PPAR agonists for the treatment of primary biliary cholangitis: Old and new tales

by Selleckchem | Apr 20 2023

Introduction: Primary biliary cholangitis (PBC) is an autoimmune liver disease involving the small intrahepatic bile ducts; when untreated or undertreated, it may evolve to liver fibrosis and cirrhosis. Ursodeoxycholic Acid (UDCA) is the standard of care treatment, Obeticholic Acid (OCA) has been approved as second-line therapy for those non responder or intolerant to UDCA. However, due to moderate rate of UDCA-non responders and to warnings recently issued against OCA use in patients with cirrhosis, further therapies are needed.Areas covered. Deep investigations into the pathogenesis of PBC is leading to proposal of new therapeutic agents, among which peroxisome proliferator-activated receptor (PPAR) ligands seem to be highly promising given the preliminary, positive results in Phase 2 and 3 trials. Bezafibrate, the most evaluated, is currently used in clinical practice in combination with UDCA in referral centers. We herein describe completed and ongoing trials involving PPAR agonists use in PBC, analyzing pits and falls.

Expert opinion: Testing new therapeutic opportunities in PBC is challenging due to its low prevalence and slow progression. However, new drugs including PPAR agonists, are currently under investigation and should be considered for at-risk PBC patients.

Comments：
Primary biliary cholangitis (PBC) is a rare, chronic autoimmune liver disease that primarily affects middle-aged women. Its pathogenesis is not fully understood, but it is thought to be caused by a combination of genetic, environmental, and immune factors.

The standard treatment for PBC is ursodeoxycholic acid (UDCA), which improves liver biochemistry, delays disease progression, and reduces the risk of liver transplantation and death. However, approximately 30% of PBC patients do not respond adequately to UDCA, and some develop adverse effects.

Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist, was approved by the US FDA as a second-line therapy for PBC patients who have an inadequate response to UDCA. However, a recent clinical trial showed that OCA increased the risk of liver-related adverse events in PBC patients with cirrhosis.

Peroxisome proliferator-activated receptor (PPAR) agonists are a new class of drugs that have been proposed as a potential therapy for PBC. PPARs are nuclear receptors that regulate lipid metabolism, inflammation, and fibrosis. PPAR agonists have anti-inflammatory, anti-fibrotic, and anti-cholestatic effects, and they have been shown to improve liver biochemistry and histology in animal models and human studies.

Bezafibrate, a PPARα/γ agonist, has been evaluated in several clinical trials in PBC patients. A randomized controlled trial showed that the combination of bezafibrate and UDCA improved liver biochemistry and histology in UDCA non-responders. Another trial showed that bezafibrate reduced serum bilirubin levels in PBC patients with cholestasis.

Other PPAR agonists, such as elafibranor (PPARα/δ agonist) and seladelpar (PPARδ agonist), are currently being evaluated in Phase 2 and 3 clinical trials in PBC patients.

In conclusion, PPAR agonists represent a promising new class of drugs for PBC treatment, especially for UDCA non-responders or intolerant patients. However, further studies are needed to confirm their efficacy, safety, and long-term benefits, and to identify the optimal dose and duration of therapy. Patients with PBC should always consult with their healthcare provider before considering any new treatment option.