Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA.
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
25 Dec 2023
25 Dec 2023
Historique:
received:
09
08
2023
accepted:
18
11
2023
medline:
26
12
2023
pubmed:
26
12
2023
entrez:
26
12
2023
Statut:
aheadofprint
Résumé
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. 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. 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.
Sections du résumé
BACKGROUND AND AIMS
OBJECTIVE
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
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
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.
Identifiants
pubmed: 38146932
doi: 10.1097/HEP.0000000000000727
pii: 01515467-990000000-00695
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.