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

Author:

Hansen Bettina E.123,Vandriel Shannon M.4,Vig Pamela5,Garner Will5,Mogul Douglas B.5,Loomes Kathleen M.6,Piccoli David A.6,Rand Elizabeth B.6,Jankowska Irena7,Czubkowski Piotr7,Gliwicz-Miedzińska Dorota7,Gonzales Emmanuel M.8,Jacquemin Emmanuel8,Bouligand Jérôme9,D’Antiga Lorenzo10,Nicastro Emanuele10,Arnell Henrik11,Fischler Björn12,Sokal Étienne13,Demaret Tanguy13,Siew Susan14,Stormon Michael14,Karpen Saul J.15,Romero Rene15,Ebel Noelle H.16,Feinstein Jeffrey A.17,Roberts Amin J.18,Evans Helen M.18,Sundaram Shikha S.19,Chaidez Alexander19,Hardikar Winita20,Shankar Sahana21,Fischer Ryan T.22,Lacaille Florence23,Debray Dominique24,Lin Henry C.25,Jensen M. Kyle26,Jaramillo Catalina26,Karthikeyan Palaniswamy27,Indolfi Giuseppe28,Verkade Henkjan J.29,Larson-Nath Catherine30,Quiros-Tejeira Ruben E.31,Valentino Pamela L.32,Rogalidou Maria33,Dezsőfi Antal34,Squires James E.35,Schwarz Kathleen36,Calvo Pier Luigi37,Bernabeu Jesus Quintero3839,Zizzo Andréanne N.40,Nebbia Gabriella41,Bulut Pinar42,Santos-Silva Ermelinda43,Fawaz Rima44,Nastasio Silvia45,Karnsakul Wikrom46,Tamara María Legarda47,Busoms Cristina Molera48,Kelly Deirdre49,Sandahl Thomas Damgaard50,Jimenez-Rivera Carolina51,Banales Jesus M.52,Mujawar Quais53,Li Li-Ting54,She Huiyu54,Wang Jian-She54,Kim Kyung Mo55,Oh Seak Hee55,Sanchez Maria Camila56,Cavalieri Maria Lorena56,Lee Way Seah57,Hajinicolaou Christina58,Lertudomphonwanit Chatmanee59,Waisbourd-Zinman Orith60,Arikan Cigdem61,Alam Seema62,Carvalho Elisa63,Melere Melina64,Eshun John65,Önal Zerrin66,Desai Dev M.67,Wiecek Sabina68,Pinto Raquel Borges69,Wolters Victorien M.70,Garcia Jennifer71,Beretta Marisa72,Kerkar Nanda73,Brecelj Jernej74,Rock Nathalie75,Lurz Eberhard76,Blondet Niviann32,Shah Uzma77,Thompson Richard J.78,Kamath Binita M.4,

Affiliation:

1. Toronto General Hospital University Health Network, Toronto, ON, Canada

2. Institute of Health Policy, Management and Evaluation, Toronto, ON, Canada

3. Department of Epidemiology, Erasmus MC, Rotterdam, Netherlands

4. The Hospital for Sick Children and the University of Toronto, Division of Gastroenterology, Hepatology and Nutrition, Toronto, ON, Canada

5. Mirum Pharmaceuticals, Inc., Foster City, CA, USA

6. The Children’s Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Philadelphia, PA, USA

7. The Children’s Memorial Health Institute, Department of Gastroenterology, Hepatology, Nutrition Disturbances and Pediatrics, Warsaw, Poland

8. 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

9. Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Hôpitaux Universitaires Paris-Saclay, Assistance PubliqueHôpitaux de Paris, Centre Hospitalier Universitaire de Bicêtre, Le Kremlin-Bicêtre, France

10. Ospedale Papa Giovanni XXIII, Pediatric Hepatology, Gastroenterology and Transplantation, Bergamo, Italy

11. Astrid Lindgren Children’s Hospital, Department of Paediatric Gastroenterology, Hepatology and Nutrition, Karolinska University Hospital and Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden

