Clin Res Hepatol Gastroenterol. 2021 Jun 25;101751. doi: 10.1016/j.clinre.2021.101751.Online ahead of print.

Ulrich Baumann ¹, Ekkehard Sturm ², Florence Lacaille ³, Emmanuel Gonzalès ⁴, Henrik Arnell ⁵, Björn Fischler ⁵, Marianne Hørby Jørgensen ⁶, Richard J Thompson ⁷, Jan P Mattsson ⁸, Mats Ekelund ⁸, Erik Lindström ⁸, Per-Göran Gillberg ⁸, Kristina Torfgård ⁸, Paresh N Soni ⁹

Author information

• ¹Paediatric Gastroenterology and Hepatology, Department of Paediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany. Electronic address: Baumann.U@mh-hannover.de.
• ²Pediatric Gastroenterology and Hepatology, University Children's Hospital T?bingen, T?bingen, Germany.
• ³Pediatric Gastroenterology-Hepatology-Nutrition, Necker-Enfants Malades Hospital, Paris, France.
• ⁴Hépatologie et Transplantation Hépatique Pédiatriques, Centre de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques, FSMR FILFOIE, ERN RARE LIVER, Hôpital Bicêtre, AP-HP, Université Paris-Saclay, Hépatinov, Inserm U 1193, Paris, France.
• ⁵Pediatric Gastroenterology, Hepatology and Nutrition, Astrid Lindgren Children's Hospital, Karolinska University Hospital, CLINTEC, Karolinska Institutet, Stockholm, Sweden.
• ⁶Pediatric and Adolescent Clinic, Rigshospitalet, Copenhagen, Denmark.
• ⁷Institute of Liver Studies, King's College London, London, United Kingdom.
• ⁸Albireo AB, Gothenburg, Sweden.
• ⁹Albireo Pharma, Boston, MA, United States.

Abstract

Purpose: Ileal bile acid transporter inhibition is a novel therapeutic concept for cholestatic pruritus and cholestatic liver disease progression. Odevixibat, a potent, selective, reversible ileal bile acid transporter inhibitor, decreases enteric bile acid reuptake with minimal systemic exposure. Oral odevixibat safety, tolerability, and efficacy in pediatric patients with cholestatic liver disease and pruritus were evaluated.

Patients and methods: In this phase 2, open-label, multicenter study, children received 10?200 μg/kg oral odevixibat daily for 4 weeks. Changes in serum bile acid levels (primary efficacy endpoint), pruritus, and sleep disturbance were explored.

Results: Twenty patients were enrolled (8 females; 1?17 years; 4 re-entered at a different dose). Diagnoses included progressive familial intrahepatic cholestasis (n=13; 3 re-entries), Alagille syndrome (n=6), biliary atresia (n=3), and other intrahepatic cholestasis causes (n=2; 1 re-entry). Mean baseline serum bile acid levels were high (235 µmol/L; range, 26?564) and were reduced in the majority (-123.1 μmol/L; range, -394 to 14.5, reflecting reductions of up to 98%). Patient-reported diary data documented improved pruritus (3 scales) and sleep. With 100 μg/kg, mean (SEM) decrease was 2.8 (1.1) points for pruritus (visual analogue itch scale 0-10) and 2.9 (0.9) points for sleep disturbance (Patient-Oriented Scoring Atopic Dermatitis scale 0-10). Reduced pruritus correlated significantly with reduced serum bile acids (P≤0.007). Significant correlations were also observed between autotaxin levels and pruritus. All patients completed the study. No serious adverse events were treatment related; most adverse events, including increased transaminases, were transient.

Conclusions: Orally administered odevixibat was well tolerated, reduced serum bile acids, and improved pruritus and sleep disturbance in children with cholestatic diseases.