David Jones1, Pol F Boudes2, Mark G Swain3, Christopher L Bowlus4, Michael R Galambos5, Bruce R Bacon6, Yvonne Doerffel7, Norman Gitlin8, Stuart C Gordon9, Joseph A Odin10, David Sheridan11, Markus-Alexander Wörns12, Virginia Clark13, Linsey Corless14, Heinz Hartmann15, Mark E Jonas16, Andreas E Kremer17, George F Mells18, Peter Buggisch19, Bradley L Freilich20, Cynthia Levy21, John M Vierling22, David E Bernstein23, Marek Hartleb24, Ewa Janczewska25, Fedja Rochling26, Hemant Shah27, Mitchell L Shiffman28, John H Smith29, Yun-Jung Choi30, Alexandra Steinberg30, Monika Varga30, Harinder Chera30, Robert Martin30, Charles A McWherter30, Gideon M Hirschfield31. 1. University of Newcastle, Newcastle upon Tyne, UK. 2. CymaBay Therapeutics, Newark, CA, USA. Electronic address: pboudes@cymabay.com. 3. University of Calgary Liver Unit, Calgary, Canada. 4. University of California Davis, Sacramento, CA, USA. 5. Digestive Healthcare of Georgia, Atlanta, GA, USA. 6. Saint Louis University Hospital, Saint Louis, MO, USA. 7. Charité Universitaetsmedizin Berlin, Berlin, Germany. 8. Atlanta Gastroenterology Associates, Atlanta, GA, USA. 9. Henry Ford Health System, Detroit, MI, USA. 10. Icahn School of Medicine at Mount Sinai, New York, NY, USA. 11. Plymouth Hospitals NHS Trust & Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK. 12. Universitaetsmedizin der Johannes Gutenberg-Universitaet, Mainz, Germany. 13. UF Hepatology Research at CTRB, Gainesville, FL, USA. 14. Hull and East Yorkshire Hospitals NHS Trust, Hull, UK. 15. Gastroenterologische Gemeinschaftspraxis, Herne, Germany. 16. Ohio Gastroenterology and Liver Institute, Cincinnati, OH, USA. 17. Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany. 18. Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. 19. Institut für interdisziplinäre Medizin Studien GmbH an der Asklepiosklinik Saint Georg, Hamburg, Germany. 20. Kansas City Research Institute, LLC, Kansas City, KS, USA. 21. Division of Hepatology, University of Miami, Miami, FL, USA. 22. Advanced Liver Therapies, Baylor College of Medicine, Houston, TX, USA. 23. North Shore University Hospital, Lake Success, NY, USA. 24. Department of Gastroenterology and Hepatology, Medical University of Silesia, School of Medicine in Katowice, Katowice, Poland. 25. ID Clinic Arkadiusz Pisula, Myslowice, Poland. 26. University of Nebraska Medical Center, Omaha, NE, USA. 27. Toronto General Hospital, University Health Network, Toronto, Canada. 28. Liver Institute of Virginia, Richmond, VA, USA. 29. Digestive and Liver Disease Specialists, Norfolk, VA, USA. 30. CymaBay Therapeutics, Newark, CA, USA. 31. Center for Liver Research, Birmingham NIHR Biomedical Research Center, University of Birmingham, Birmingham, UK.
Abstract
BACKGROUND: Many patients with primary biliary cholangitis have an inadequate response to first-line therapy with ursodeoxycholic acid. Seladelpar is a potent, selective agonist for the peroxisome proliferator-activated receptor-delta (PPAR-δ), which is implicated in bile acid homoeostasis. This first-in-class study evaluated the anti-cholestatic effects and safety of seladelpar in patients with an inadequate response to ursodeoxycholic acid. METHODS: The study was a 12-week, double-blind, placebo-controlled, phase 2 trial of patients with alkaline phosphatase of at least 1·67 times the upper limit of normal (ULN) despite treatment with ursodeoxycholic acid. Patients, recruited at 29 sites in North America and Europe, were randomly assigned to placebo, seladelpar 50 mg/day, or seladelpar 200 mg/day while ursodeoxycholic acid was continued. Randomisation was done centrally (1:1:1) by a computerised system using an interactive voice-web response system with a block size of three. Randomisation was stratified by region (North America and Europe). The primary outcome was the percentage change from baseline in alkaline phosphatase over 12 weeks, analysed in the modified intention-to-treat (ITT) population (any randomised patient who received at least one dose of medication and had at least one post-baseline alkaline phosphatase evaluation). This study is registered with ClinicalTrials.gov (NCT02609048) and the EU Clinical Trials Registry (EudraCT2015-002698-39). FINDINGS: Between Nov 4, 2015, and May 26, 2016, 70 patients were screened at 29 sites in North America and Europe. During recruitment, three patients treated with seladelpar developed fully reversible, asymptomatic grade 3 alanine aminotransferase increases (one on 50 mg, two on 200 mg), ranging from just over five to 20 times the ULN; as a result, the study was terminated after 41 patients were randomly assigned. The modified ITT population consisted of 12 patients in the placebo group, 13 in the seladelpar 50 mg group, and 10 in the seladelpar 200 mg group. Mean changes from baseline in alkaline phosphatase were -2% (SD 16) in the placebo group, -53% (14) in the seladelpar 50 mg group, and -63% (8) in the seladelpar 200 mg group. Changes in both seladelpar groups versus placebo were significant (p<0·0001 for both groups vs placebo), with no significant difference between the two seladelpar groups (p=0·1729). All five patients who received seladelpar for 12 weeks had normal alkaline phosphatase values at the end of treatment, based on a central laboratory ULN for alkaline phosphatase of 116 U/L. The most frequently reported adverse events were pruritus (16%; one patient on placebo, four on seladelpar 50 mg, and one on seladelpar 200 mg), nausea (13%; one patient on placebo, three on seladelpar 50 mg, and one on seladelpar 200 mg), diarrhoea (10%; two patients on placebo, one on seladelpar 50 mg, and one on seladelpar 200 mg), dyspepsia (8%; two patients on seladelpar 50 mg and one on seladelpar 200 mg), muscle spasms (8%; three patients on seladelpar 200 mg), myalgia (8%; one patient on placebo and two on seladelpar 200 mg), and dizziness (8%; one patient on placebo and two on seladelpar 50 mg). INTERPRETATION: Seladelpar normalised alkaline phosphatase levels in patients who completed 12 weeks of treatment. However, treatment was associated with grade 3 increases in aminotransferases and the study was stopped early. The effects of seladelpar should be explored at lower doses. FUNDING: CymaBay Therapeutics.
