Author information

¹Institute of Liver Studies, King's College London, London, UK.

²Department of Pediatric Gastroenterology, Akdeniz University, Antalya, Turkey.

³Pediatric Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany.

⁴Pediatric Gastroenterology Unit, Regina Margherita Children's Hospital, Azienda Ospedaliera-Città della Salute e della Scienza di Torino, Turin, Italy.

⁵Department of Gastroenterology, Hepatology, Nutritional Disorders, and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland.

⁶Department of Pediatric Gastroenterology, Gazi University Faculty of Medicine, Ankara, Turkey.

⁷Pediatric Hepatology, Gastroenterology, and Transplantation, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.

⁸Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey.

⁹Hépatologie 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.

¹⁰Pediatric Liver, GI, and Nutrition Center and MowatLabs, King's College Hospital NHS Trust, London, UK.

¹¹Liver Unit and Small Bowel Transplantation, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.

¹²Department of Gastroenterology, Royal Children's Hospital, Melbourne, Australia.

¹³Department of Pediatric Gastroenterology at the Wilhelmina Children's Hospital and University Medical Center, Utrecht, The Netherlands.

¹⁴Division of Gastroenterology, Hepatology, and Nutrition, Hospital for Sick Children and the University of Toronto, Toronto, ON, Canada.

¹⁵Pediatrics Department, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, GA, USA.

¹⁶Pediatric Gastroenterology-Hepatology-Nutrition Unit, Hôpital Universitaire Necker-Enfants Malades, Paris, France.

¹⁷Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service D'hépatogastoentérologie et Nutrition Pédiatrique, Lyon, France.

¹⁸Department of Pediatric Gastroenterology, Hepatology, and Liver Transplantation, University Children's Hospital, Essen, Germany.

¹⁹Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

²⁰Pediatric Gastroenterology, Hepatology, & Nutrition, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA.

²¹Albireo Pharma, Inc., Boston, MA, USA.

²²Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Hacettepe University Faculty of Medicine, Ankara, Turkey.

²³Children's Liver Unit, Leeds Teaching Hospitals NHS Trust, Leeds Children's Hospital, Leeds, UK.

²⁴CHU, Hospital de la Timone, Marseille, France.

²⁵Faculty of Medicine, Hebrew University of Jerusalem, Juliet Keidan Department of Pediatric Gastroenterology, Shaare Zedek Medical Center, Jerusalem, Israel.

²⁶Université Catholique de Louvain, Cliniques St Luc, Brussels, Belgium.

²⁷University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, CO, USA.

²⁸Pediatrics Department, Children's Hospital Los Angeles, Los Angeles, CA, USA.

²⁹Pediatric Gastroenterology and Hepatology, University Children's Hospital Tübingen, Tübingen, Germany.

³⁰Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Baylor College of Medicine/Texas Children's Hospital, Houston, TX, USA.

³¹Department of Pediatrics, University of Groningen, Beatrix Children's Hospital/University Medical Center Groningen, Groningen, The Netherlands.

³²Department of Surgery, Center for Liver Disease and Transplantation, Columbia University Medical Center, New York, NY, USA.

Abstract

Background & aims: PEDFIC 2, an ongoing, open-label, 72-week study, evaluates odevixibat, an ileal bile acid transporter inhibitor, in patients with progressive familial intrahepatic cholestasis.

Methods: PEDFIC 2 enrolled and dosed 69 patients across two cohorts; all received odevixibat 120 μg/kg per day. Cohort 1 comprised children from PEDFIC 1, and cohort 2 comprised new patients (any age). We report data through 15 July 2020, with Week 24 of PEDFIC 2 the main time point analysed. This represents up to 48 weeks of cumulative exposure for patients treated with odevixibat from the 24-week PEDFIC 1 study (cohort 1A) and up to 24 weeks of treatment for those who initiated odevixibat in PEDFIC 2 (patients who received placebo in PEDFIC 1 [cohort 1B] or cohort 2 patients). Primary endpoints for this prespecified interim analysis were change from baseline to Weeks 22-24 in serum bile acids (sBAs) and proportion of positive pruritus assessments (≥1-point drop from PEDFIC 2 baseline in pruritus on a 0-4 scale or score ≤1) over the 24-week period. Safety monitoring included evaluating treatment-emergent adverse events (TEAEs).

Results: In cohort 1A, mean change from PEDFIC 1 baseline to Weeks 22-24 of PEDFIC 2 in sBAs was -201 μmol/L (p <0.0001). For cohort 1B and cohort 2, mean changes from odevixibat initiation to weeks 22-24 in sBAs were -144 and -104 μmol/L, respectively. The proportion of positive pruritus assessments in the first 24-week period of PEDFIC 2 was 33%, 56%, and 62% in cohorts 1A, 1B, and 2, respectively. Most TEAEs were mild or moderate. No drug-related serious TEAEs occurred.

Conclusions: Odevixibat in patients with progressive familial intrahepatic cholestasis was generally well tolerated and associated with sustained reductions in sBAs and pruritus.

Clinical trials registration: This study is registered at ClinicalTrials.gov (NCT03659916).

Impact and implications: Disrupted bile flow is a hallmark feature of patients with progressive familial intrahepatic cholestasis and can result in build-up of bile constituents in the liver with spill over into the bloodstream; other effects that patients can experience include extremely itchy skin, and because not enough bile reaches the gut, patients can have problems digesting food, which may lead to poor growth. Odevixibat is an orally administered medication that shunts bile acids away from the liver. The current study, called PEDFIC 2, suggested that odevixibat can improve the problematic signs and symptoms of progressive familial intrahepatic cholestasis and was generally safe for patients.