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Research Article
18 September 2026

Indirect treatment comparison of odevixibat and maralixibat for the treatment of cholestatic pruritus in patients with Alagille syndrome

Authors: Emmanuelle Kaltenbach https://orcid.org/0000-0002-4916-0465 [email protected], Alice Guiraud-Diawara, Jérémie Schwarzbard, and Cécile ArtaudAuthor Info & Affiliations
Volume 15, Number 10
https://doi.org/10.57264/cer-2026-0138
PDFFormats

Abstract

Aim: Alagille syndrome (ALGS) is a rare genetic disorder associated with cholestasis and subsequent severe pruritus, which significantly impacts patient quality of life (QoL). Odevixibat (ODX) and maralixibat (MRX) are ileal bile acid transporter inhibitors approved for the treatment of cholestatic pruritus in ALGS. In the absence of head-to-head data, this study aimed to compare the efficacy, safety, and health-related QoL (HRQoL) associated with ODX and MRX. Materials & methods: A population-adjusted unanchored indirect treatment comparison was conducted using patient-level data from the Phase III ASSERT/ASSERT-EXT studies (ODX) and published data from the Phase IIb ICONIC study (MRX). A regression-adjusted matching approach was applied to adjust for cross-trial differences in baseline characteristics and estimate treatment effects. Outcomes assessed at week 48 included pruritus, serum bile acid (sBA) levels, HRQoL (PedsQL) and safety. Results: In adjusted analyses, ODX demonstrated numerically greater improvements in pruritus and reductions in sBA than MRX. ODX was associated with significantly greater improvements in HRQoL, including overall PedsQL scores (mean difference: 14.64; 95% CI: 5.70–23.58). ODX was better tolerated, with significantly lower rates of gastrointestinal adverse events (odds ratio [OR]: 0.22; 95% CI: 0.06–0.87) and abdominal pain (OR: 0.06; 95% CI: 0–0.83), and numerically lower rates of other adverse events. Conclusion: In this first indirect treatment comparison of ileal bile acid transporter inhibitors in ALGS, ODX demonstrated a differentiated clinical profile versus MRX, with significant benefits in HRQoL and tolerability, and consistent trends favoring better efficacy. These results may support informed treatment decision-making for patients.

Plain language summary

What is this article about?

Alagille syndrome (ALGS) is a rare genetic condition that affects the liver and other body organs. Many children with ALGS experience severe itching caused by a buildup in the blood of a substance called bile acid, which normally helps digest fats in the food we eat. Severe itching can be distressing, disrupt sleep and reduce quality of life. Two medicines, odevixibat and maralixibat, are approved to treat severe itching in ALGS, but there are no studies directly comparing them. This study compared the two medicines by using data from separate clinical trials. As the patients in each trial had different characteristics before treatment, researchers used statistical methods to adjust for these differences and make the comparison as fair as possible.

What were the results?

The results showed that odevixibat led to greater, although not statistically significant, improvements in itching and reductions in bile acid levels than maralixibat. Children treated with odevixibat also had significantly greater improvements in health-related quality of life, including physical, emotional, and social well-being and sleep. In addition, odevixibat was better tolerated than maralixibat, with significantly fewer episodes of common side effects like diarrhea and abdominal pain. Better tolerability may lead to fewer pauses in treatment, help patients stay on treatment and reduce the impact on daily life and the burden on caregivers.

Why is this important?

Overall, this first comparison of the two treatments for ALGS suggests that odevixibat may offer meaningful benefits for children with ALGS, which can help patients, caregivers and doctors make informed treatment decisions.

