Author information
1Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern, Dallas, Texas, USA.
2Department of Medicine, Section of Gastroenterology and Hepatology, Department of Surgery, Division of Abdominal Transplantation, Baylor College of Medicine, Houston, Texas, USA.
3Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, Sacramento, California, USA.
4Division of Digestive Health and Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA.
5Schiff Center for Liver Diseases, University of Miami, Miami, Florida, USA.
6Toronto Centre for Liver Disease, Toronto, Ontario, Canada.
7Covenant Metabolic Specialists LLC, Sarasota and Fort Myers, Florida, USA.
8Digestive Healthcare of Georgia, Atlanta, Georgia, USA.
9Division of Hepatology, Henry Ford Health, Wayne State University School of Medicine, Detroit, Michigan, USA.
10Southern Therapy and Advanced Research LLC, Jackson, Mississippi, USA.
11Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
12Institute of Digestive Health and Liver Diseases, Mercy Medical Center, Baltimore, Maryland, USA.
13Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
14Department of Medicine, Stanford University, Palo Alto, California, USA.
15Liver Institute of Virginia, Bon Secours Mercy Health, Richmond and Newport News, Virginia, USA.
16Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
17Institute of Cellular Medicine and National Institute for Health Research (NIHR), Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, UK.
18National Institute for Health Research Birmingham (NIHR) Biomedical Research Centre (BRC), Centre for Liver and Gastrointestinal Research, University of Birmingham, Birmingham, UK.
19Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland.
20Department of Gastroenterology and Hepatology, Portsmouth Hospitals University NHS Trust, Queen Alexandra Hospital, Portsmouth, UK.
21Faculty of Health, University of Plymouth and South West Liver Unit, University Hospitals Plymouth NHS Trust, Plymouth, UK.
22Medical Outpatient Department, Charité Universitätsmedizin, Berlin, Germany.
23Biometrics, CymaBay Therapeutics, Inc, Newark, California, USA.
24Research and Development, CymaBay Therapeutics, Inc, Newark, California, USA.
Abstract
Background: Seladelpar is a potent and selective peroxisome proliferator-activated receptor-δ agonist that targets multiple cell types involved in primary biliary cholangitis (PBC), leading to anti-cholestatic, anti-inflammatory and anti-pruritic effects.
Aims: To evaluate the long-term safety and efficacy of seladelpar in patients with PBC.
Methods: In an open-label, international, long-term extension study, patients with PBC completing seladelpar lead-in studies continued treatment. Seladelpar was taken orally once daily at doses of 5 or 10 mg with dose adjustment permitted for safety or tolerability. The primary analysis was for safety and the secondary efficacy analysis examined biochemical markers of cholestasis and liver injury. The study was terminated early due to the unexpected histological findings in a concurrent study for non-alcoholic steatohepatitis, which were subsequently found to predate treatment. Safety and efficacy data were analysed through 2 years.
Results: There were no serious treatment-related adverse events observed among 106 patients treated with seladelpar for up to 2 years. There were four discontinuations for safety, one possibly related to seladelpar. Among 53 patients who completed 2 years of seladelpar, response rates increased from years 1 to 2 for the composite endpoint (alkaline phosphatase [ALP] <1.67 × ULN, ≥15% decrease in ALP, and total bilirubin ≤ULN) and ALP normalisation from 66% to 79% and from 26% to 42%, respectively. In those with elevated bilirubin at baseline, 43% achieved normalisation at year 2.
Conclusions: Seladelpar was safe, and markedly improved biochemical markers of cholestasis and liver injury in patients with PBC. These effects were maintained or improved throughout the second year.
Clinicaltrials: gov: NCT03301506; Clinicaltrialsregister.eu: 2017-003910-16.