Author information
1University Health Network and Division of Gastroenterology and Hepatology, Toronto Centre for Liver Disease, University of Toronto, Toronto, Ontario, Canada.
2Liver Institute of Virginia, Bon Secours Mercy Health, Bon Secours Liver Institute of Richmond, Richmond, Virginia, USA.
3Bon Secours Liver Institute of Hampton Roads, Newport News, Virginia, USA.
4University Health Network and Department of Medicine, Toronto Centre for Liver Disease, University of Toronto, Toronto, Ontario, Canada.
5Liver Institute Northwest, Seattle, Washington, USA.
6Departments of Medicine and Surgery, Baylor College of Medicine, Houston, Texas, USA.
7Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA.
8Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland.
9Center for Autoimmune Liver Diseases, Tel-Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
10Department of Medical and Surgical Sciences, Division of Internal Medicine, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, Modena, Italy.
11Postgraduate School of Allergy and Clinical Immunology, University of Modena and Reggio Emilia, Italy.
12Division of Hepatology, Henry Ford Hospital, Wayne State University School of Medicine, Detroit, Michigan, USA.
13Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, Sacramento, California, USA.
14Texas Liver Institute, University of Texas Health San Antonio, San Antonio, Texas, USA.
15Department of Hepatology, Portsmouth Liver Centre, Portsmouth Hospitals National Health Service Trust, Queen Alexandra Hospital, Portsmouth, UK.
16Autoimmune and Cholestatic Liver Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
17Saint Petersburg State University, St. Petersburg, Russia.
18City Hospital 31, St. Petersburg, Russia.
19Metepec Edo Mex., Mexico.
20King's College Hospital National Health Service Foundation Trust, London, UK.
21Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
22Center of Research and Gastroenterology, Mexico City, Mexico.
23Division of Digestive and Liver Diseases, University of Texas Southwestern, Dallas, Texas, USA.
24Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), General University Hospital of Larissa, Larissa, Greece.
25Department of Gastroenterology and Hepatology, Radboudumc, Nijmegen, The Netherlands.
26Department of Basic Medical Sciences, Faculty of Health Sciences in Bytom, Medical University of Silesia, Katowice, Poland.
27ID Clinic, Myslowice, Poland.
28School of Medicine, University of Queensland, Herston, Queensland, Australia.
29University Hospitals KU Leuven, Belgium.
30Center of European Reference Network (ERN) RARE-LIVER, Leuven, Belgium.
31Liver Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Bellaterra, Spain.
32Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.
33Liver Unit, Carmel Medical Center, Technion, Faculty of Medicine, Israeli Association for the Study of the Liver, Haifa, Israel.
34Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Hepatology and Gastroenterology Department (MIVB-H), Filière Maladies Rares: Maladies Rares du Foie de l'Adulte et de l'Enfant (FILFOIE), European Reference Network (ERN) RARE-LIVER, Inserm, Centre de Recherche Saint-Antoine (CRSA), Assistance Publique-Hopitaux of Paris (AP-HP), Saint-Antoine Hospital, Sorbonne Universités, Paris, France.
35DIM Clínica Privada, Ramos Mejía, Buenos Aires province, Argentina.
36Gastroenterology-Hepatology Center Kiel, Kiel, Germany.
37Department of Medicine and Surgery, Center for Autoimmune Liver Diseases, University of Milano-Bicocca, Monza, Italy.
38Division of Gastroenterology, Fondazione IRCCS San Gerardo dei Tintori & European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Monza, Italy.
39National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, Centre for Liver and Gastroenterology Research, University of Birmingham, UK.
40Liver Unit, University Hospitals Birmingham Queen Elizabeth, Birmingham, UK.
41Institute of Immunology and Immunotherapy, University of Birmingham, UK.
42Institute of Applied Health Research, University of Birmingham, UK.
43University of Colorado, Aurora, Colorado, USA.
44Institute of Cellular Medicine and National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, UK.
45National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre at Nottingham University Hospitals National Health Service (NHS) Trust and the University of Nottingham, Queens Medical Centre, Nottingham, UK.
46Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
47CymaBay Therapeutics, Newark, California, USA.
Abstract
Background and aims: ENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-δ (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA).
Approach and results: Patients were randomized 1:1:1 to oral seladelpar 5 mg (n=89), 10 mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67×upper limit of normal (ULN), ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ≥4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10 mg: 78.2%) versus placebo (12.5%) ( p < 0.0001). ALP normalization occurred in 5.4% ( p =0.08) and 27.3% ( p < 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: -3.14 ( p =0.02); placebo: -1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% ( p =0.0008); 10 mg: 16.7% ( p =0.03); placebo: 4%]. There were no serious treatment-related adverse events.
Conclusions: Patients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated.