Odevixibat Safe for Alagille Syndrome Based on Hepatic Changes

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Pooled phase 3 data presented at NASPGHAN 2023 support the benefit-risk profile of the IBAT inhibtor in treating the rare liver disease.

Odevixibat is not associated with parameters of hepatic change that

which would quality as drug-induced liver injury among patients treated for Alagille syndrome, according to new research.1

In a pooled analysis of pivotal phase 3 data—presented in an abstract at the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) 2023 Annual Meeting in San Diego this week—the ileal bile acid transporter (IBAT) inhibitor was linked to increased mean levels of serum aminotransferases (ALTs) in patents being treated for the rare hepatic disease. However, investigators additionally observed no concurrent increases in total bilirubin, and significant improvements to patients’ pruritus outcomes regardless of ALT change.

The findings contribute to understanding how odevixibat—approved earlier this year by the US Food and Drug Administration (FDA) to treat Alagille syndrome2—impacts hepatic outcomes while benefitting symptomatic outcomes in young patients with the rare condition.

Led by Nadia Ovchinsky, MD,of the pediatric gastroenterology and hepatology at Hassenfeld Children’s Hospital at NYU Langone, investigators pooled data from the ASSERT and ASSERT-EXT trials to examine changes to hepatic parameters in patients treated with odevixibat versus placebo for Alagille syndrome.

Characterized by intrahepatic bile duct paucity and manifested in diverse symptoms including pruritus and elevated serum bile acid and hepatic levels including ALT and bilirubin, as well as progressive liver fibrosis, Alagille syndrome presents multifactorial burdens to children and adolescents, that which IBAT inhibitors like odevixibat have been researched to treat.

ASSERT was a phase 3, 24-week trial analyzing odevixibat 120 μg/kg/day versus placebo in patients with diagnosed Alagille syndrome, a history of significant pruritus and elevated serum bile acids on a 2:1 randomization cohort versus placebo. Once patients completed the assessment, they were invited to the 72-week ASSERT-EXT extension trial, during which all patients received the set odevixibat dose. Ovchinsky used data from the first dose of either trial to a cutoff date of September 9, 2022 for their assessment; they additionally compared hepatic parameter outcomes versus placebo based solely on ASSERT data.

Observed outcomes included laboratory assessments for serum ALT; aspartate aminotransferase (AST); gamma-glutamyl transferase (GGT), and total bilirubin levels. The team additionally assessed clinician-reported outcomes for patient pruritus per the PRUCISION instrument.

The analysis included 52 patients treated with odevixibat for a median 30 weeks (range, 1 - 74). Of them, 17 (32.7%) had initially received placebo in ASSERT. Both cohorts reported mean elevated hepatic levels at baseline.

Among patients receiving odevixibat, ALT and GGT levels generally increased from baseline to week 4 (mean 55 and 46 U/L, respectively); levels then generally plateaued or decreased from then until week 48. Total bilirubin changed very little from baseline through week 48.

Another 4 patients receiving the IBAT inhibitor reported potentially clinically significant elevations in AST and/or ALT—rates more than three-fold greater from baseline to end of analysis, versus just 1 patient receiving placebo. Among all 4 treated patients with significant increases, concurrent total bilirubin levels were <2-fold greater from baseline. Two of the patients experienced treatment interruption with subsequent improvement in these hepatic parameters; the other 2 improved their levels with continued odevixibat.

“In addition, review of pertinent clinical information suggested drug- induced liver injury was unlikely, and all patients remained on treatment at the data cutoff,” investigators noted. “Overall, odevixibat-treated patients showed substantial improvements in pruritus regardless of increases from baseline in aminotransferases.”

Among patients receiving placebo, investigators observed minimal changes in each of ALT, AST and total bilirubin from baseline to week 24.

Ovchinsky and colleagues concluded that the observed mean increases in serum ALT levels among patients with Alagille syndrome receiving odevixibat were without concurrent increases in total bilirubin.

“These changes did not meet Hy’s Law criteria for drug-induced liver injury and did not exclude the possibility of a beneficial treatment (ie, pruritus) response,” they wrote. “Longer follow-up times are needed to confirm these findings.”


  1. Ovchinsky N, Aumar M, Baker A, Baumann U, et al. Changes in Hepatic Parameters with Alagille Syndrome Treated with Odevixibat: Pooled Data from the Phase 3 ASSERT and ASSERT-EXT Studies. Paper presented at: North American Society for Pediatric Gastroenterology, Hepatology and Nutrition 2023 Annual Meeting; October 4 - 7; San Diego, CA. Accessed October 4, 2023.
  2. Kunzmann K. FDA Approves Odevixibat for Cholestatic Pruritus in Alagille Syndrome. HCPLive. Published June 13, 2023.