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 language | English |
|---|---|
| Pages (from-to) | 397-415 |
| Number of pages | 19 |
| Journal | Hepatology |
| Volume | 78 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 1 Aug 2023 |
| Externally published | Yes |
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In: Hepatology, Vol. 78, No. 2, 01.08.2023, p. 397-415.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis
T2 - ENHANCE, a phase 3, randomized, placebo-controlled study
AU - Hirschfield, Gideon M.
AU - Shiffman, Mitchell L.
AU - Gulamhusein, Aliya
AU - Kowdley, Kris V.
AU - Vierling, John M.
AU - Levy, Cynthia
AU - Kremer, Andreas E.
AU - Zigmond, Ehud
AU - Andreone, Pietro
AU - Gordon, Stuart C.
AU - Bowlus, Christopher L.
AU - Lawitz, Eric J.
AU - Aspinall, Richard J.
AU - Pratt, Daniel S.
AU - Raikhelson, Karina
AU - Gonzalez-Huezo, Maria S.
AU - Heneghan, Michael A.
AU - Jeong, Sook-Hyang
AU - Ladrón de Guevara, Alma L.
AU - Mayo, Marlyn J.
AU - Dalekos, George N.
AU - Drenth, Joost P. H.
AU - Janczewska, Ewa
AU - Leggett, Barbara A.
AU - Nevens, Frederik
AU - Vargas, Victor
AU - Zuckerman, Eli
AU - Corpechot, Christophe
AU - Fassio, Eduardo
AU - Hinrichsen, Holger
AU - Invernizzi, Pietro
AU - Trivedi, Palak J.
AU - Forman, Lisa
AU - Jones, David E. J.
AU - Ryder, Stephen D.
AU - Swain, Mark G.
AU - Steinberg, Alexandra
AU - Boudes, Pol F.
AU - Choi, Yun-Jung
AU - McWherter, Charles A.
AU - Adrover, Raul
AU - Agrawal, Saurabh
AU - Aigner, Elmar
AU - Martinez, Agustin A.
AU - Alden, Abu-Mouch S.
AU - Bellido, Raul Jesús Andrade
AU - Jiménez, Marco Antonio Arrese
AU - Ayoub, Walid
AU - Baum, Seth J.
AU - Ben-Ari, Ziv
AU - Berenguer, Marina
AU - Berg, Christoph
AU - Bessone, Fernando O.
AU - Bonder, Alan
AU - Borg, Brian B.
AU - Ruiz, Carlos Gustavo Bresky
AU - Buggisch, Peter
AU - Panero, Jose Luis Calleja
AU - Carey, Elizabeth J.
AU - Carmiel-Haggai, Michal
AU - Carubbi, Francesca
AU - Grau, Pilar Castillo
AU - Ch'ng, Chin L.
AU - Cimpoeru, Nicoleta-Claudia
AU - Omaña, Raúl C.
AU - Corless, Lynsey
AU - Costentin, Charlotte
AU - Deschênes, Marc
AU - Dörffel, Yvonne
AU - Dugalic, Predrag
AU - Farrell, Geoffrey C.
AU - Fernández, José L.
AU - Floreani, Annarosa
AU - Francque, Sven
AU - Freilich, Bradley L.
AU - Saldias, Francisco Alejandro Fuster
AU - Galambos, Michael R.
AU - Galati, Joseph
AU - Galli, Andrea
AU - Ganne-Carrie, Nathalie
AU - Geyvandova, Natalia
AU - Gheorghe, Liliana-Simona
AU - Gilroy, Richard
AU - Goel, Aparna
AU - Goeser, Tobias
AU - Greenbloom, Susan
AU - Halota, Waldemar
AU - Harrison, Stephen A.
AU - Hartleb, Marek
AU - Heo, Jeong
AU - Hofer, Harald
AU - Horváth, G. bor
AU - Huang, Jonathan C.
AU - Huffman, Jason L.
AU - Hunyady, B. la
AU - Johnson, Steven
AU - Kallis, Yiannis
AU - Khazanchi, Arun
AU - Kim, Kyung-Ah
AU - Kim, Seung Up
AU - Kim, Yoon Jun
AU - Kohli, Anita
AU - Kontorinis, Nicholas
AU - Lake, John R.
AU - Lee, Kwan Sik
AU - Mach, Tomasz
AU - Manch, Richard
AU - Maor-Kendler, Yaakov
AU - Mateescu, Radu-Bogdan
AU - Minuk, Gerald
AU - Modi, Apurva A.
AU - Moehlen, Martin W.
AU - Rodríguez, Cristina M.
AU - Cunill, Rosa Maria Morillas
AU - Mouzas, Ioannis
AU - Muir, Andrew
AU - Nagy, István
AU - Ngu, Jing Hieng (Jeffrey)
AU - Odin, Joseph
AU - Ogurtsov, Pavel
AU - Pabjan, Pawel
AU - Pagadala, Mangesh
AU - Papp, M. ria
AU - Parés, Albert
AU - Peskov, Andrey
AU - Peyton, Adam
AU - Phillips, John
AU - Porayko, Michael
AU - Post, Anthony
AU - Pound, David C.
AU - Rabinovitz, Mordechai
AU - Rank, Kevin
AU - Reddy, K. Gautham
AU - Regula, Jaroslaw
AU - Riley, Thomas
AU - Gómez, Manuel R.
AU - Safadi, Rifaat
AU - Sheridan, David A.
AU - Silva, Marcelo O.
AU - Silveira, Marina G.
AU - Sood, Siddarth
AU - Sporea, Ioan
AU - Stanca, Carmen
AU - Stauber, Rudolf
AU - Svorcan, Petar
AU - Tak, Won Young
AU - Taylor, Ryan M.
AU - Thorburn, Douglas
AU - Tobias, Hillel
AU - Zekry, Arnany T.
AU - Trauner, Michael
AU - Triantos, Christos
AU - Veitsman, Ella
AU - Thompson, Alexander James Venn
AU - Verhelst, Xavier
AU - Verna, Elizabeth C.
AU - von der Ohe, Manfred
AU - Weilert, Frank
AU - Wiegand, Johannes
AU - Yimam, Kidist K.
AU - Yoon, Seung Kew
AU - Younes, Ziad
AU - Zivony, Adam S.
AU - Zuin, Massimo
N1 - Funding Information: 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. Funding Information: 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. Publisher Copyright: © 2023 John Wiley and Sons Inc.. All rights reserved.
PY - 2023/8/1
Y1 - 2023/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85165221969&partnerID=8YFLogxK
U2 - https://doi.org/10.1097/HEP.0000000000000395
DO - https://doi.org/10.1097/HEP.0000000000000395
M3 - Article
C2 - 37386786
SN - 0270-9139
VL - 78
SP - 397
EP - 415
JO - Hepatology
JF - Hepatology
IS - 2
ER -