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

Bettina E. Hansen*, Shannon M. Vandriel, Pamela Vig, The Global ALagille Alliance (GALA) Study Group, Will Garner, Douglas B. Mogul, Kathleen M. Loomes, David A. Piccoli, Elizabeth B. Rand, Irena Jankowska, Piotr Czubkowski, Dorota Gliwicz-Miedzińska, Emmanuel M. Gonzales, Emmanuel Jacquemin, Jérôme Bouligand, Lorenzo D’Antiga, Emanuele Nicastro, Henrik Arnell, Björn Fischler, Étienne SokalTanguy Demaret, Susan Siew, Michael Stormon, Saul J. Karpen, Rene Romero, Noelle H. Ebel, Jeffrey A. Feinstein, Amin J. Roberts, Helen M. Evans, Shikha S. Sundaram, Alexander Chaidez, Winita Hardikar, Sahana Shankar, Ryan T. Fischer, Florence Lacaille, Dominique Debray, Henry C. Lin, M. Kyle Jensen, Catalina Jaramillo, Palaniswamy Karthikeyan, Giuseppe Indolfi, Henkjan J. Verkade, Catherine Larson-Nath, Ruben E. Quiros-Tejeira, Pamela L. Valentino, Maria Rogalidou, Antal Dezsőfi, James E. Squires, Kathleen Schwarz, Pier Luigi Calvo, Li Ting Li

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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 Global ALagille Alliance (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.

Original languageEnglish
Pages (from-to)1279-1292
Number of pages14
Issue number6
Publication statusPublished - Jun 2024

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Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.


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