Efficacy of ileal bile acid transport inhibitors in children with Alagille syndrome: a meta-analysis

Abstract

Cholestatic pruritus is a debilitating and treatment-resistant symptom in children with Alagille syndrome (ALGS), impairing sleep, psychosocial functioning, and quality of life. Current therapies are limited. Ileal bile acid transport inhibitors (IBATIs) are a novel therapeutic option, but evidence remains fragmented. This study aimed to assess the efficacy and safety of IBATIs (maralixibat and odevixibat) versus placebo in pediatric ALGS. Data sources from PubMed, EMBASE, and the Cochrane databases were searched up to November 30, 2024. Randomized placebo-controlled trials enrolling children with genetically or clinically confirmed ALGS and reporting validated pruritus or sBA outcomes were eligible. Two reviewers independently extracted data on design, participants, interventions, outcomes, and adverse events. The risk of bias was assessed using RoB2, and the certainty of evidence was evaluated with GRADE. Four RCTs including 138 children (mean age 6.1 years; 54% male) were analyzed. IBATIs reduced pruritus severity (SMD - 1.00; 95% CI - 1.64 to - 0.35), lowered sBA levels (MD - 91.09 µmol/L; 95% CI - 136.11 to - 46.06; P < .0001), and improved PedsQL scores (MD 10.13 points; 95% CI 4.88 to 15.39). Transient ALT elevations were observed; gastrointestinal events were common, but mild and self-limiting. The limitations of this study include heterogeneity in pruritus measures and dosing, short follow-up (≤ 24 weeks), and the use of non-interchangeable pruritus instruments across trials, requiring SMD pooling and precluding between-drug comparisons.

Conclusion: IBATIs are effective and well tolerated in pediatric ALGS, providing meaningful improvements in pruritus and quality of life. Longer trials are needed to confirm durability, safety, and transplant-free survival impact.

What is known: • Children with Alagille syndrome often experience severe cholestatic pruritus with limited relief from current treatments. • Ileal bile acid transport inhibitors (IBATIs) have emerged as a promising targeted approach.

What is new: • This meta-analysis shows that IBATIs significantly reduce pruritus and improve quality of life in affected children. • IBATIs are effective and well tolerated, supporting their use as a novel therapeutic option.

Keywords: Alagille syndrome; Cholestatic pruritus; Ileal bile acid transport inhibitors.