Pediatric Gastroenterology, Hepatology and Nutrition, and Department of Pediatrics, Faculty of Medicine, University Medical Center Ljubljana, Ljubljana, Slovenia
  • 72 Department of Pediatrics, Gynecology, and Obstetrics, Division of Pediatric Specialties, Swiss Pediatric Liver Center, University Hospitals Geneva and University of Geneva, Geneva, Switzerland
  • 73 Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
  • 74 Department of Pediatrics, Harvard Medical School, Massachusetts General Hospital for Children, Boston, Massachusetts, USA
  • 75 Department of Inflammation Biology, Institute of Liver Studies, King's College London, London, UK
Hepatology, 2023 Dec 25.
PMID: 38146932 DOI: 10.1097/HEP.0000000000000727

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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