Supplementary Material

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References

Papers of special note have been highlighted as: • of interest; •• of considerable interest
1.
Leonard LD, Chao G, Baker A, Loomes K, Spinner NB. Clinical utility gene card for: Alagille syndrome (ALGS). Eur. J. Hum. Genet. 22(3), doi: (2014) (Epub ahead of print).
PubMed
Google Scholar
2.
Gilbert MA, Bauer RC, Rajagopalan R et al. Alagille syndrome mutation update: comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification. Hum. Mutat. 40(12), 2197–2220 (2019).
PubMed
Google Scholar
3.
Vandriel SM, Li LT, She H et al. Natural history of liver disease in a large international cohort of children with Alagille syndrome: results from the GALA study. Hepatology 77(2), 512–529 (2023).
PubMed
Google Scholar
4.
Kamath BM, Abetz-Webb L, Kennedy C et al. Development of a novel tool to assess the impact of itching in pediatric cholestasis. Patient 11(1), 69–82 (2018).
PubMed
Google Scholar
5.
Kamath BM, Baker A, Houwen R, Todorova L, Kerkar N. Systematic review: the epidemiology, natural history, and burden of Alagille syndrome. J. Pediatr. Gastroenterol. Nutr. 67(2), 148–156 (2018).
PubMed
Google Scholar
6.
Kamath BM, Yin W, Miller H et al. Outcomes of liver transplantation for patients with Alagille syndrome: the studies of pediatric liver transplantation experience. Liver Transpl. 18(8), 940–948 (2012).
PubMed
Google Scholar
7.
EASL. EASL Clinical Practice Guidelines on genetic cholestatic liver diseases. J. Hepatol. 81(2), 303–325 (2024).
PubMed
Google Scholar
•• The most recent international clinical practice guideline for genetic cholestatic liver diseases. It recommends ileal bile acid transporter inhibitors for cholestatic pruritus in Alagille syndrome (ALGS) and provides the current standard of care against which this study should be interpreted.
8.
Dawson PA, Haywood J, Craddock AL et al. Targeted deletion of the ileal bile acid transporter eliminates enterohepatic cycling of bile acids in mice. J. Biol. Chem. 278(36), 33920–33927 (2003).
PubMed
Google Scholar
9.
Yang N, Dong YQ, Jia GX et al. ASBT(SLC10A2): a promising target for treatment of diseases and drug discovery. Biomed. Pharmacother. 132, 110835 (2020).
PubMed
Google Scholar
10.
Bylvay. Prescribing Information. Ipsen Biopharmaceuticals, Inc, MA, USA (2025).
Google Scholar
11.
Kayfanda. Summary of Product Characteristics. Ipsen Pharma, France (2025).
Google Scholar
12.
Ovchinsky N, Aumar M, Baker A et al. Efficacy and safety of odevixibat in patients with Alagille syndrome (ASSERT): a Phase III, double-blind, randomised, placebo-controlled trial. Lancet Gastroenterol. Hepatol. 9(7), 632–645 (2024).
PubMed
Google Scholar
•• The pivotal Phase III trial establishes the efficacy and safety of odevixibat in ALGS. This study provides the patient-level data used in the present indirect treatment comparison.
13.
Ovchinsky N, Aumar M, Baker A et al. ASSERT-EXT: final data from an open-label, Phase III study of odevixibat in patients with Alagille syndrome. Presented at: The 75th AmeriCAn Association for the Study of Liver Disease Annual Meeting, CA, USA (15–19 November 2024).
Google Scholar
14.
Livmarli. Prescribing Information. Mirum Pharmaceuticals, Inc, CA, USA (2025).
Google Scholar
15.
Livmarli. Summary of Product Characteristics. Mirum Pharmaceuticals International B.V, The Netherlands (2025).
Google Scholar
16.
Gonzales E, Hardikar W, Stormon M et al. Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised Phase II study. Lancet 398(10311), 1581–1592 (2021).
PubMed
Google Scholar
•• The pivotal trial supporting approval of maralixibat in ALGS. It serves as the comparator study for the indirect treatment comparison performed here.
17.
Kreif N, Grieve R, Radice R, Sekhon JS. Regression-adjusted matching and double-robust methods for estimating average treatment effects in health economic evaluation. Health Serv. Outcomes Res. Methodol. 13(2), 174–202 (2013).
Google Scholar
18.
Kamath BM, Goldstein A, Howard R et al. Maralixibat treatment response in Alagille syndrome is associated with improved health-related quality of life. J. Pediatr. 252, 68–75; e65 (2023).
PubMed
Google Scholar
• Demonstrates the relationship between treatment response and improvements in health-related quality of life in patients receiving maralixibat, supporting the importance of patient-reported outcomes in ALGS.
19.
Phillippo DM, Ades T, Dias S, Palmer S, Abrams KR, Welton NJ. NICE DSU Technical Support Document 18: Methods for population-adjusted indirect comparisons in submissions to NICE. NICE, UK (2016).
Google Scholar
•• The foundational methodological guidance for population-adjusted indirect treatment comparisons, including matching-adjusted indirect comparison (MAIC) and related approaches, underpinning the statistical methods used in this study.
20.
Methodological Guideline for Quantitative Evidence Synthesis: Direct and Indirect Comparisons. Member State Coordination Group on Health Technology Assessment (2024) (Accessed September 2026). Available at: https://health.ec.europa.eu/document/download/1f6b8a70-5ce0-404e-9066-120dc9a8df75_en?filename=hta_practical-guideline_direct-and-indirect-comparisons_en.pdf.
Google Scholar
•• The latest European methodological guidance supporting the use of robust population-adjusted indirect comparisons when head-to-head evidence is unavailable.
21.
Sturm E, Aumar M, Baker A et al. Long-term efficacy and safety of odevixibat in patients with Alagille syndrome: pooled results from Phase III, randomized, double-blind ASSERT and open-label ASSERT-EXT studies. Presented at: The European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Congress, Helsinki, Finland (2025).
Google Scholar
• Provides the most comprehensive long-term efficacy and safety evidence for odevixibat in ALGS, demonstrating sustained improvements in pruritus and reductions in serum bile acids with continued treatment.
22.
Li N, Koester ST, Lachance DM, Dutta M, Cui JY, Dey N. Microbiome-encoded bile acid metabolism modulates colonic transit times. iScience 24(6), 102508 (2021).
PubMed
Google Scholar
23.
Alemi F, Poole DP, Chiu J et al. The receptor TGR5 mediates the prokinetic actions of intestinal bile acids and is required for normal defecation in mice. Gastroenterology 144(1), 145–154 (2013).
PubMed
Google Scholar
24.
Nomden M, Kuipers F, Lexmond WS et al. Pretreatment serum bile acid composition and predictability of subsequent response to odevixibat in patients with bile salt export pump (BSEP) deficiency. Hepatology 83(4), 708–720 (2026).
PubMed
Google Scholar
25.
Zhao X, Zhang W, Vig P, Kostrub C, Setchell KDR. Serum bile acid profiling and mixed model analysis reveal biomarkers associated with pruritus reduction in maralixibat-treated patients with BSEP deficiency. Metabolites 12(10), 952 (2022).
PubMed
Google Scholar