Document Type
Article
Publication Date
6-1-2024
Identifier
DOI: 10.1097/HEP.0000000000000727; PMCID: PMC11095900
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.
Journal Title
Hepatology (Baltimore, Md.)
Volume
79
Issue
6
First Page
1279
Last Page
1292
MeSH Keywords
Humans; Alagille Syndrome; Female; Male; Retrospective Studies; Child; Infant; Child, Preschool; Progression-Free Survival; Adolescent; Carrier Proteins; Membrane Glycoproteins
Keywords
Alagille Syndrome; Retrospective Studies; Progression-Free Survival; Carrier Proteins; Membrane Glycoproteins
Recommended Citation
Hansen BE, Vandriel SM, Vig P, et al. Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA. Hepatology. 2024;79(6):1279-1292. doi:10.1097/HEP.0000000000000727
Comments
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.
Publisher's Link: https://journals.lww.com/hep/fulltext/2024/06000/event_free_survival_of_maralixibat_treated.11.aspx