Richard J Thompson1, Henrik Arnell2, Reha Artan3, Ulrich Baumann4, Pier Luigi Calvo5, Piotr Czubkowski6, Buket Dalgic7, Lorenzo D'Antiga8, Özlem Durmaz9, Björn Fischler10, Emmanuel Gonzalès11, Tassos Grammatikopoulos12, Girish Gupte13, Winita Hardikar14, Roderick H J Houwen15, Binita M Kamath16, Saul J Karpen17, Lise Kjems18, Florence Lacaille19, Alain Lachaux20, Elke Lainka21, Cara L Mack22, Jan P Mattsson18, Patrick McKiernan13, Hasan Özen23, Sanjay R Rajwal24, Bertrand Roquelaure25, Mohammad Shagrani26, Eyal Shteyer27, Nisreen Soufi28, Ekkehard Sturm29, Mary Elizabeth Tessier30, Henkjan J Verkade31, Patrick Horn18. 1. Institute of Liver Studies, King's College London, London, UK. Electronic address: richard.j.thompson@kcl.ac.uk. 2. Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden. 3. Department of Paediatric Gastroenterology, Akdeniz University, Antalya, Turkey. 4. Paediatric Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany. 5. Paediatric Gastroenterology Unit, Regina Margherita Children's Hospital, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Turin, Italy. 6. Department of Gastroenterology, Hepatology, Nutritional Disorders and Paediatrics, The Children's Memorial Health Institute, Warsaw, Poland. 7. Department of Paediatric Gastroenterology, Gazi University Faculty of Medicine, Ankara, Turkey. 8. Department of Paediatric Hepatology, Gastroenterology, and Transplantation, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy. 9. Istanbul University Istanbul Faculty of Medicine, Department of Paediatric Gastroenterology and Hepatology, Istanbul, Turkey. 10. Department of Paediatrics, CLINTEC, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden. 11. Hépatologie 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 U1193, Paris, France. 12. Institute of Liver Studies, King's College London, London, UK; Paediatric Liver, GI and Nutrition Centre and MowatLabs, King's College Hospital NHS Trust, London, UK. 13. Liver Unit and Small Bowel Transplantation, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK. 14. Department of Gastroenterology, Royal Children's Hospital, Melbourne, VIC, Australia. 15. Department of Paediatric Gastroenterology, Wilhelmina Children's Hospital and University Medical Centre, Utrecht, Netherlands. 16. Department of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children and the University of Toronto, Toronto, ON, Canada. 17. Paediatrics Department, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, GA, USA. 18. Albireo Pharma, Boston, MA, USA. 19. Paediatric Gastroenterology-Hepatology-Nutrition Unit, Hôpital Universitaire Necker-Enfants Malades, Paris, France. 20. Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service D'hépatogastoentérologie et Nutrition Pédiatrique, Lyon, France. 21. Children's Hospital, Department of Paediatric Gastroenterology, Hepatology, and Transplant Medicine, University Duisburg-Essen, Essen, Germany. 22. Paediatrics Department, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA. 23. Division of Paediatric Gastroenterology, Hepatology, and Nutrition, Hacettepe University Faculty of Medicine, Ankara, Turkey. 24. Children's Liver Unit, Leeds Teaching Hospitals NHS Trust, Leeds Children's Hospital, Leeds, UK. 25. APHM, Service de Pédiatrie Multidisciplinaire, Hôpital de la Timone Enfants, Marseille, France. 26. Department of Liver and SB Transplant and Hepatobiliary-Paediatric Surgery, King Faisal Specialist Hospital and Research Centre-Organ Transplant Centre and College Of Medicine-Alfaisal University, Riyadh, Saudi Arabia. 27. Faculty of Medicine, Hebrew University of Jerusalem, Juliet Keidan Department of Paediatric Gastroenterology, Shaare Zedek Medical Centre, Jerusalem, Israel. 28. Paediatrics Department, Children's Hospital Los Angeles, Los Angeles, CA, USA. 29. Paediatric Gastroenterology and Hepatology, University Children's Hospital Tübingen, Tübingen, Germany. 30. Department of Paediatrics, Section of Paediatric Gastroenterology, Hepatology, and Nutrition, Baylor College of Medicine-Texas Children's Hospital, Houston, TX, USA. 31. Department of Paediatrics, University of Groningen, Beatrix Children's Hospital-University Medical Centre Groningen, Groningen, Netherlands.