12. Astrid Lindgren Children’s Hospital, Department of Paediatric Gastroenterology, Hepatology and Nutrition, Karolinska University Hospital and CLINTEC, Karolinska Institutet, Stockholm, Sweden

13. Cliniques Universitaires Saint-Luc, Service De Gastroentérologie & Hépatologie Pédiatrique, Brussels, Belgium

14. The Children’s Hospital at Westmead, Department of Gastroenterology, Sydney, NSW, Australia

15. Children’s Healthcare of Atlanta & Emory University School of Medicine, Division of Pediatric Gastroenterology, Hepatology & Nutrition, Atlanta, Georgia

16. Division of Gastroenterology, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA, USA

17. Department of Pediatrics (Cardiology), Stanford University School of Medicine, Lucile Packard Children’s Hospital, Palo Alto, CA, USA

18. Starship Child Health, Department of Paediatric Gastroenterology, Auckland, New Zealand

19. 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, CO, USA

20. Royal Children’s Hospital, Department of Gastroenterology and Clinical Nutrition, Melbourne, Vic, Australia

21. Mazumdar Shaw Medical Center, Narayana Health, Bangalore, India

22. Children’s Mercy Kansas City, Department of Gastroenterology, Section of Hepatology, Kansas City, MO, USA

23. Department of Pediatric Gastroenterology, and Nutrition, Necker-Enfants Malades Hospital, University of Paris, Paris, France

24. 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

25. Oregon Health and Science University, Division of Pediatric Gastroenterology, Department of Pediatrics, Portland, OR, USA

26. University of Utah, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Primary Children’s Hospital, Salt Lake City, UT, USA

27. Leeds Teaching Hospitals NHS Trust, Leeds Children’s Hospital, Leeds, UK

28. Department Neurofarba, University of Florence and Meyer Children’s University Hospital, Paediatric and Liver Unit, Florence, Italy

29. University Medical Center Groningen, Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, Groningen, The Netherlands

30. University of Minnesota, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Minneapolis, MN, USA

31. Children’s Hospital & Medical Center and University of Nebraska Medical Center, Department of Pediatrics, Omaha, NE, USA

32. Gastroenterology & Hepatology Division, Department of Pediatrics, University of Washington, Seattle Children’s Hospital, Seattle, WA, USA

33. Division of Gastroenterology & Hepatology, “Agia Sofia” Children’s Hospital, First Department of Pediatrics, University of Athens, Athens, Greece

34. First Department of Paediatrics, Semmelweis University, Budapest, Hungary

35. University of Pittsburgh School of Medicine, Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, Pittsburgh, PA, USA

36. University of California San Diego, Rady Children’s Hospital San Diego, Division of Pediatric Gastroenterology, San Diego, CA, USA

37. Pediatric Gastroenterology Unit, Regina Margherita Children’s Hospital, Azienda Ospedaliera-Universitaria Citta’ della Salute e della Scienza, Turin, Italy

38. Hospital Universitari Vall d’Hebron, Pediatric Hepatology and Liver Transplant Department, Barcelona, Spain

39. Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute – Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain

40. Children’s Hospital, London Health Sciences Centre, Division of Paediatric Gastroenterology and Hepatology, Western University, London, ON, Canada

41. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Servizio di Epatologia Pediatrica, Milan, Italy

42. Phoenix Children’s Hospital, Division of Pediatric Gastroenterology and Hepatology, Phoenix, AZ, USA

43. Centro Hospitalar Universitário Do Porto, Pediatric Gastroenterology Unit, Porto, Portugal

44. Yale University School of Medicine, Department of Pediatrics, New Haven, CT, USA

45. Boston Children’s Hospital and Harvard Medical School, Division of Gastroenterology, Hepatology, & Nutrition, Boston, MA, USA

