Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study

David Jones, Pol F. Boudes, Mark G. Swain, Christopher L. Bowlus, Michael R. Galambos, Bruce R. Bacon, Yvonne Doerffel, Norman Gitlin, Stuart C. Gordon, Joseph A. Odin, David Sheridan, Markus Alexander Wörns, Virginia Clark, Linsey Corless, Heinz Hartmann, Mark E. Jonas, Andreas E. Kremer, George F. Mells, Peter Buggisch, Bradley L. FreilichCynthia Levy, John M. Vierling, David E. Bernstein, Marek Hartleb, Ewa Janczewska, Fedja Rochling, Hemant Shah, Mitchell L. Shiffman, John H. Smith, Yun Jung Choi, Alexandra Steinberg, Monika Varga, Harinder Chera, Robert Martin, Charles A. McWherter, Gideon M. Hirschfield

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)716-726
Number of pages11
JournalThe Lancet Gastroenterology and Hepatology
Volume2
Issue number10
DOIs
StatePublished - Oct 1 2017

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PPAR delta
Ursodeoxycholic Acid
Cholangitis
Placebos
Alkaline Phosphatase
North America
(2-methyl-4-(5-methyl-2-(4-trifluoromethyl-phenyl)-2H-(1,2,3)triazol-4-ylmethylsulfanyl)phenoxy)acetic acid
Random Allocation
Therapeutics

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid : a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study. / Jones, David; Boudes, Pol F.; Swain, Mark G.; Bowlus, Christopher L.; Galambos, Michael R.; Bacon, Bruce R.; Doerffel, Yvonne; Gitlin, Norman; Gordon, Stuart C.; Odin, Joseph A.; Sheridan, David; Wörns, Markus Alexander; Clark, Virginia; Corless, Linsey; Hartmann, Heinz; Jonas, Mark E.; Kremer, Andreas E.; Mells, George F.; Buggisch, Peter; Freilich, Bradley L.; Levy, Cynthia; Vierling, John M.; Bernstein, David E.; Hartleb, Marek; Janczewska, Ewa; Rochling, Fedja; Shah, Hemant; Shiffman, Mitchell L.; Smith, John H.; Choi, Yun Jung; Steinberg, Alexandra; Varga, Monika; Chera, Harinder; Martin, Robert; McWherter, Charles A.; Hirschfield, Gideon M.

In: The Lancet Gastroenterology and Hepatology, Vol. 2, No. 10, 01.10.2017, p. 716-726.

Research output: Contribution to journalArticle

Jones, D, Boudes, PF, Swain, MG, Bowlus, CL, Galambos, MR, Bacon, BR, Doerffel, Y, Gitlin, N, Gordon, SC, Odin, JA, Sheridan, D, Wörns, MA, Clark, V, Corless, L, Hartmann, H, Jonas, ME, Kremer, AE, Mells, GF, Buggisch, P, Freilich, BL, Levy, C, Vierling, JM, Bernstein, DE, Hartleb, M, Janczewska, E, Rochling, F, Shah, H, Shiffman, ML, Smith, JH, Choi, YJ, Steinberg, A, Varga, M, Chera, H, Martin, R, McWherter, CA & Hirschfield, GM 2017, 'Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study', The Lancet Gastroenterology and Hepatology, vol. 2, no. 10, pp. 716-726. https://doi.org/10.1016/S2468-1253(17)30246-7
Jones, David ; Boudes, Pol F. ; Swain, Mark G. ; Bowlus, Christopher L. ; Galambos, Michael R. ; Bacon, Bruce R. ; Doerffel, Yvonne ; Gitlin, Norman ; Gordon, Stuart C. ; Odin, Joseph A. ; Sheridan, David ; Wörns, Markus Alexander ; Clark, Virginia ; Corless, Linsey ; Hartmann, Heinz ; Jonas, Mark E. ; Kremer, Andreas E. ; Mells, George F. ; Buggisch, Peter ; Freilich, Bradley L. ; Levy, Cynthia ; Vierling, John M. ; Bernstein, David E. ; Hartleb, Marek ; Janczewska, Ewa ; Rochling, Fedja ; Shah, Hemant ; Shiffman, Mitchell L. ; Smith, John H. ; Choi, Yun Jung ; Steinberg, Alexandra ; Varga, Monika ; Chera, Harinder ; Martin, Robert ; McWherter, Charles A. ; Hirschfield, Gideon M. / Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid : a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study. In: The Lancet Gastroenterology and Hepatology. 2017 ; Vol. 2, No. 10. pp. 716-726.
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title = "Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study",
abstract = "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.",
author = "David Jones and Boudes, {Pol F.} and Swain, {Mark G.} and Bowlus, {Christopher L.} and Galambos, {Michael R.} and Bacon, {Bruce R.} and Yvonne Doerffel and Norman Gitlin and Gordon, {Stuart C.} and Odin, {Joseph A.} and David Sheridan and W{\"o}rns, {Markus Alexander} and Virginia Clark and Linsey Corless and Heinz Hartmann and Jonas, {Mark E.} and Kremer, {Andreas E.} and Mells, {George F.} and Peter Buggisch and Freilich, {Bradley L.} and Cynthia Levy and Vierling, {John M.} and Bernstein, {David E.} and Marek Hartleb and Ewa Janczewska and Fedja Rochling and Hemant Shah and Shiffman, {Mitchell L.} and Smith, {John H.} and Choi, {Yun Jung} and Alexandra Steinberg and Monika Varga and Harinder Chera and Robert Martin and McWherter, {Charles A.} and Hirschfield, {Gideon M.}",
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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.

PY - 2017/10/1

Y1 - 2017/10/1

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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