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Clinical Trial
. 2023 Aug 1;78(2):397-415.
doi: 10.1097/HEP.0000000000000395. Epub 2023 Apr 6.

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

Gideon M Hirschfield  1 , Mitchell L Shiffman  2   3 , Aliya Gulamhusein  4 , Kris V Kowdley  5 , John M Vierling  6 , Cynthia Levy  7 , Andreas E Kremer  8 , Ehud Zigmond  9 , Pietro Andreone  10   11 , Stuart C Gordon  12 , Christopher L Bowlus  13 , Eric J Lawitz  14 , Richard J Aspinall  15 , Daniel S Pratt  16 , Karina Raikhelson  17   18 , Maria S Gonzalez-Huezo  19 , Michael A Heneghan  20 , Sook-Hyang Jeong  21 , Alma L Ladrón de Guevara  22 , Marlyn J Mayo  23 , George N Dalekos  24 , Joost P H Drenth  25 , Ewa Janczewska  26   27 , Barbara A Leggett  28 , Frederik Nevens  29   30 , Victor Vargas  31   32 , Eli Zuckerman  33 , Christophe Corpechot  34 , Eduardo Fassio  35 , Holger Hinrichsen  36 , Pietro Invernizzi  37   38 , Palak J Trivedi  39   40   41   42 , Lisa Forman  43 , David E J Jones  44 , Stephen D Ryder  45 , Mark G Swain  46 , Alexandra Steinberg  47 , Pol F Boudes  47 , Yun-Jung Choi  47 , Charles A McWherter  47 ; ENHANCE Study Group*
Collaborators, Affiliations
Clinical Trial

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

Gideon M Hirschfield et al. Hepatology. .

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.

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Conflict of interest statement

