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

“…PPAR‐γ has an anti‐inflammatory effect in an animal model, and pregnane X receptor is reported to reduce nuclear factor kappa B expression . In a recent randomized controlled trial, seladelpar, a PPAR‐δ agonist, showed biochemical improvement as well as a decreased level of C4, which is a marker of bile acid synthesis in PBC patients . Bezafibrate, a pan‐PPAR agonist, is reported to have an additional PPAR‐δ agonistic effect, and it is expected that bezafibrate might be more effective than fenofibrate, that is a PPAR‐α agonist.…”

Section: Discussionmentioning

confidence: 99%

Additional fibrate treatment in UDCA‐refractory PBC patients

Chung

Lee

Kim

et al. 2019

Liver International

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Background & Aims There is no proven treatment for ursodeoxycholic acid (UDCA)‐refractory primary biliary cholangitis (PBC) other than obeticholic acid. Although fibrates have been reported to improve biochemical parameters, the long‐term effects remain unclear. This study evaluated the effect of fibrate on clinical outcomes of UDCA‐refractory PBC. Methods Patients whose alkaline phosphatase (ALP) was not normalized with at least 13 mg/kg of UDCA treatment for >1 year were included from two tertiary referral centres. The primary outcome was ALP normalization. Secondary outcomes included the development of cirrhosis and hepatic deterioration. Immortal time bias was adjusted using the Mantel‐Byar method. Results A total of 100 UDCA‐refractory PBC patients were included: 71 patients received UDCA alone (the UDCA group) and 29 patients received UDCA plus additional fibrate treatment of 160 mg/d fenofibrate or 400 mg/d bezafibrate (the fibrate/UDCA group). During the follow‐up period, the probability of ALP normalization was significantly higher in the fibrate/UDCA group (hazard ratio [HR] = 5.00, 95% confidence interval = 2.87‐8.27, P < 0.001). Among 58 non‐cirrhotic patients (43 in the UDCA group and 15 in the fibrate/UDCA group), 19 patients (44.1%) in the UDCA group and none in the fibrate/UDCA group developed cirrhosis (HR = 0.12, P = 0.04). Hepatic deterioration (Child‐Pugh score increase or signs of decompensated cirrhosis) occurred in 17 patients (23.9%) of the UDCA group and none in the fibrate/UDCA group in which the difference was significant (HR = 0.12, P = 0.04). Conclusions In patients with UDCA‐refractory PBC, additional fibrate treatment is associated with a higher probability of ALP normalization and a lower risk of cirrhosis development and hepatic deterioration.

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“…Seladelpar reduces the number of macrophages, fibrosis and other markers of stellate cell activity in a mouse model [177]. In patients with mixed dyslipidemia [176] or homozygous familial hypercholesterolemia, seladelpar reduced LDL-C and induced sustained decreases in biochemical markers of cholestasis such as alkaline phosphatase, γ-glutamyl transpeptidase (GGT) and total bilirubin [178]. In phase Ш trials, seladelpar treatment normalized alkaline phosphatase levels but this treatment was associated with grade 3 increases in aminotransferases and the study was stopped early.…”

Section: Ppar Ligand Therapeutics In Other Diseasesmentioning

confidence: 99%

The Opportunities and Challenges of Peroxisome Proliferator-Activated Receptors Ligands in Clinical Drug Discovery and Development

Hong

Zhai

2018

IJMS

108

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Peroxisome proliferator-activated receptors (PPARs) are a well-known pharmacological target for the treatment of multiple diseases, including diabetes mellitus, dyslipidemia, cardiovascular diseases and even primary biliary cholangitis, gout, cancer, Alzheimer’s disease and ulcerative colitis. The three PPAR isoforms (α, β/δ and γ) have emerged as integrators of glucose and lipid metabolic signaling networks. Typically, PPARα is activated by fibrates, which are commonly used therapeutic agents in the treatment of dyslipidemia. The pharmacological activators of PPARγ include thiazolidinediones (TZDs), which are insulin sensitizers used in the treatment of type 2 diabetes mellitus (T2DM), despite some drawbacks. In this review, we summarize 84 types of PPAR synthetic ligands introduced to date for the treatment of metabolic and other diseases and provide a comprehensive analysis of the current applications and problems of these ligands in clinical drug discovery and development.

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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: CymaBay Therapeutics.

Cited by 124 publications

References 46 publications

Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases

Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases

Additional fibrate treatment in UDCA‐refractory PBC patients

The Opportunities and Challenges of Peroxisome Proliferator-Activated Receptors Ligands in Clinical Drug Discovery and Development

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