Interim results from an ongoing, open-label, single-arm trial of odevixibat in progressive familial intrahepatic cholestasis
Richard J. Thompson,
Reha Artan,
Ulrich Baumann,
Pier Luigi Calvo,
Piotr Czubkowski,
Buket Dalgic,
Lorenzo D’Antiga,
Angelo Di Giorgio,
Özlem Durmaz,
Emmanuel Gonzalès,
Tassos Grammatikopoulos,
Girish Gupte,
Winita Hardikar,
Roderick H.J. Houwen,
Binita M. Kamath,
Saul J. Karpen,
Florence Lacaille,
Alain Lachaux,
Elke Lainka,
Kathleen M. Loomes,
Cara L. Mack,
Jan P. Mattsson,
Patrick McKiernan,
Quanhong Ni,
Hasan Özen,
Sanjay R. Rajwal,
Bertrand Roquelaure,
Eyal Shteyer,
Etienne Sokal,
Ronald J. Sokol,
Nisreen Soufi,
Ekkehard Sturm,
Mary Elizabeth Tessier,
Wendy L. van der Woerd,
Henkjan J. Verkade,
Jennifer M. Vittorio,
Terese Wallefors,
Natalie Warholic,
Qifeng Yu,
Patrick Horn,
Lise Kjems
Affiliations
Richard J. Thompson
Institute of Liver Studies, King’s College London, London, UK; Corresponding author. Address: Institute of Liver Studies, King’s College Hospital, Denmark Hill, London, SE5 9RS, UK. Tel.: +44-7775686643.
Reha Artan
Department of Pediatric Gastroenterology, Akdeniz University, Antalya, Turkey
Ulrich Baumann
Pediatric Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany
Pier Luigi Calvo
Pediatric Gastroenterology Unit, Regina Margherita Children’s Hospital, Azienda Ospedaliera-Città della Salute e della Scienza di Torino, Turin, Italy
Piotr Czubkowski
Department of Gastroenterology, Hepatology, Nutritional Disorders, and Pediatrics, The Children’s Memorial Health Institute, Warsaw, Poland
Buket Dalgic
Department of Pediatric Gastroenterology, Gazi University Faculty of Medicine, Ankara, Turkey
Lorenzo D’Antiga
Pediatric Hepatology, Gastroenterology, and Transplantation, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
Angelo Di Giorgio
Pediatric Hepatology, Gastroenterology, and Transplantation, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
Özlem Durmaz
Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey
Emmanuel Gonzalès
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 U 1193, Paris, France
Tassos Grammatikopoulos
Institute of Liver Studies, King’s College London, London, UK; Pediatric Liver, GI, and Nutrition Center and MowatLabs, King’s College Hospital NHS Trust, London, UK
Girish Gupte
Liver Unit and Small Bowel Transplantation, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UK
Winita Hardikar
Department of Gastroenterology, Royal Children's Hospital, Melbourne, Australia
Roderick H.J. Houwen
Department of Pediatric Gastroenterology at the Wilhelmina Children’s Hospital and University Medical Center, Utrecht, The Netherlands
Binita M. Kamath
Division of Gastroenterology, Hepatology, and Nutrition, Hospital for Sick Children and the University of Toronto, Toronto, ON, Canada
Saul J. Karpen
Pediatrics Department, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, GA, USA
Florence Lacaille
Pediatric Gastroenterology-Hepatology-Nutrition Unit, Hôpital Universitaire Necker-Enfants Malades, Paris, France
Alain Lachaux
Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service D’hépatogastoentérologie et Nutrition Pédiatrique, Lyon, France
Elke Lainka
Department of Pediatric Gastroenterology, Hepatology, and Liver Transplantation, University Children’s Hospital, Essen, Germany
Kathleen M. Loomes
Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Cara L. Mack
Pediatric Gastroenterology, Hepatology, & Nutrition, Children’s Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, USA
Jan P. Mattsson
Albireo Pharma, Inc., Boston, MA, USA
Patrick McKiernan
Liver Unit and Small Bowel Transplantation, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UK
Quanhong Ni
Albireo Pharma, Inc., Boston, MA, USA
Hasan Özen
Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Hacettepe University Faculty of Medicine, Ankara, Turkey
Sanjay R. Rajwal
Children’s Liver Unit, Leeds Teaching Hospitals NHS Trust, Leeds Children’s Hospital, Leeds, UK
Bertrand Roquelaure
CHU, Hospital de la Timone, Marseille, France
Eyal Shteyer
Faculty of Medicine, Hebrew University of Jerusalem, Juliet Keidan Department of Pediatric Gastroenterology, Shaare Zedek Medical Center, Jerusalem, Israel
Etienne Sokal
Université Catholique de Louvain, Cliniques St Luc, Brussels, Belgium
Ronald J. Sokol
University of Colorado School of Medicine, Children’s Hospital Colorado, Aurora, CO, USA
Nisreen Soufi
Pediatrics Department, Children's Hospital Los Angeles, Los Angeles, CA, USA
Ekkehard Sturm
Pediatric Gastroenterology and Hepatology, University Children’s Hospital Tübingen, Tübingen, Germany
Mary Elizabeth Tessier
Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Baylor College of Medicine/Texas Children’s Hospital, Houston, TX, USA
Wendy L. van der Woerd
Department of Pediatric Gastroenterology at the Wilhelmina Children’s Hospital and University Medical Center, Utrecht, The Netherlands
Henkjan J. Verkade
Department of Pediatrics, University of Groningen, Beatrix Children’s Hospital/University Medical Center Groningen, Groningen, The Netherlands
Jennifer M. Vittorio
Department of Surgery, Center for Liver Disease and Transplantation, Columbia University Medical Center, New York, NY, USA
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.