Abstract
BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a group of inherited paediatric liver diseases resulting from mutations in genes that impact bile secretion. We aimed to evaluate the effects of odevixibat, an ileal bile acid transporter inhibitor, versus placebo in children with PFIC. METHODS: Patients eligible for this 24-week, randomised, double-blind, completed, phase 3 study were paediatric outpatients diagnosed with PFIC1 or PFIC2 who had pruritus and elevated serum bile acids at screening. Patients were randomly assigned (1:1:1) using an interactive web-based system to once a day oral placebo, odevixibat 40 μg/kg, or odevixibat 120 μg/kg. Randomisation was done in a block size of six and stratified by PFIC type and patient age; patients, clinicians, and study staff were blinded to treatment allocation. Patients were enrolled at one of 33 global sites. Two primary endpoints were evaluated: proportion of positive pruritus assessments (PPAs; ie, scratching score of ≤1 or ≥1-point decrease as assessed by caregivers using the Albireo observer-reported outcome [ObsRO] PRUCISION instrument) over 24 weeks, and proportion of patients with serum bile acid response (ie, serum bile acids reduced by ≥70% from baseline or concentrations of ≤70 μmol/L) at week 24. Efficacy and safety were analysed in randomly allocated patients who received one or more doses of study drug. This study is registered with ClinicalTrials.gov, NCT03566238. FINDINGS: Between June 21, 2018, and Feb 10, 2020, 62 patients (median age 3·2 [range 0·5-15·9] years) were randomly allocated to placebo (n=20), odevixibat 40 μg/kg per day (n=23), or odevixibat 120 μg/kg per day (n=19). Model-adjusted (least squares) mean proportion of PPAs was significantly higher with odevixibat versus placebo (55% [SE 8] in the combined odevixibat group [58% in the 40 μg/kg per day group and 52% in the 120 μg/kg per day group] vs 30% [SE 9] in the placebo group; model-adjusted mean difference 25·0% [95% CI 8·5-41·5]; p=0·0038). The percentage of patients with serum bile acid response was also significantly higher with odevixibat versus placebo (14 [33%] of 42 patients in the combined odevixibat group [10 in the 40 μg/kg per day group and four in the 120 μg/kg per day group] vs none of 20 in the placebo group; adjusting for stratification factor [PFIC type], the proportion difference was 30·7% [95% CI 12·6-48·8; p=0·0030]). The most common treatment-emergent adverse events (TEAEs) were diarrhoea or frequent bowel movements (13 [31%] of 42 for odevixibat vs two [10%] of 20 for placebo) and fever (12 [29%] of 42 vs five [25%] of 20); serious TEAEs occurred in three (7%) of 42 odevixibat-treated patients and in five (25%) of 20 placebo-treated patients. INTERPRETATION: In children with PFIC, odevixibat effectively reduced pruritus and serum bile acids versus placebo and was generally well tolerated. Odevixibat, administered as once a day oral capsules, is a non-surgical, pharmacological option to interrupt the enterohepatic circulation in patients with PFIC. FUNDING: Albireo Pharma.
BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a group of inherited paediatric liver diseases resulting from mutations in genes that impact bile secretion. We aimed to evaluate the effects of odevixibat, an ileal bile acid transporter inhibitor, versus placebo in children with PFIC. METHODS: Patients eligible for this 24-week, randomised, double-blind, completed, phase 3 study were paediatric outpatients diagnosed with PFIC1 or PFIC2 who had pruritus and elevated serum bile acids at screening. Patients were randomly assigned (1:1:1) using an interactive web-based system to once a day oral placebo, odevixibat 40 μg/kg, or odevixibat 120 μg/kg. Randomisation was done in a block size of six and stratified by PFIC type and patient age; patients, clinicians, and study staff were blinded to treatment allocation. Patients were enrolled at one of 33 global sites. Two primary endpoints were evaluated: proportion of positive pruritus assessments (PPAs; ie, scratching score of ≤1 or ≥1-point decrease as assessed by caregivers using the Albireo observer-reported outcome [ObsRO] PRUCISION instrument) over 24 weeks, and proportion of patients with serum bile acid response (ie, serum bile acids reduced by ≥70% from baseline or concentrations of ≤70 μmol/L) at week 24. Efficacy and safety were analysed in randomly allocated patients who received one or more doses of study drug. This study is registered with ClinicalTrials.gov, NCT03566238. FINDINGS: Between June 21, 2018, and Feb 10, 2020, 62 patients (median age 3·2 [range 0·5-15·9] years) were randomly allocated to placebo (n=20), odevixibat 40 μg/kg per day (n=23), or odevixibat 120 μg/kg per day (n=19). Model-adjusted (least squares) mean proportion of PPAs was significantly higher with odevixibat versus placebo (55% [SE 8] in the combined odevixibat group [58% in the 40 μg/kg per day group and 52% in the 120 μg/kg per day group] vs 30% [SE 9] in the placebo group; model-adjusted mean difference 25·0% [95% CI 8·5-41·5]; p=0·0038). The percentage of patients with serum bile acid response was also significantly higher with odevixibat versus placebo (14 [33%] of 42 patients in the combined odevixibat group [10 in the 40 μg/kg per day group and four in the 120 μg/kg per day group] vs none of 20 in the placebo group; adjusting for stratification factor [PFIC type], the proportion difference was 30·7% [95% CI 12·6-48·8; p=0·0030]). The most common treatment-emergent adverse events (TEAEs) were diarrhoea or frequent bowel movements (13 [31%] of 42 for odevixibat vs two [10%] of 20 for placebo) and fever (12 [29%] of 42 vs five [25%] of 20); serious TEAEs occurred in three (7%) of 42 odevixibat-treated patients and in five (25%) of 20 placebo-treated patients. INTERPRETATION: In children with PFIC, odevixibat effectively reduced pruritus and serum bile acids versus placebo and was generally well tolerated. Odevixibat, administered as once a day oral capsules, is a non-surgical, pharmacological option to interrupt the enterohepatic circulation in patients with PFIC. FUNDING: Albireo Pharma.