A phase II, randomized, open-label, 52-week study of seladelpar in patients with primary biliary cholangitis

Authors

• Christopher L. Bowlus, University of California at Davis
• Michael R. Galambos, Piedmont Atlanta Hospital
• Richard J. Aspinall, Portsmouth Hospitals University NHS Trust
• Gideon M. Hirschfield, University Health Network University of Toronto
• David E.J. Jones, Newcastle University
• Yvonne Dörffel, Charité Universitätsmedizin Berlin
• Stuart C. Gordon, Henry Ford Health System
• Stephen A. Harrison, Pinnacle Clinical Research
• Andreas E. Kremer, Friedrich-Alexander University Erlangen-Nürnberg
• Marlyn J. Mayo, University of Texas Southwestern Medical Center
• Paul J. Thuluvath, Mercy Medical Center Baltimore
• Cynthia Levy, University of Miami
• Mark G. Swain, University of Calgary
• Guy W. Neff, LLC
• David A. Sheridan, Peninsula Medical School
• Carmen M. Stanca, New York University
• Christoph P. Berg, University of Tübingen
• Aparna Goel, Stanford University
• Mitchell L. Shiffman, Liver Institute of Virginia
• John M. Vierling, Baylor College of Medicine
• Pol Boudes, Inc.
• Alexandra Steinberg, Inc.
• Yun Jung Choi, Inc.
• Charles A. McWherter, Inc.

ORCID

• David A. Sheridan: 0000-0001-5100-814X

Abstract

Background & AimsWe examined the efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-delta agonist, in adults with primary biliary cholangitis (PBC) at risk of disease progression (alkaline phosphatase [ALP] ≥1.67xupper limit of normal [ULN]) who were receiving or intolerant to ursodeoxycholic acid.MethodsIn this 52-week, phase II, dose-ranging, open-label study, patients were randomized (1:1) to seladelpar 5 mg/day (n = 53) or 10 mg/day (n = 55) or assigned to 2 mg/day (n = 11; United Kingdom sites after interim analysis) for 12 weeks. Doses could then be uptitrated to 10 mg/day. The primary efficacy endpoint was ALP change from baseline to Week 8.ResultsMean baseline ALP was 300, 345, and 295 U/L in the 2 mg, 5 mg, and 10 mg cohorts, respectively. Twenty-one percent of patients had cirrhosis, 71% had pruritus. At Week 8, mean ± standard error ALP reductions from baseline were 26 ± 2.8%, 33 ± 2.6%, and 41 ± 1.8% in the 2 mg (n = 11), 5 mg (n = 49), and 10 mg (n = 52) cohorts (all p ≤0.005), respectively. Responses were maintained or improved at Week 52, after dose escalation in 91% and 80% of the 2 mg and 5 mg cohorts, respectively. At Week 52, composite response (ALP <1.67xULN, ≥15% ALP decrease, and normal total bilirubin) rates were 64%, 53%, and 67%, and ALP normalization rates were 9%, 13%, and 33% in the 2 mg, 5 mg, and 10 mg cohorts, respectively. Pruritus visual analog scale score was decreased in the 5 mg and 10 mg cohorts. There were no treatment-related serious adverse events, and 4 patients discontinued due to adverse events.ConclusionsSeladelpar demonstrated robust, dose-dependent, clinically significant, and durable improvements in biochemical markers of cholestasis and inflammation in patients with PBC at risk of disease progression. Seladelpar appeared safe and well tolerated and was not associated with any increase in pruritus.

DOI Link

10.1016/j.jhep.2022.02.033

Publication Date

2022-08-01

Publication Title

Journal of Hepatology

Volume

77

Issue

2

ISSN

0168-8278

Acceptance Date

2022-02-28

Deposit Date

2022-04-22

Embargo Period

2022-04-23

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

First Page

353

Last Page

364

Recommended Citation

Bowlus, C., Galambos, M., Aspinall, R., Hirschfield, G., Jones, D., Dörffel, Y., Gordon, S., Harrison, S., Kremer, A., Mayo, M., Thuluvath, P., Levy, C., Swain, M., Neff, G., Sheridan, D., Stanca, C., Berg, C., Goel, A., Shiffman, M., Vierling, J., Boudes, P., Steinberg, A., Choi, Y., & McWherter, C. (2022) 'A phase II, randomized, open-label, 52-week study of seladelpar in patients with primary biliary cholangitis', Journal of Hepatology, 77(2), pp. 353-364. Available at: 10.1016/j.jhep.2022.02.033