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 Global ALagille Alliance (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.
