Abstract

Background: Alagille syndrome (ALGS) is a rare, genetic, multisystem disorder in which cholestatic liver disease is common and that may include clinical manifestations of severe pruritus and elevated bile acids (BAs). The efficacy and safety of odevixibat, an ileal bile acid transporter inhibitor, were assessed in patients with ALGS in the phase 3 ASSERT and ASSERT-EXT trials. Using data from these studies, we analyzed the effects of odevixibat on pruritus and BAs over time.

Methods: ASSERT (NCT04674761) was a randomized, placebo-controlled study that enrolled patients with ALGS who had a history of significant pruritus and elevated serum BAs. Patients were randomized 2:1 to odevixibat 120 µg/kg/day or placebo, respectively, and received treatment for 24 weeks. Patients who completed ASSERT could enter ASSERT-EXT (NCT05035030), an ongoing, 72‑week open-label extension study in which all patients receive odevixibat 120 µg/kg/day. The primary endpoint in these studies was related to change in pruritus scores, evaluated using the PRUCISION observer-reported instrument (range, 0−4, with higher scores indicating worse symptoms). A secondary endpoint in both studies was change in serum BAs. Changes over time in scratching scores and BAs were analyzed in odevixibat-treated patients from ASSERT and/or ASSERT-EXT in a pooled analysis of data that spans from patients’ first dose of odevixibat to a data cutoff date of September 9, 2022; data from patients who received placebo in ASSERT are presented for comparison.

Results: At the data cutoff, 52 odevixibat-treated patients comprised the pooled population; 17 patients who received placebo in ASSERT subsequently received odevixibat in ASSERT-EXT. Odevixibat-treated patients had rapid reductions in mean scratching scores and BA levels that were sustained over time; responses in individual patients are shown in the Figure. At the data cutoff date, treatment-emergent adverse events (TEAEs) were reported in 83% (43 of 52) of odevixibat-treated patients and in 71% (12 of 17) of placebo-treated patients. The most common TEAEs during odevixibat treatment were diarrhea (29%; 6% with placebo) and pyrexia (21%; 24% with placebo). Drug-related TEAEs occurred in 29% of odevixibat-treated patients (15 of 52) and in 18% of placebo-treated patients (3 of 17). In the odevixibat-treated group, the only drug-related TEAEs occurring in >1 patient were diarrhea (6 patients, 12%) and abdominal pain, upper abdominal pain, and vomiting (each in 2 patients, 4% each). No odevixibat-treated patients had TEAEs leading to treatment discontinuation as of the data cutoff date.

Conclusion: In patients with ALGS, odevixibat treatment for up to 36 weeks resulted in improvements in pruritus and reduced BA levels; these changes occurred rapidly, with effects sustained over time. Most TEAEs with odevixibat were related to diarrhea and were mild or moderate in severity.