Gideon M. Hirschfield consults for and received payment/honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from GlaxoSmithKline, Intercept Pharma, and Ipsen. He consults for CymaBay Therapeutics, Escient, Gilead, Mirum, and Pliant. Mitchell L. Shiffman consults for, is on the speakers’ bureau for, and received grants from Intercept. He consults for and is on the speakers’ bureau for Intra-Sana. He is on the speakers’ bureau for and received grants from Cymbay. He received grants from Genfit, Hightide, and Mirum. Aliya Gulamhusein consults for and is on the speakers’ bureau for Intercept. She consults for CymaBay. Kris V. Kowdley consults for, is on the speakers’ bureau for and received grants from 89 Bio, Genfit, Gilead, Intercept, and CymbaBay. He consults for and received grants from Madrigal, Mirum, NGM, Pliant, and Zydus. He consults for and owns stock in Inipharm. He consults for Calliditas and Ipsen. He is on the speakers’ bureau for AbbVie. He received grants from GSK, Pfizer, Hanmi, HighTide, Viking, and Janssen. He receives royalties from UpToDate. He received payment for expert testimony from the Department of Justice. He participated in a data safety monitoring board or advisory board for CTI, Durect, and Labcorp. He received equipment, materials, drugs, medical writing, gifts, or other services from Sonic Insight. John M. Vierling advises and received grants from CymaBay, Intercept, Lilly, Novartis, and Sagiment. He advises Arena, Blade, Kezar, Labcorp, Fractyl, Ipsen, Moderna, and Taiwan J. He received grants from Genfit. He is a board member of and owns stock in Athenex. Cynthia Levy consults for, advises, and received grants from Cara Therapeutics, CymaBay Therapeutics, and GlaxoSmith Kline. She consults for and received grants from Calliditas, Escient, Genfit, Gilead, Intercept, Ipsen, Mirum, and Target RWE. She received grants from HighTide, Novartis, and Zydus. Andreas E. Kremer consults for, received payment/honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from, received grants from, and advises AbbVie, Bayer, CymaBay Therapeutics, Gilead, GlaxoSmithKline, Intercept Pharma, and MSD. He received payment/honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from and received grants from AOP Orphan, Bristol Myers Squibb, CMS, Dr. Falk, Eisai, Eli Lily, Janssen, Newbridge, Novartis, and Zambon. He consults for and advises Beiersdorf, Escient, FMC, Guidepoint, Medscape, Mirum, Myr, Roche, and Viofor. Ehud Zigmond advises, received lecture fees from, and received grants from Neopharm LTD. Stuart C. Gordon consults for and received grants from CymaBay, Gilead, and GSK. He received grants from AbbVie, DURECT, Genfit, Hightide, Intercept Pharma, Merck, Mirum, Pliant, and Viking. Christopher L. Bowlus consults for and received grants from CymaBay Therapeutics, Eli Lilly, and GlaxoSmithKline. He consults for BiomX, Mirum, Shire, and Trevi Therapeutics. He received grants from Arena Pharmaceuticals, Bristol Myers Squibb, Calliditas Therapeutics, Chemomab, COUR Pharmaceuticals, Genfit, Gilead, GlaxoSmithKline, Hanmi, Intercept, Novartis, NovoNordisk, Pliant, Takeda, and TARGET. Eric J. Lawitz consults for, is on the speakers’ bureau for, and received grants from Intercept. He consults for and received grants from Akero, Boheringer Ingelheim, BMS, Novo Nordisk, Metacrine, Sagimet, and Terns. He is on the speakers’ bureau for and received grants from AbbVie and Gilead. He received grants from 89Bio Inc., Allergan, Alnylam Pharmaceuticals Inc., Amgen, Ascelia Pharma, Assemblybio, AstraZeneca, Axcella Health, Biocryst Pharmaceuticals, Bird Rock Bio Inc., Conatus Pharmaceuticals, CymaBay Therapeutics, CytoDyn, DSM, Durect Corporation, Eli Lilly, Enanta Pharmaceuticals, Enyo Pharma, Exalenz Bioscience, Galectin Therapeutics, Galmed Pharmaceuticals, Genentech, Genfit, GlaxoSmithKline, Hanmi Pharmaceuticals, HighTide Biopharma, Inventiva, Janssen Pharmaceuticals, Laboratory for Advanced Medicine, Loxo Oncology, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals Inc., Northsea Therapeutics, Novartis, Pfizer, Poxel Co., Roche, Synlogic Therapeutics, Viking Therapeutics, and Zydus Pharmaceuticals. Richard J. Aspinall consults for and is on the speakers’ bureau for Norgine UK. He is on the speakers’ bureau for Intercept UK. He owns stock in CymaBay. Daniel S. Pratt consults for Mediar Therapeutics. Karina Raikhelson received payment/honoraria for lectures presentations, speakers bureaus, manuscript writing, or educational events from Abbott Laboratories GmbH, Alfasigma Rus, Binnopharm Group, Dr. Falk Pharma GmbH, JSC Nizhfarm, and JSC Pharmstandard. She received payment/honoraria for lectures presentations, speakers bureaus, manuscript writing, or educational events and was expert witness for STPF “Polisan.” She received grants from CymaBay and Novartis. Michael A. Heneghan consulting for Ipsen, Eledon, and Moderna He recieved payment/honoraria for lectures, presentations, speakers bureau, manuscript writing, or educational events from Falk, Advanz Pharma, and Intercept Pharma. He receives royalties from UpToDate. Sook-Hyang Jeong received grants from Bristol Myers Squibb, CymaBay Therapeutics, Galmed, Gilead, Hoffmann-La Roche Ltd, Intercept, and MSD. Alma L. Ladrón de Guevara received grants from AstraZeneca, Cymabay, Lilly, Madrigal, Akero, Galectin, MSD and Novo Nordisk, and Viking. Marlyn J. Mayo consults for and received grants from CymaBay Therapeutics, GlaxoSmithKline, and Mallinckrodt. She received grants from Genfit, Intercept, Mirum, and TARGET. She consults for Ipsen. She is on the speaker’s bureau for Intra-Sana. George N. Dalekos advises, is on the speakers’ bureau for, and serves as principal investigator for Genkeyotex, Pfizer, and Sobi. He advises and is on the speakers’ bureau for Ipsen and Sanofi. He is a principal investigator for Amyndas Pharmaceuticals, CymBay Therapeutics, Intercept, Novo Nordisk, Regulus Therapeutics, and Tiziana Life Sciences. Joost P.H. Drenth consults for Camurus. He received grants from AbbVie and Gilead. He is on a data safety monitoring board or advisory board for COIN B Study. Ewa Janczewska advises and received grants from Novo Nordisk and Cellaion. She is on the speakers’ bureau for and received grants from Abbvie. She is on the speakers’ bureau for Roche. She received grants from Axella, Exelixis, CymaBay, Calliditas, BMS, GSK, Janssen-Cilag, Dr. Falk, Inventiva, and MSD. Barbara A. Leggett received grants from CymaBay Therapeutics. Frederik Nevens consults for and received grants from Gilead. He consults for Abbvie, W.L. Gore, Cook Medical, TwinPharma, Intercept, Genkyotex, Camurus, Chemomab Therapeutics, Agomab Therapeutics, Novartis Pharma, Mayoly Spindler, Calliditas Therapeutics, Norgine, Takeda, and Dynacure. He received grants from Promethera Therapeutics and Ipsen. Victor Vargas consults for Genfit. He is on the speakers’ bureau for Intercept. He is on the data safety monitoring board or advisory board for Promethera Biosciences/Cellaion. He received grants from Advanz Pharma. Christophe Corpechot consults for and received grants from Intercept and CymaBay. He consults for Genkyotex/Calliditas. He received grants from Arrow Génériques, Biotest, and Gilead. Eduardo L. Fassio received grants from Gador. Eli Zuckerman consults and is a speaker for AbbVie, Gilead, GlaxoSmithKline, Janssen, Merck, Neopharm, NovoNordisk, and Roche. He is also a speaker for Bristol Meyers Squibb and Novartis. Holger Hinrichsen consults for and received payment/honoraria for lectures, presentations, and speakers bureaus from AbbVie, Gilead, and Intercept Pharma. He received payment/honoraria for lectures, presentations, and speakers bureaus Norgine. Pietro Invernizzi advises, is on the speakers’ bureau for, and received grants from Intercept. He advises Calliditas and Zydus. He received grants from Abbvie. Palak J. Trivedi consults for and advises CymaBay. David E.J. Jones consults for, is on the speakers’ bureau for, and received funding from Intercept. He consults for CymaBay Therapeutics, Kowa, and Umecrine. He is on the speakers’ bureau for Falk, GlaxoSmithKline, and Ipsen. Mark G. Swain consults for, is on the speakers’ bureau for, and received grants from Gilead. He consults for and received grants from Pfizer and Novartis. He consults for Ipsen. He is on the speakers’ bureau for Abbott. He received grants from AbbVie, Ancella, AstraZeneca, Bristol Myers Squibb, Calliditas Therapeutics, Celgene, CymaBay Therapeutics, Galectin, Genfit, GlaxoSmithKline, Intercept, and Novo Nordisk. Alexandra Steinberg owns stock, has intellectual property rights in and was employed by CymaBay Therapeutics when the work was conducted, and is employed by Carmot Therapeutics. Pol F. Boudes was employed by CymaBay Therapeutics when the work was conducted and declares a seladelpar method of use patent for PBC. He is currently employed by Galectin Therapeutics. Yun-Jung Choi is employed by CymaBay Therapeutics. Charles A. McWherter owns stock and intellectual property rights in and is employed by CymaBay. He declares a seladelpar method of use patent for PBC and for cholestatic pruritus. The remaining authors have no conflicts to report.

