Maralixibat Improves Xanthomas and Hypercholesterolemia in Children with Alagille Syndrome: A Post Hoc Integrated Analysis From Two Clinical Trials

OBJECTIVES: To characterize baseline xanthoma prevalence and severity in Alagille syndrome, assess their impact on quality of life, evaluate longitudinal changes in xanthoma burden with maralixibat therapy, and identify clinical and biochemical predictors of treatment response in children enrolled across 2 clinical trials. STUDY DESIGN: This integrated analysis from the ICONIC and ITCH trials assessed xanthoma severity using the Clinician Xanthoma Scale (CXS). Response was defined as a ≥1-point reduction from baseline in CXS. Outcomes included changes in serum lipids, serum bile acids (sBA), pruritus, and Pediatric Quality of Life Inventory scores through week 96. Baseline characteristics were compared across xanthoma severity groups using the Jonckheere-Terpstra test for continuous variables and the Cochran-Armitage trend test for categorical variables. The changes in xanthoma severity category (3 levels) from baseline to weeks 48 and 96 were tested using Bowker's test of symmetry. Change from baseline (CFB) of continuous outcomes were tested using the Wilcoxon signed-rank test. Differences in CFB of outcomes between xanthoma responders and nonresponders were evaluated using the Wilcoxon rank-sum test for continuous variables and Fisher exact test for categorical outcomes. RESULTS: Among 63 children (ICONIC, n=29; ITCH, n=34), 43% had xanthomas at baseline. Higher CXS was associated with younger age (P=0.03); elevated sBA (P<0.001), bilirubin (P<0.001), alanine aminotransferase (P=0.008), and gamma-glutamyl transferase (P=0.02); and worse lipid profiles (total cholesterol, P<0.001; high-density lipoprotein, P<0.001). Quality of life declined with increasing CXS. After 96 weeks of follow-up (ICONIC, n=18; ITCH, n=17), mean CXS decreased (P=0.004), and CXS 0 prevalence increased from 60% to 86% (P=0.03). There was a significant decline in cholesterol (mean CFB, -55 mg/dL, P<0.001) and sBA (mean CFB, -85 μmol/L, P<0.001). Among participants with baseline CXS ≥1 (n=14; ICONIC, n=8; ITCH, n=6), 71% and 64% were xanthoma responders at weeks 48 and 96. Responders had greater cholesterol reductions at week 48 (mean CFB, -189 vs -11 mg/dL, P=0.005) and more frequent pruritus improvement (94% vs 68%, P=0.047). CONCLUSIONS: Maralixibat may reduce xanthoma burden and improve metabolic parameters, supporting therapeutic potential of the drug for xanthomas in ALGS.