Background: Unlike other causes of cholestasis, a unique manifestation of Alagille syndrome (ALGS) is xanthomas in one-quarter of patients and no approved medical therapies for xanthomas exist. As xanthomas have not been well-characterized, we evaluated their baseline characteristics, impact of maralixibat, an ileal bile acid transporter inhibitor approved for the treatment of cholestatic pruritus in patients with ALGS ≥3 months of age in the US and ≥2 months of age in the EU, on xanthomas, and correlates of xanthoma reduction following treatment.

Methods: Data were obtained from the maralixibat ALGS clinical trial program. Xanthomas were assessed using the Clinician Xanthoma Scale (CXS) with response defined as ≥1-point reduction in CXS (xanthomas at Baseline present) versus non-response as unchanged/worsened CXS.

Results: 27 of 63 (43%) individuals had xanthomas at Baseline. At Baseline, higher CXS was associated with lower age (p=0.0284), higher total/direct bilirubin (p<0.0001; p<0.0001), higher sBA (p=0.0004), higher total cholesterol and LDL (p<0.0001; p=0.0556), lower HDL (p=0.0005), lower PedsQL social functioning (SF; p=0.0193), and lower PedsQL physical functioning (PF, p=0.0367). With maralixibat, the proportion with no xanthomas (CXS 0) increased over 96 weeks, from 60% to 86%, while the proportion with moderate xanthomas (CXS 1-2) decreased from 33% to 9%, and the proportion with severe xanthomas (CXS 3-4) decreased from 9% to 6% (p=0.0039). Follow-up data to Week 96 were available for 35 individuals of which 14 (40%) had xanthomas at Baseline. From Baseline to Week 96, there was a decrease in total cholesterol (-57 mg/dL, p=0.0009) and LDL (-22 mg/dL, p=0.0041) and increase in HDL (14 mg/dL, p<0.0001). Of those with week 96 data,  10/14 (71%) were xanthoma-responders.  Responders with QoL assessments (n=9) had improved PedsQL‑SF (20) and PedsQL-PF (15.4), whereas non-responders had little change in PedsQL-SF (1.2) and PedsQL-PF (3.1). At Week 48, xanthoma-responders vs non-responders had decreased total cholesterol (-189 mg/dL vs -11 mg/dL; p=0.0045).

Conclusions: At Baseline, increased xanthomas was associated with biomarkers of disease and QoL. Xanthomas improved following treatment with maralixibat over 96 weeks. Xanthoma reduction was associated with improved QoL and total cholesterol.