TY - JOUR
T1 - Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid
T2 - a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study
AU - Jones, David
AU - Boudes, Pol F.
AU - Swain, Mark G.
AU - Bowlus, Christopher L.
AU - Galambos, Michael R.
AU - Bacon, Bruce R.
AU - Doerffel, Yvonne
AU - Gitlin, Norman
AU - Gordon, Stuart C.
AU - Odin, Joseph A.
AU - Sheridan, David
AU - Wörns, Markus Alexander
AU - Clark, Virginia
AU - Corless, Linsey
AU - Hartmann, Heinz
AU - Jonas, Mark E.
AU - Kremer, Andreas E.
AU - Mells, George F.
AU - Buggisch, Peter
AU - Freilich, Bradley L.
AU - Levy, Cynthia
AU - Vierling, John M.
AU - Bernstein, David E.
AU - Hartleb, Marek
AU - Janczewska, Ewa
AU - Rochling, Fedja
AU - Shah, Hemant
AU - Shiffman, Mitchell L.
AU - Smith, John H.
AU - Choi, Yun Jung
AU - Steinberg, Alexandra
AU - Varga, Monika
AU - Chera, Harinder
AU - Martin, Robert
AU - McWherter, Charles A.
AU - Hirschfield, Gideon M.
N1 - Funding Information:
DJ reports grants and personal fees from Intercept. Intercept, GlaxoSmithKline, Novartis, Cymabay, FFPharma, Shire, and Pfizer are all UK-PBC partners, for which DJ is project director. PFB is an employee of CymaBay Therapeutics and owns options to buy shares of the company. PFB is named on a CymaBay Therapeutics patent covering the use of MBX-8025 (seladelpar) for the treatment of primary biliary cholangitis. MGS reports grants and personal fees from Gilead, grants and personal fees from Intercept, and grants and fees from CymaBay, Merck, AbbVie, BMS, GRI Inc, Allergan/Tobira, Novartis, GlaxoSmithKline, Genfit, and Novo-Nordisk, outside the submitted work. CLB has participated in research with Intercept Pharmaceuticals, NGM Biosciences, Gilead, Takeda, BMS, GlaxoSmithKline, Galectin Therapeutics, and CymaBay. CLB is on the advisory board of Intercept Pharmaceuticals, GlaxoSmithKline, and Takeda and on the speakers bureau of Intercept Pharmaceuticals. YD reports investigator's fees from CymaBay Therapeutics, during the conduct of the study. NG has received a grant from, and is on the speakers bureau for, Intercept Pharmaceuticals. SCG reports grants from AbbVie Pharmaceuticals, Exalenz, Gilead Pharmaceuticals, Intercept Pharmaceuticals, and Merck, and grants and fees from AbbVie Pharmaceuticals, CVS Caremark, Gilead Pharmaceuticals, and Merck, outside the submitted work. JAO received payments from CymaBay for this trial, and is an advisory board member for Intercept Pharmaceuticals. VC reports receipt of grants from CymaBay Therapeutics. AEK reports grants and personal fees from Intercept Pharmaceuticals, and personal fees from Falk Pharma, GlaxoSmithKline, MSD, and Beiersdorf. GFM reports grants from Medical Research Council and National Institute for Health Research Rare Diseases—Translational Research Collaboration. GFM works with a collaborating centre in Intercept-sponsored Clinical Trial of an Investigational Medicinal Product (CTIMP) and Novartis-sponsored CTIMP. BLF reports grants from CymaBay Therapeutics and Intercept, and speakers bureau fees from Intercept. CL reports grants and personal fees from Intercept, grants from Gilead, grants and personal fees from Novartis, grants from NGM, grants from Shire, grants from GlaxoSmithKline, and grants and personal fees from TARGET PharmaSolutions. JMV reports grants from Intercept, personal fees from Intercept, grants from Genfit, grants from Gilead, and personal fees from Gilead. EJ reports personal fees from CymaBay Therapeutics, and has served as a lecturer, consultant, or investigator for AbbVie, Gilead, Bristol-Myers Squibb, MSD, and Roche. HS reports personal fees from Intercept. MLS reports grants from CymaBay, grants and personal fees from Gilead, and grants from NGMBio. MV and HC are employees of CymaBay Therapeutics and own options for its stock. CAM is an employee of CymaBay Therapeutics and owns stock and is an option grantee for the company. GMH has consulted for GlaxoSmithKline, Novartis, Intercept, Univar, and Falk. MRG, BRB, DS, M-AW, LC, HH, PB, DEB, MH, FR, JHS, Y-JC, AS, RM, and MEJ declare no competing interests.
Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2017/10
Y1 - 2017/10
N2 - 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.
AB - 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.
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U2 - 10.1016/S2468-1253(17)30246-7
DO - 10.1016/S2468-1253(17)30246-7
M3 - Article
C2 - 28818518
AN - SCOPUS:85031869367
VL - 2
SP - 716
EP - 726
JO - The Lancet Gastroenterology and Hepatology
JF - The Lancet Gastroenterology and Hepatology
SN - 2468-1253
IS - 10
ER -