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 D, Boudes PF, Swain MG, Bowlus CL, Galambos MR, Bacon BR, Doerffel Y, Gitlin N, Gordon SC, Odin JA, Sheridan D, Woerns MA, Clark V, Corless L, Hartmann H, Jonas ME, Kremer A, 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)

Publication Type: Journal article

Publication year: 2017

Journal

Book Volume: 2

Pages Range: 716-726

Journal Issue: 10

DOI: 10.1016/S2468-1253(17)30246-7

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.

Authors with CRIS profile

Involved external institutions

Northwell Health United States (USA) (US) Houston Texas Medical Center United States (USA) (US) Kansas City Research Institute United States (USA) (US) University Health Network (UHN) Canada (CA) Hull and East Yorkshire Hospitals NHS Trust United Kingdom (GB) Asklepios Kliniken Verwaltungsgesellschaft mbH Germany (DE) Cambridge University Hospital United Kingdom (GB) University of Birmingham United Kingdom (GB) University of Miami United States (USA) (US) University of Nebraska-Lincoln United States (USA) (US) CymaBay Therapeutic United States (USA) (US) University of Newcastle (UoN) Australia (AU) University Hospitals Plymouth NHS Trust United Kingdom (GB) Atlanta Gastroenterology Associates United States (USA) (US) Bon Secours Liver Institute of Richmond United States (USA) (US) Henry Ford Health System (HFHS) United States (USA) (US) Saint Louis University Hospital (SLU Hospital) United States (USA) (US) Universitätsmedizin der Johannes Gutenberg-Universität Mainz Germany (DE) ID Clinic Poland (PL) Charité - Universitätsmedizin Berlin Germany (DE) University of Calgary Canada (CA) Icahn School of Medicine at Mount Sinai United States (USA) (US) University of California Davis (UCDAVIS) United States (USA) (US) Medical University of Silesia in Katowice / Śląski Uniwersytet Medyczny w Katowicach (SUM) Poland (PL)

How to cite

APA:

Jones, D., Boudes, P.F., Swain, M.G., Bowlus, C.L., Galambos, M.R., Bacon, B.R.,... Hirschfield, G.M. (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. Lancet Gastroenterology and Hepatology, 2(10), 716-726. https://doi.org/10.1016/S2468-1253(17)30246-7

MLA:

Jones, David, et al. "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." Lancet Gastroenterology and Hepatology 2.10 (2017): 716-726.

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