46. Johns Hopkins University School of Medicine, Department of Pediatrics, Baltimore, MD, USA

47. Paediatric Gastroenterology Unit, Cruces University Hospital, Bilbao, Spain

48. Pediatric Gastroenterology Hepatology and Nutrition Unit, Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain

49. Liver Unit, Birmingham Women’s & Children’s Hospital NHS Trust and University of Birmingham, Birmingham, UK

50. Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark

51. Children’s Hospital of Eastern Ontario, Division of Gastroenterology, Hepatology and Nutrition, Ottawa, ON, Canada

52. Department of Hepatology and Gastroenterology, Biodonostia Health Research Institute - Donostia University Hospital, Universidad del País Vasco (UPV/EHU), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), San Sebastián, Spain

53. University of Manitoba, Section of Pediatric Gastroenterology, Department of Pediatrics, Winnipeg, MB, Canada

54. Children’s Hospital of Fudan University, The Center for Pediatric Liver Diseases, Shanghai, China

55. Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children’s Hospital, Seoul, South Korea

56. Hospital Italiano Buenos Aires, Pediatric Gastroenterology and Hepatology Division, Buenos Aires, Argentina

57. Faculty of Medicine, Department of Paediatrics, University of Malaya, Kuala Lumpur, Malaysia

58. Division of Paediatric Gastroenterology, Chris Hani Baragwanath Academic Hospital, Department of Paediatrics and Child Health, University of the Witwatersrand, Johannesburg, South Africa

59. Ramathibodi Hospital Mahidol University, Division of Gastroenterology, Department of Pediatrics, Bangkok, Thailand

60. Schneider Children’s Medical Center of Israel, Institute of Gastroenterology, Nutrition and Liver Diseases, Petah Tikva, Sackler Faculty of Medicine, Tel-Aviv University, Israel

61. Koç University School of Medicine, Department of Pediatric Gastroenterology and Organ Transplant, Istanbul, Turkey

62. Institute of Liver and Biliary Sciences, Department of Pediatric Hepatology, New Delhi, India

63. Pediatric Gastroenterology Department, Hospital de Base do Distrito Federal, Hospital da Criança de Brasília, Centro Universitário de Brasília, Brasília, DF, Brazil

64. 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

65. Department of Pediatric Gastroenterology, Le Bonheur Children’s Hospital and The University of Tennessee Health Science Center, Memphis, Tennessee

66. Pediatric Gastroenterology, Hepatology and Nutrition Department, Istanbul University Istanbul Medical Faculty, Istanbul, Turkey

67. Solid Organ Transplant Department, Children’s Health – Children’s Medical Center, Dallas, Texas

68. Medical University of Silesia in Katowice, Department of Pediatrics, Katowice, Poland

69. Division of Pediatric Gastroenterology of Hospital da Criança Conceição do Grupo Hospitalar Conceição, Porto Alegre, RS, Brazil

70. Department of Pediatric Gastroenterology, University Medical Center Utrecht, Utrecht, Netherlands

71. Division of Pediatric Gastroenterology, Hepatology and Nutrition/Miami Transplant Institute, University of Miami, Miami, Florida

72. Faculty of Health Sciences, Wits Donald Gordon Medical Centre, University of the Witwatersrand, Johannesburg, South Africa

73. University of Rochester Medical Center, Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Rochester, NY, USA

74. University Medical Center Ljubljana, Pediatric Gastroenterology, Hepatology and Nutrition, and Department of Pediatrics, Faculty of Medicine, Ljubljana, Slovenia

75. Swiss Pediatric Liver Center, Division of Pediatric Specialties, Department of Pediatrics, Gynecology, and Obstetrics, University Hospitals Geneva and University of Geneva, Geneva, Switzerland

76. Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany

77. Harvard Medical School, Massachusetts General Hospital for Children, Boston, MA, USA

78. 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 the first-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≤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 (sBA) could not be included in the GALA filtering criteria as these are routinely performed in clinical practice. Index time was determined via maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival (EFS), defined as 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 (TB), gamma-glutamyl transferase (GGT), and alanine aminotransferase (ALT) were balanced between groups with no statistical differences. EFS in the maralixibat cohort was significantly better than the GALA cohort (hazard ratio 0.305; 95% CI, 0.189-0.491; p<0.0001). Multiple sensitivity and subgroup analyses (including sBA 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 EFS in patients with ALGS.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Hepatology

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