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Abstract Details
Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA
Hepatology. 2023 Dec 25. doi: 10.1097/HEP.0000000000000727. Online ahead of print.
Bettina E Hansen123, Shannon M Vandriel4, Pamela Vig5, Will Garner5, Douglas B Mogul5, Kathleen M Loomes6, David A Piccoli6, Elizabeth B Rand6, Irena Jankowska7, Piotr Czubkowski7, Dorota Gliwicz-Miedzinska7, Emmanuel M Gonzales8, Emmanuel Jacquemin8, Jérôme Bouligand9, Lorenzo D'Antiga10, Emanuele Nicastro10, Henrik Arnell11, Björn Fischler12, Étienne Sokal13, Tanguy Demaret13, Susan Siew14, Michael Stormon14, Saul J Karpen15, Rene Romero15, Noelle H Ebel16, Jeffrey A Feinstein17, Amin J Roberts18, Helen M Evans18, Shikha S Sundaram19, Alexander Chaidez19, Winita Hardikar20, Sahana Shankar21, Ryan T Fischer22, Florence Lacaille23, Dominique Debray24, Henry C Lin25, M Kyle Jensen26, Catalina Jaramillo26, Palaniswamy Karthikeyan27, Giuseppe Indolfi28, Henkjan J Verkade29, Catherine Larson-Nath30, Ruben E Quiros-Tejeira31, Pamela L Valentino32, Maria Rogalidou33, Antal Dezsofi34, James E Squires35, Kathleen Schwarz36, Pier Luigi Calvo37, Jesus Quintero Bernabeu3839, Andréanne N Zizzo40, Gabriella Nebbia41, Pinar Bulut42, Ermelinda Santos-Silva43, Rima Fawaz44, Silvia Nastasio45, Wikrom Karnsakul46, María Legarda Tamara47, Cristina Molera Busoms48, Deirdre Kelly49, Thomas Damgaard Sandahl50, Carolina Jimenez-Rivera51, Jesus M Banales52, Quais Mujawar53
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 the first-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≤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 (sBA) could not be included in the GALA filtering criteria as these are routinely performed in clinical practice. Index time was determined via maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival (EFS), defined as 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 (TB), gamma-glutamyl transferase (GGT), and alanine aminotransferase (ALT) were balanced between groups with no statistical differences. EFS in the maralixibat cohort was significantly better than the GALA cohort (hazard ratio 0.305; 95% CI, 0.189-0.491; p<0.0001). Multiple sensitivity and subgroup analyses (including sBA 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 EFS in patients with ALGS.
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