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  • OC7 Maralixibat-treated patients with Alagille syndrome demonstrate event-free survival in a natural history comparison with patients with from the GALA database: application of real-world evidence analytics

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OC7 Maralixibat-treated patients with Alagille syndrome demonstrate event-free survival in a natural history comparison with patients with from the GALA database: application of real-world evidence analytics
  1. BE Hansen1,2,3,
  2. SM Vandriel4,
  3. P Vig5,
  4. W Garner5,
  5. DB Mogul5,
  6. KM Loomes6,
  7. DA Piccoli6,
  8. EB Rand6,
  9. I Jankowska7,
  10. P Czubkowski7,
  11. D Gliwicz-Miedzińska7,
  12. EM Gonzales8,
  13. E Jacquemin8,
  14. J Bouligand9,
  15. L D’Antiga10,
  16. E Nicastro10,
  17. H Arnell11,
  18. B Fischler12,
  19. É Sokal13,
  20. T Demaret13,
  21. S Siew14,
  22. M Stormon14,
  23. SJ Karpen15,
  24. R Romero15,
  25. NH Ebel16,
  26. JA Feinstein17,
  27. AJ Roberts18,
  28. HM Evans18,
  29. SS Sundaram19,
  30. A Chaidez19,
  31. W Hardikar20,
  32. S Shankar21,
  33. RT Fischer22,
  34. F Lacaille23,
  35. D Debray24,
  36. HC Lin25,
  37. MK Jensen26,
  38. C Jaramillo26,
  39. P Karthikeyan27,
  40. G Indolfi28,
  41. HJ Verkade29,
  42. C Larson-Nath30,
  43. RE Quiros-Tejeira31,
  44. PL Valentino32,
  45. M Rogalidou33,
  46. A Dezsőfi34,
  47. JE Squires35,
  48. K Schwarz36,
  49. PL Calvo37,
  50. J Quintero Bernabeu38,39,
  51. AN Zizzo40,
  52. G Nebbia41,
  53. P Bulut42,
  54. E Santos-Silva43,
  55. R Fawaz44,
  56. S Nastasio45,
  57. W Karnsakul46,
  58. M Legarda Tamara47,
  59. C Molera Busoms48,
  60. D Kelly49,
  61. T Damgaard Sandahl50,
  62. C Jimenez-Rivera51,
  63. JM Banales52,
  64. Q Mujawar53,
  65. LT Li54,
  66. H She54,
  67. JS Wang54,
  68. KM Kim55,
  69. SH Oh55,
  70. MC Sanchez56,
  71. ML Cavalieri56,
  72. WS Lee57,
  73. C Hajinicolaou58,
  74. C Lertudomphonwanit59,
  75. O Waisbourd-Zinman60,
  76. C Arikan61,
  77. S Alam62,
  78. E Carvalho63,
  79. M Melere64,
  80. J Eshun65,
  81. Z Önal66,
  82. DM Desai67,
  83. S Wiecek68,
  84. RB Pinto69,
  85. VM Wolters70,
  86. J Garcia71,
  87. M Beretta72,
  88. N Kerkar73,
  89. J Brecelj74,
  90. N Rock75,
  91. E Lurz76,
  92. N Blondet32,
  93. U Shah77,
  94. RJ Thompson78,
  95. BM Kamath4,
  96. The Global ALagille Alliance (GALA) Study Group
  1. 1Toronto General Hospital University Health Network, Toronto, ON, Canada
  2. 2Institute of Health Policy, Management and Evaluation, Toronto, ON, Canada
  3. 3Department of Epidemiology, Erasmus MC, Rotterdam, Netherlands
  4. 4The Hospital for Sick Children and the University of Toronto, Division of Gastroenterology, Hepatology and Nutrition, Toronto, ON, Canada
  5. 5Mirum Pharmaceuticals, Inc., Foster City, CA, USA
  6. 6The Children’s Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Philadelphia, PA, USA
  7. 7The Children’s Memorial Health Institute, Department of Gastroenterology, Hepatology, Nutrition Disturbances and Pediatrics, Warsaw, Poland
  8. 8Service 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. 9Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Hôpitaux Universitaires Paris-Saclay, Assistance PubliqueHôpitaux de Paris, Centre Hospitalier Universitaire de Bicêtre, Le Kremlin-Bicêtre, France
  10. 10Ospedale Papa Giovanni XXIII, Pediatric Hepatology, Gastroenterology and Transplantation, Bergamo, Italy
  11. 11Astrid 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. 12Astrid Lindgren Children’s Hospital, Department of Paediatric Gastroenterology, Hepatology and Nutrition, Karolinska University Hospital and CLINTEC, Karolinska Institutet, Stockholm, Sweden
  13. 13Cliniques Universitaires Saint-Luc, Service De Gastroentérologie and Hépatologie Pédiatrique, Brussels, Belgium
  14. 14The Children’s Hospital at Westmead, Department of Gastroenterology, Sydney, NSW, Australia
  15. 15Children’s Healthcare of Atlanta and Emory University School of Medicine, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Atlanta, GA, USA
  16. 16Division of Gastroenterology, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA, USA
  17. 17Department of Pediatrics (Cardiology), Stanford University School of Medicine, Lucile Packard Children’s Hospital, Palo Alto, CA, USA
  18. 18Starship Child Health, Department of Paediatric Gastroenterology, Auckland, New Zealand
  19. 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, CO, USA
  20. 20Royal Children’s Hospital, Department of Gastroenterology and Clinical Nutrition, Melbourne, Vic, Australia
  21. 21Mazuar Shaw Medical Center, Narayana Health, Bangalore, India
  22. 22Children’s Mercy Kansas City, Department of Gastroenterology, Section of Hepatology, Kansas City, MO, USA
  23. 23Department of Pediatric Gastroenterology, and Nutrition, Necker-Enfants Malades Hospital, University of Paris, Paris, France
  24. 24Pediatric 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. 25Oregon Health and Science University, Division of Pediatric Gastroenterology, Department of Pediatrics, Portland, OR, USA
  26. 26University of Utah, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Primary Children’s Hospital, Salt Lake City, UT, USA
  27. 27Leeds Teaching Hospitals NHS Trust, Leeds Children’s Hospital, Leeds, UK
  28. 28Department Neurofarba, University of Florence and Meyer Children’s University Hospital, Paediatric and Liver Unit, Florence, Italy
  29. 29University Medical Center Groningen, Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, Groningen, The Netherlands
  30. 30University of Minnesota, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Minneapolis, MN, USA
