Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study

Gideon M. Hirschfield, Mitchell L. Shiffman, Aliya Gulamhusein, Kris V. Kowdley, John M. Vierling, Cynthia Levy, Andreas E. Kremer, Ehud Zigmond, Pietro Andreone, Stuart C. Gordon, Christopher L. Bowlus, Eric J. Lawitz, Richard J. Aspinall, Daniel S. Pratt, Karina Raikhelson, Maria S. Gonzalez-Huezo, Michael A. Heneghan, Sook Hyang Jeong, Alma L. Ladrón De Guevara, Marlyn J. MayoGeorge N. Dalekos, Joost P.H. Drenth, Ewa Janczewska, Barbara A. Leggett, Frederik Nevens, Victor Vargas, Eli Zuckerman, Christophe Corpechot, Eduardo Fassio, Holger Hinrichsen, Pietro Invernizzi, Palak J. Trivedi, Lisa Forman, David E.J. Jones, Stephen D. Ryder, Mark G. Swain, Alexandra Steinberg, Pol F. Boudes, Yun Jung Choi, Charles A. McWherter, Raul Adrover, Saurabh Agrawal, Elmar Aigner, Agustin A. Martinez, Abu Mouch S. Alden, Raul Jesús Andrade Bellido, Marco Antonio Arrese Jiménez, Walid Ayoub, Seth J. Baum, Ziv Ben-Ari, Marina Berenguer, Christoph Berg, Fernando O. Bessone, Alan Bonder, Brian B. Borg, Carlos Gustavo Bresky Ruiz, Peter Buggisch, Jose Luis Calleja Panero, Elizabeth J. Carey, Michal Carmiel-Haggai, Francesca Carubbi, Pilar Castillo Grau, Chin L. Ch'ng, Nicoleta Claudia Cimpoeru, Raúl C. Omaña, Lynsey Corless, Charlotte Costentin, Marc Deschênes, Yvonne Dörffel, Predrag Dugalic, Geoffrey C. Farrell, José L. Fernández, Annarosa Floreani, Sven Francque, Bradley L. Freilich, Francisco Alejandro Fuster Saldias, Michael R. Galambos, Joseph Galati, Andrea Galli, Nathalie Ganne-Carrie, Natalia Geyvandova, Liliana Simona Gheorghe, Richard Gilroy, Aparna Goel, Tobias Goeser, Susan Greenbloom, Waldemar Halota, Stephen A. Harrison, Marek Hartleb, Jeong Heo, Harald Hofer, Gábor Horváth, Jonathan C. Huang, Jason L. Huffman, Béla Hunyady, Steven Johnson, Yiannis Kallis, Arun Khazanchi, Kyung Ah Kim, Seung Up Kim, Yoon Jun Kim, Anita Kohli, Nicholas Kontorinis, John R. Lake, Kwan Sik Lee, Tomasz Mach, Richard Manch, Yaakov Maor-Kendler, Radu Bogdan Mateescu, Gerald Minuk, Apurva A. Modi, Martin W. Moehlen, Cristina M. Rodríguez, Rosa Maria Morillas Cunill, Ioannis Mouzas, Andrew Muir, István Nagy, Jing Hieng (Jeffrey) Ngu, Joseph Odin, Pavel Ogurtsov, Pawel Pabjan, Mangesh Pagadala, Mária Papp, Albert Parés, Andrey Peskov, Adam Peyton, John Phillips, Michael Porayko, Anthony Post, David C. Pound, Mordechai Rabinovitz, Kevin Rank, K. Gautham Reddy, Jaroslaw Regula, Thomas Riley, Manuel R. Gómez, Rifaat Safadi, David A. Sheridan, Marcelo O. Silva, Marina G. Silveira, Siddarth Sood, Ioan Sporea, Carmen Stanca, Rudolf Stauber, Petar Svorcan, Won Young Tak, Ryan M. Taylor, Douglas Thorburn, Hillel Tobias, Arnany T. Zekry, Michael Trauner, Christos Triantos, Ella Veitsman, Alexander James Venn Thompson, Xavier Verhelst, Elizabeth C. Verna, Manfred Von Der Ohe, Frank Weilert, Johannes Wiegand, Kidist K. Yimam, Seung Kew Yoon, Ziad Younes, Adam S. Zivony, Massimo Zuin

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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.

Original languageEnglish
Pages (from-to)397-415
Number of pages19
JournalHepatology
Volume78
Issue number2
DOIs
StatePublished - 1 Aug 2023

Bibliographical note

Publisher Copyright:
© 2023 John Wiley and Sons Inc.. All rights reserved.

Funding

This study and preparation of this manuscript were funded by CymaBay Therapeutics, which had a role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. Palak J. Trivedi received institutional salary support from the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre (BRC). This paper presents independent research supported by the Birmingham NIHR BRC based at the University Hospitals Birmingham National Health Service Foundation Trust and the University of Birmingham. The views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR, or the Department of Health. The authors thank Ke Yang and Kalyan Palla of CymaBay Therapeutics Inc., for assistance with statistical analyses and Holly Capasso-Harris of Certara Synchrogenix for writing assistance that was funded by CymaBay Therapeutics.

FundersFunder number
University Hospitals Birmingham National Health Service Foundation Trust
CymaBay Therapeutics
National Institute for Health and Care Research
University of Birmingham
NIHR Imperial Biomedical Research Centre
Birmingham Biomedical Research Centre

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