BACKGROUND: Many patients with primary biliary cholangitis have an inadequate response to first-line therapy with ursodeoxycholic acid. Seladelpar is a potent, selective agonist for the peroxisome proliferator-activated receptor-delta (PPAR-δ), which is implicated in bile acid homoeostasis. This first-in-class study evaluated the anti-cholestatic effects and safety of seladelpar in patients with an inadequate response to ursodeoxycholic acid. METHODS: The study was a 12-week, double-blind, placebo-controlled, phase 2 trial of patients with alkaline phosphatase of at least 1·67 times the upper limit of normal (ULN) despite treatment with ursodeoxycholic acid. Patients, recruited at 29 sites in North America and Europe, were randomly assigned to placebo, seladelpar 50 mg/day, or seladelpar 200 mg/day while ursodeoxycholic acid was continued. Randomisation was done centrally (1:1:1) by a computerised system using an interactive voice-web response system with a block size of three. Randomisation was stratified by region (North America and Europe). The primary outcome was the percentage change from baseline in alkaline phosphatase over 12 weeks, analysed in the modified intention-to-treat (ITT) population (any randomised patient who received at least one dose of medication and had at least one post-baseline alkaline phosphatase evaluation). This study is registered with ClinicalTrials.gov (NCT02609048) and the EU Clinical Trials Registry (EudraCT2015-002698-39). FINDINGS: Between Nov 4, 2015, and May 26, 2016, 70 patients were screened at 29 sites in North America and Europe. During recruitment, three patients treated with seladelpar developed fully reversible, asymptomatic grade 3 alanine aminotransferase increases (one on 50 mg, two on 200 mg), ranging from just over five to 20 times the ULN; as a result, the study was terminated after 41 patients were randomly assigned. The modified ITT population consisted of 12 patients in the placebo group, 13 in the seladelpar 50 mg group, and 10 in the seladelpar 200 mg group. Mean changes from baseline in alkaline phosphatase were -2% (SD 16) in the placebo group, -53% (14) in the seladelpar 50 mg group, and -63% (8) in the seladelpar 200 mg group. Changes in both seladelpar groups versus placebo were significant (p<0·0001 for both groups vs placebo), with no significant difference between the two seladelpar groups (p=0·1729). All five patients who received seladelpar for 12 weeks had normal alkaline phosphatase values at the end of treatment, based on a central laboratory ULN for alkaline phosphatase of 116 U/L. The most frequently reported adverse events were pruritus (16%; one patient on placebo, four on seladelpar 50 mg, and one on seladelpar 200 mg), nausea (13%; one patient on placebo, three on seladelpar 50 mg, and one on seladelpar 200 mg), diarrhoea (10%; two patients on placebo, one on seladelpar 50 mg, and one on seladelpar 200 mg), dyspepsia (8%; two patients on seladelpar 50 mg and one on seladelpar 200 mg), muscle spasms (8%; three patients on seladelpar 200 mg), myalgia (8%; one patient on placebo and two on seladelpar 200 mg), and dizziness (8%; one patient on placebo and two on seladelpar 50 mg). INTERPRETATION: Seladelpar normalised alkaline phosphatase levels in patients who completed 12 weeks of treatment. However, treatment was associated with grade 3 increases in aminotransferases and the study was stopped early. The effects of seladelpar should be explored at lower doses. FUNDING: CymaBay Therapeutics.
Authors: Alena Laschtowitz; Rozanne C de Veer; Adriaan J Van der Meer; Christoph Schramm Journal: United European Gastroenterol J Date: 2020-04-16 Impact factor: 4.623
Authors: Jia Li; Stuart C Gordon; Loralee B Rupp; Talan Zhang; Sheri Trudeau; Scott D Holmberg; Anne C Moorman; Philip R Spradling; Eyasu H Teshale; Joseph A Boscarino; Mark A Schmidt; Yihe G Daida; Mei Lu Journal: Aliment Pharmacol Ther Date: 2019-01-16 Impact factor: 8.171