  31. 31Children’s Hospital and Medical Center and University of Nebraska Medical Center, Department of Pediatrics, Omaha, NE, USA
  32. 32Gastroenterology and Hepatology Division, Department of Pediatrics, University of Washington, Seattle Children’s Hospital, Seattle, WA, USA
  33. 33Division of Gastroenterology and Hepatology, “Agia Sofia” Children’s Hospital, First Department of Pediatrics, University of Athens, Athens, Greece
  34. 34First Department of Paediatrics, Semmelweis University, Budapest, Hungary
  35. 35University of Pittsburgh School of Medicine, Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, Pittsburgh, PA, USA
  36. 36University of California San Diego, Rady Children’s Hospital San Diego, Division of Pediatric Gastroenterology, San Diego, CA, USA
  37. 37Pediatric Gastroenterology Unit, Regina Margherita Children’s Hospital, Azienda Ospedaliera-Universitaria Citta’ della Salute e della Scienza, Turin, Italy
  38. 38Hospital Universitari Vall d’Hebron, Pediatric Hepatology and Liver Transplant Department, Barcelona, Spain
  39. 39Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute – Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
  40. 40Children’s Hospital, London Health Sciences Centre, Division of Paediatric Gastroenterology and Hepatology, Western University, London, ON, Canada
  41. 41Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Servizio di Epatologia Pediatrica, Milan, Italy
  42. 42Phoenix Children’s Hospital, Division of Pediatric Gastroenterology and Hepatology, Phoenix, AZ, USA
  43. 43Centro Hospitalar Universitário Do Porto, Pediatric Gastroenterology Unit, Porto, Portugal
  44. 44Yale University School of Medicine, Department of Pediatrics, New Haven, CT, USA
  45. 45Boston Children’s Hospital and Harvard Medical School, Division of Gastroenterology, Hepatology, and Nutrition, Boston, MA, USA
  46. 46Johns Hopkins University School of Medicine, Department of Pediatrics, Baltimore, , USA
  47. 47Paediatric Gastroenterology Unit, Cruces University Hospital, Bilbao, Spain
  48. 48Pediatric Gastroenterology Hepatology and Nutrition Unit, Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
  49. 49Liver Unit, Birmingham Women’s and Children’s Hospital NHS Trust and University of Birmingham, Birmingham, UK
  50. 50Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
  51. 51Children’s Hospital of Eastern Ontario, Division of Gastroenterology, Hepatology and Nutrition, Ottawa, ON, Canada
  52. 52Department 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. 53University of Manitoba, Section of Pediatric Gastroenterology, Department of Pediatrics, Winnipeg, MB, Canada
  54. 54Children’s Hospital of Fudan University, The Center for Pediatric Liver Diseases, Shanghai, China
  55. 55Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children’s Hospital, Seoul, South Korea
  56. 56Hospital Italiano Buenos Aires, Pediatric Gastroenterology and Hepatology Division, Buenos Aires, Argentina
  57. 57Faculty of Medicine, Department of Paediatrics, University of Malaya, Kuala Lumpur, Malaysia
  58. 58Division of Paediatric Gastroenterology, Chris Hani Baragwanath Academic Hospital, Department of Paediatrics and Child Health, University of the Witwatersrand, Johannesburg, South Africa
  59. 59Ramathibodi Hospital Mahidol University, Division of Gastroenterology, Department of Pediatrics, Bangkok, Thailand
  60. 60Schneider Children’s Medical Center of Israel, Institute of Gastroenterology, Nutrition and Liver Diseases, Petah Tikva, Sackler Faculty of Medicine, Tel-Aviv University, Israel
  61. 61Koç University School of Medicine, Department of Pediatric Gastroenterology and Organ Transplant, Istanbul, Turkey
  62. 62Institute of Liver and Biliary Sciences, Department of Pediatric Hepatology, New Delhi, India
  63. 63Pediatric Gastroenterology Department, Hospital de Base do Distrito Federal, Hospital da Criança de Brasília, Centro Universitário de Brasília, Brasília, DF, Brazil
  64. 64Pediatric 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. 65Department of Pediatric Gastroenterology, Le Bonheur Children’s Hospital and The University of Tennessee Health Science Center, Memphis, TN, USA
  66. 66Pediatric Gastroenterology, Hepatology and Nutrition Department, Istanbul University Istanbul Medical Faculty, Istanbul, Turkey
  67. 67Solid Organ Transplant Department, Children’s Health – Children’s Medical Center, Dallas, TX, USA
  68. 68Medical University of Silesia in Katowice, Department of Pediatrics, Katowice, Poland
  69. 69Division of Pediatric Gastroenterology of Hospital da Criança Conceição do Grupo Hospitalar Conceição, Porto Alegre, RS, Brazil
  70. 70Department of Pediatric Gastroenterology, University Medical Center Utrecht, Utrecht, Netherlands
  71. 71Division of Pediatric Gastroenterology, Hepatology and Nutrition/Miami Transplant Institute, University of Miami, Miami, FL, USA
  72. 72Faculty of Health Sciences, Wits Donald Gordon Medical Centre, University of the Witwatersrand, Johannesburg, South Africa
  73. 73University of Rochester Medical Center, Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Rochester, NY, USA
  74. 74University Medical Center Ljubljana, Pediatric Gastroenterology, Hepatology and Nutrition, and Department of Pediatrics, Faculty of Medicine, Ljubljana, Slovenia
  75. 75Swiss Pediatric Liver Center, Division of Pediatric Specialties, Department of Pediatrics, Gynecology, and Obstetrics, University Hospitals Geneva and University of Geneva, Geneva, Switzerland
  76. 76Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany
  77. 77Harvard Medical School, Massachusetts General Hospital for Children, Boston, MA, USA
  78. 78Institute of Liver Studies, King’s College London, London, UK

