Bettina E. Hansen
Shannon M. Vandriel
Pamela Vig
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 Sokal
Tanguy 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, Children's Mercy HospitalFollow
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
Jesus Quintero Bernabeu
Andréanne N Zizzo
Gabriella Nebbia
Pinar Bulut
Ermelinda Santos-Silva
Rima Fawaz
Silvia Nastasio
Wikrom Karnsakul
María Legarda Tamara
Cristina Molera Busoms
Deirdre A. Kelly
Thomas Damgaard Sandahl
Carolina Jimenez-Rivera
Jesus M. Banales
Quais Mujawar
Li-Ting Li
Huiyu She
Jian-She Wang
Kyung Mo Kim
Seak Hee Oh
Maria Camila Sanchez
Maria Lorena Cavalieri
Way Seah Lee
Christina Hajinicolaou
Chatmanee Lertudomphonwanit
Orith Waisbourd-Zinman
Cigdem Arikan
Seema Alam
Elisa Carvalho
Melina Melere
John Eshun
Zerrin Önal
Dev M. Desai
Sabina Wiecek
Raquel Borges Pinto
Victorien M. Wolters
Jennifer Garcia
Marisa Beretta
Nanda Kerkar
Jernej Brecelj
Nathalie Rock
Eberhard Lurz
Niviann Blondet
Uzma Shah
Richard J. Thompson
Binita M. Kamath
Global ALagille Alliance (GALA) Study Group

Document Type


Publication Date



DOI: 10.1097/HEP.0000000000000727; PMCID: PMC11095900


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.

Journal Title

Hepatology (Baltimore, Md.)





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MeSH Keywords

Humans; Alagille Syndrome; Female; Male; Retrospective Studies; Child; Infant; Child, Preschool; Progression-Free Survival; Adolescent; Carrier Proteins; Membrane Glycoproteins


Alagille Syndrome; Retrospective Studies; Progression-Free Survival; Carrier Proteins; Membrane Glycoproteins


This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed.

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