Figures

None
Graphical abstract
FIGURE 1
FIGURE 1
Patient flowchart. Screen failures (a patient may be counted in >1 reason for failure): alkaline phosphatase < 1.67× upper limit of normal (ULN) n=149, estimated glomerular filtration rate <60 mL/min/1.73 m2 n=27, alanine aminotransferase >3×ULN n=11, total bilirubin > 2.0×ULN n=11, aspartate aminotransferase >3×ULN n=10, did not meet primary biliary cholangitis (PBC) diagnosis criteria n=8, not on a stable and recommended dose of ursodeoxycholic acid (UDCA) for past 12 months OR intolerant to UDCA (last dose >3 months before screening) n=7, creatine kinase >1.0×ULN n=6, platelet count <100×103/µL n=6, had advanced PBC per Rotterdam criteria n=4, international normalized ratio >1.0×ULN n=4, presence of clinically significant hepatic decompensation n=4, presence of chronic liver disease n=4, presence of any other condition that would compromise patient safety/clinical trial quality n=4, did not provide written informed consent n=4, evidence of drug abuse n=3, use of fibrates within 30 days before screening n=2, use of simvastatin within 7 days before screening n=2. Abbreviations: AE, adverse event; mITT, modified intent-to-treat; N, number of patients assigned to the treatment group; n, number of patients in the category.
FIGURE 2
FIGURE 2
Proportion of patients who achieved the composite biochemical end point at month 3. Composite end point was defined as alkaline phosphatase (ALP) serum levels < 1.67× upper limit of normal (ULN), ≥15% decrease in ALP serum levels, and total bilirubin serum levels ≤ ULN. p-values are based on the Cochran-Mantel-Haenszel test adjusted for both randomization stratification variables. Patients who discontinued treatment before month 3 due to reasons other than study termination and who did not have evaluable data at month 3 were considered nonresponders.
FIGURE 3
FIGURE 3
Proportion of patients who achieved alkaline phosphatase (ALP) normalization at month 3 ALP normalization. ALP normalization was defined as serum levels ≤1.0×upper limit of normal. p-values are based on the Cochran-Mantel-Haenszel test adjusted for both randomization stratification variables. Patients who discontinued treatment before month 3 due to reasons other than study termination and who did not have evaluable data at month 3 were considered nonresponders.
FIGURE 4
FIGURE 4
Absolute LS mean (SE) change from baseline in pruritus numerical rating scale (NRS) at month 3 (A) and proportion of patients who achieved point reductions from baseline in pruritus NRS at month 3 (B). For (A) and (B), populations included only patients with pruritus NRS ≥4 at baseline. For (A), change from baseline was estimated by an analysis of covariance model with treatment group and randomization alkaline phosphatase stratification as factors and baseline pruritus score as a covariate. For (B), patients who discontinued treatment before month 3 due to reasons other than study termination and who did not have evaluable data at month 3 were considered nonresponders. p-values are per Cochran-Mantel-Haenszel test adjusted for both randomization stratification variables. Abbreviations: LS, least squares; N, number of patients in the treatment group; n, number of patients in the category.
FIGURE 5
FIGURE 5
LS mean relative (percent) change from baseline and mean absolute values for ALP (A and B) and ALT (C and D) through month 6. *p < 0.0001 versus placebo, †p ≤ 0.002 versus seladelpar 5-mg group. Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; LS, least squares; ULN, upper limit of normal.
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Comment in

  • PPARα, PPARδ, or both-that is the question!
    Wolters F, Oude Elferink RPJ, Beuers U. Wolters F, et al. Hepatology. 2024 Jul 1;80(1):8-10. doi: 10.1097/HEP.0000000000000791. Epub 2024 Feb 16. Hepatology. 2024. PMID: 38373084 No abstract available.

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