Abstract

Real-world evidence (RWE) analytics continue to advance natural history comparisons in rare diseases. The Global Alagille Alliance (GALA) is the largest global clinical research database for Alagille syndrome (ALGS). Maralixibat (MRX) is an ileal bile acid transporter inhibitor approved by the FDA for the treatment of cholestatic pruritus in patients with ALGS ≥1 year of age. A pre-specified analysis plan applied novel analytical techniques to compare RWE from GALA with a MRX cohort with the aim to compare event-free survival (EFS) in patients with ALGS.

GALA contains retrospective data for clinical parameters, biochemistries and outcomes. The MRX database comprises of 84 ALGS patients with up to 6 years of data. EFS was defined as the time to first event of hepatic decompensation (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplantation (LT), or death. GALA was filtered to align key MRX eligibility criteria. The index time was determined via maximum likelihood estimation. Balance among baseline (BL) variables was assessed. Selection of patients and index time was blinded to clinical outcomes. Sensitivity and subgroup analyses, and adjustments for covariates, were applied. Missing outcomes data were censored at last contact.

Of 1,438 patients in GALA, 469 were eligible. Age, total bilirubin (TB), gamma glutamyltransferase (GGT) and alanine aminotransferase (ALT) were well balanced between groups and no statistical differences were observed for age, mutation, region, TB, GGT and ALT. Median BL serum bile acids (sBA) was significantly higher in the MRX cohort (p=0.003); 85% of sBA data was not available in GALA. EFS rates in the MRX cohort were significantly better than those reported in the GALA control, (crude 6-year EFS: 73% and 50%, respectively, and adjusted for age, sex, TB, ALT: HR=0.305; 95% CI: 0.189–0.491; p<0.0001). Varied index times, weighted inverse probability of treatment weights, average treatment effect in the treated, LT and death only, regions, sBA sub-group, pruning events to 12 months were consistent with the primary result. Limitations include no standardised measure of pruritus and limited sBA data in GALA, and inherent bias for patients who enter a clinical trial.

This 6-year analysis suggests the potential for improved EFS with MRX in patients with ALGS. This RWE analysis provides a potential method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible. Limitations will always be present given lack of prospective conduct and inherent biases, though sensitivity analyses can help mitigate and aid interpretation.

https://doi.org/10.1136/flgastro-2023-bspghan.7

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