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

Hansen, Bettina E. (Co-premier auteur) 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, Etienne [UCL] Demaret, Tanguy [UCL] 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. et al.[show all]

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.