Odevixibat for progressive familial intrahepatic cholestasis and Alagille syndrome-associated cholestatic pruritus

Background:
Progressive familial intrahepatic cholestasis (PFIC) and Alagille syndrome (ALGS) are rare, life-threatening conditions with several possible genetic causes. Mutations affect the way bile acids are secreted and transported. In ALGS, interlobular biliary ducts are often absent or dysmorphic. These changes result in the accumulation of bile acids within the liver leading to liver damage. The release of bilirubin and bile acids into the systemic circulation causes jaundice and severe pruritus that affects quality of life. The conditions usually present in childhood and impair growth. Many patients eventually require a liver transplant.

Mechanism of action:
Bile acids are reabsorbed from the distal ileum and returned to the liver. A key part of this enterohepatic circulation is the ileal bile acid transporter (IBAT). By selectively inhibiting this transporter, oral odevixibat reduces reabsorption so more bile acids are excreted in the faeces and systemic concentrations fall. This can help to relieve itching and has the potential to improve the health of the patient’s liver.

Clinical trials:
PFIC: The main double-blind trial of odevixibat for PFIC was PEDFIC1,¹ which recruited 62 children aged 6 months to 18 years. Most participants were under 5 years old and were experiencing significant pruritus. They were randomised to receive daily doses of odevixibat 40 micrograms/kg, 120 micrograms/kg or placebo. The effect was evaluated by measuring serum bile acids and twice-daily assessments of pruritus on a scale of 0 to 4. After 24 weeks, bile acid concentrations had declined by at least 70%, or fallen to 70 micromol/L or less, in 33% of the 42 children given odevixibat but in none of the 20 children in the placebo group. There was a scratching score of 1 or less, or a decrease of at least 1 point on the pruritus scale, in 55% of the odevixibat group compared with 30% of the placebo group.¹ After the trial, 53 children continued treatment with odevixibat in an open-label extension study (PEDFIC2).² They were joined by 16 additional patients with PFIC. All participants in the extension study took a daily dose of 120 micrograms/kg. A prespecified interim analysis occurred after 22 to 24 weeks. For previously treated children, bile acid concentrations remained reduced and the improvement in pruritus was sustained. Similar effects were seen in the additional patients.²

ALGS: Odevixibat for ALGS-associated cholestatic pruritus was evaluated in the double-blind ASSERT trial,³ which recruited 52 children aged 6 months to 18 years (mostly between 2 and 12 years). Participants were randomised to receive odevixibat 120 micrograms/kg or placebo once daily for 24 weeks. Treatment with odevixibat led to significant improvements in pruritus symptoms and lower serum bile acid concentrations compared with placebo. There were also improvements in sleep parameters.³ In an open-label extension study, improvements were maintained over at least 72 weeks.⁴

Adverse effects:
As odevixibat increases the excretion of bile acids, gastrointestinal adverse effects are common. In the PEDFIC1 trial, diarrhoea occurred in 31% of the odevixibat group versus 10% of the placebo group, and vomiting affected 17% of the children taking odevixibat but none of those taking placebo.¹ Concentrations of alanine aminotransferase increased in 14% of the odevixibat group compared with 5% of the placebo group.¹ No new adverse effects emerged during the PEDFIC2 extension study.² Adverse effects in the ASSERT trial were consistent with the PEDFIC trials.³

Dosage and administration:
For PFIC, the recommended dose is 40 micrograms/kg once daily. Reduction of bile acid concentrations and improvement in pruritus may occur gradually. If there is insufficient improvement after 3 months, the dose can be increased to 120 micrograms/kg (maximum 7200 micrograms) per day for a further 3-month trial; odevixibat should be stopped if there is still no benefit.⁴

For ALGS, the recommended dose is 120 micrograms/kg once daily; dose reduction may be considered if tolerability issues occur.⁴

The capsules are taken each morning, with or without food. They can be pulled apart and the contents sprinkled on food or mixed with a liquid and administered using an oral syringe.⁴

Precautions:
PFIC and ALGS affect the absorption of fat-soluble vitamins. Some patients developed fat-soluble vitamin deficiency during treatment with odevixibat. Monitoring of vitamin concentrations, liver function and international normalised ratio (INR) should be routine. The implications for the absorption of fat-soluble drugs are unknown.

Use in pregnancy and breastfeeding:
Based on animal studies, odevixibat may cause cardiac malformations when a fetus is exposed during pregnancy. Odevixibat is classified as Therapeutic Goods Administration pregnancy category D and should not be used in pregnancy or women of childbearing potential not using contraception.⁴

Place in therapy:
Drugs such as colestyramine, ursodeoxycholic acid and rifampicin have been used to modify bile acid concentrations. Although there is limited evidence of their effectiveness, most of the children in the trials of odevixibat were using ursodeoxycholic acid or rifampicin. In practice, they may be continued when odevixibat is started, with subsequent treatment simplification depending on the response to odevixibat.

Not all patients will respond to odevixibat. For patients who do respond, the reduction in pruritus, compared with placebo, appears to be clinically relevant.^1,3 There were also improvements in growth in patients with PFIC.²

Cholestasis can be managed with surgical procedures, such as external biliary diversion, but this is not without risk. At present, it is unknown if odevixibat will delay the need for surgery, including liver transplantation.

This new drug comment was finalised on 30 June 2026. It was prepared by John Dowden, Medical Writer, and reviewed by Vanessa Inserra, Senior Gastroenterology Pharmacist and Surgical Team Lead, Northern Health, Victoria.

At the time this new drug comment was prepared, the Australian Public Assessment Report was available from the Therapeutic Goods Administration. The sponsor did not provide the Clinical Evaluation Report.

This article is peer reviewed.

 

References

1. Thompson RJ, Arnell H, Artan R, Baumann U, Calvo PL, Czubkowski P, et al. Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol 2022;7:830–42.
2. Thompson RJ, Artan R, Baumann U, Calvo PL, Czubkowski P, Dalgic B, et al. Interim results from an ongoing, open-label, single-arm trial of odevixibat in progressive familial intrahepatic cholestasis. JHEP Rep 2023;5:100782.
3. Ovchinsky N, Aumar M, Baker A, Baumann U, Bufler P, Cananzi M, et al. Efficacy and safety of odevixibat in patients with Alagille syndrome (ASSERT): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Gastroenterol Hepatol 2024;9:632–45.
4. Therapeutic Goods Administration. Australian Product Information - Bylvay odevixibat. Department of Health, Disability and Ageing; 2026. [cited 2026 Jun 30]

 

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