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

Abstract

<b>Aim:</b> 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. <b>Materials &amp; methods:</b> 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. <b>Results:</b> 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. <b>Conclusion:</b> 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. 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.