Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA
Authors: Hansen Bettina E. , Vandriel Shannon M. , Vig Pamela , Garner Will , Mogul Douglas B. , Loomes Kathleen M. , Piccoli David A. , Rand Elizabeth B. , Jankowska Irena , Czubkowski Piotr , Gliwicz-Miedzińska Dorota , Gonzales Emmanuel M. , Jacquemin Emmanuel , Bouligand Jérôme , D’Antiga Lorenzo , Nicastro Emanuele , Arnell Henrik , Fischler Björn , Sokal Étienne , Demaret Tanguy , Siew Susan , Stormon Michael , Karpen Saul J. , Romero Rene , Ebel Noelle H. , Feinstein Jeffrey A. , Roberts Amin J. , Evans Helen M. , Sundaram Shikha S. , Chaidez Alexander , Hardikar Winita , Shankar Sahana , Fischer Ryan T. , Lacaille Florence , Debray Dominique , Lin Henry C. , Jensen M. Kyle , Jaramillo Catalina , Karthikeyan Palaniswamy , Indolfi Giuseppe , Verkade Henkjan J. , Larson-Nath Catherine , Quiros-Tejeira Ruben E. , Valentino Pamela L. , Rogalidou Maria , Dezsőfi Antal , Squires James E. , Schwarz Kathleen , Calvo Pier Luigi , Bernabeu Jesus Quintero , Zizzo Andréanne N. , Nebbia Gabriella , Bulut Pinar , Santos-Silva Ermelinda , Fawaz Rima , Nastasio Silvia , Karnsakul Wikrom , Tamara María Legarda , Busoms Cristina Molera , Kelly Deirdre A. , Sandahl Thomas Damgaard , Jimenez-Rivera Carolina , Banales Jesus M. , Mujawar Quais , Li Li-Ting , She Huiyu , Wang Jian-She , Kim Kyung Mo , Oh Seak Hee , Sanchez Maria Camila , Cavalieri Maria Lorena , Lee Way Seah , Hajinicolaou Christina , Lertudomphonwanit Chatmanee , Waisbourd-Zinman Orith , Arikan Cigdem , Alam Seema , Carvalho Elisa , Melere Melina , Eshun John , Önal Zerrin , Desai Dev M. , Wiecek Sabina , Pinto Raquel Borges , Wolters Victorien M. , Garcia Jennifer , Beretta Marisa , Kerkar Nanda , Brecelj Jernej , Rock Nathalie , Lurz Eberhard , Blondet Niviann , Shah Uzma , Thompson Richard J. , Kamath Binita M. ,   The Global ALagille Alliance (GALA) Study Group
Published: December 2023

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 theGlobalALagilleAlliance (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.