Interim results from an ongoing, open-label, single-arm trial of odevixibat in progressive familial intrahepatic cholestasis

• Type of Material: Article
• Authors: Richard J Thompson, King's College London; Reha Artan, Akdeniz Üniversitesi; Ulrich Baumann, Hannover Medical School; Pier Luigi Calvo, Regina Margherita Children’s Hospital; Piotr Czubkowski, Children’s Memorial Health Institute, Warsaw; Buket Dalgic, Gazi University; Lorenzo D'Antiga, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo; Angelo Di Giorgio, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo; Özlem Durmaz, Istanbul University; Emmanuel Gonzalès, Université Paris-Saclay; Tassos Grammatikopoulos, King's College London; Girish Gupte, Birmingham Women’s and Children’s NHS Foundation Trust; Winita Hardikar, Royal Children's Hospital, Melbourne; Roderick H.J Houwen, Wilhelmina Children’s Hospital; Binita M Kamath, University of Toronto; Saul J Karpen, Emory University; Florence Lacaille, Hôpital Universitaire Necker-Enfants Malades; Alain Lachaux, Service D’hépatogastoentérologie et Nutrition Pédiatrique, Lyon; Elke Lainka, University Children’s Hospital, Essen; Kathleen M Loomes, Children’s Hospital of Philadelphia; Cara L Mack, Children’s Hospital of Wisconsin; Jan P Mattsson, Albireo Pharma, Inc., Boston; Patrick McKiernan, Birmingham Women’s and Children’s NHS Foundation Trust; Quanhong Ni, Albireo Pharma, Inc., Boston; Hasan Özen, Hacettepe University; Sanjay R Rajwal, Leeds Children’s Hospital, UK; Bertrand Roquelaure, CHU, Hospital de la Timone, Marseille; Eyal Shteyer, Hebrew University of Jerusalem; Etienne Sokal, Cliniques St Luc, Brussels, Belgium; Ronald J Sokol, University of Colorado; Nisreen Soufi, Children's Hospital Los Angeles; Ekkehard Sturm, University Children’s Hospital Tübingen; Mary Elizabeth Tessier, Texas Children’s Hospital, Houston; Wendy L van der Woerd, Wilhelmina Children’s Hospital, Utrecht; Henkjan J Verkade, University of Groningen; Jennifer M Vittorio, Columbia University; Terese Wallefors, 1Albireo Pharma, Inc., Boston; Natalie Warholic, Albireo Pharma, Inc., Boston; Qifeng Yu, Albireo Pharma, Inc., Boston; Patrick Horn, Albireo Pharma, Inc., Boston; Lise Kjems, Albireo Pharma, Inc., Boston
• Language: English
• Date: 2023-08-01
• Publisher: Elsevier B.V.
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Authors
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jhepr.2023.100782
• Title of Journal or Parent Work: JHEP Reports
• Volume: 5
• Issue: 8
• Start Page: 100782
• End Page: 100782
• Grant/Funding Information: This study was sponsored by Albireo Pharma, Inc. who had input into the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
• Keywords: Enterohepatic circulation; Bile acids and salts; Clinical trial; Liver diseases
• Research Categories: Health Sciences, Pharmacology

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.