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, Will Garner, Douglas Mogul, Kathleen M. Loomes, David A. Piccoli, Elizabeth B. Rand, Irena Jankowska, Piotr Czubkowski, Dorota Gliwicz‐Miedzińska, Emmanuel Gonzalès, Emmanuel Jacquemin, Jérôme Bouligand, Lorenzo D’Antiga, Emanuele Nicastro, Henrik Arnell, Björn Fischler, Étienne Sokal, Tanguy Demaret, Susan Siew, Michael Stormon, Saul J. Karpen, René Romero, Noelle H. Ebel, Jeffrey A. Feinstein, Amin J. Roberts, Helen 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, Rubén E. Quirós‐Tejeira, Pamela L. Valentino, Maria Rogalidou, Antal Dezsőfi, James E. Squires, Kathleen B. 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, Déirdre Kelly, Thomas Damgaard Sandahl, Carolina Jiménez‐Rivera, Jesús M. Bañales, Quais Mujawar, Liting Li, Huiyu She, Jian‐She Wang, Kyung Mo Kim, Seak Hee Oh, María Camila Sanchez, Maria Lorena Cavalieri, Way Seah Lee, Christina Hajinicolaou, Chatmanee Lertudomphonwanit, Orith Waisbourd‐Zinman, Çiğdem Arıkan, Seema Alam, Elisa de Carvalho, Melina Melere, John Eshun, Zerrin Önal, Dev M. Desai, Sabina Więcek, Raquel Borges Pinto, Victorien M. Wolters, Jennifer García, Marisa Beretta, Nanda Kerkar, Jernej Brecelj, Nathalie Rock, Eberhard Lurz, Niviann Blondet, Uzma Shah, Richard J. Thompson, Binita M. Kamath, The Global ALagille Alliance (GALA) Study Group
Abstract
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.