PPAR agonists in PBC: Where do we go from here? Or how to choose between the new and the old

Abstract

The recent phase 3 trials of peroxisome proliferator-activated receptor (PPAR) agonists in primary biliary cholangitis (PBC) patients with incomplete response to ursodeoxycholic acid (UDCA) demonstrated very promising short-term biochemical responses. However, long-term outcomes, crucial in chronic diseases like PBC, remain uncertain. While real-world data (RWD) support surrogate endpoints, there's a need to validate long-term efficacy especially with combination therapies. Bezafibrate, an off-label option with extensive RWD, demonstrated short-term response, reduced patients’ pruritus, and improved long-term outcomes. Therefore, the therapeutic choice between new selective PPAR agonists and old bezafibrate poses a challenge. Undoubtedly further investigations into new PPAR agonists in terms of long-term efficacy are warranted, but prospective, randomized trials in post-approval settings are very unlikely to be successfully conducted, necessitating alternative approaches using RWD rather than traditional trial design. Finally, it will be essential to identify patients who may be intolerant and/or unresponsive to PPAR agonists.