Seladelpar (Livdelzi®): A Comprehensive Monograph on a Novel PPARδ Agonist for the Treatment of Primary Biliary Cholangitis

Executive Summary

Seladelpar, marketed under the brand name Livdelzi®, is a first-in-class, orally administered, small-molecule drug representing a significant advancement in the treatment of primary biliary cholangitis (PBC). As a potent and highly selective agonist of the peroxisome proliferator-activated receptor delta (PPARδ), seladelpar offers a novel mechanism of action for a patient population with limited therapeutic options. In 2024, it received accelerated approval from the U.S. Food and Drug Administration (FDA) and a positive opinion for conditional marketing authorisation from the European Medicines Agency (EMA) for the treatment of PBC in adults who have an inadequate response to or are intolerant of the first-line therapy, ursodeoxycholic acid (UDCA).

The therapeutic efficacy of seladelpar is rooted in its ability to modulate critical metabolic and inflammatory pathways. By activating PPARδ, it potently inhibits bile acid synthesis through the downregulation of the rate-limiting enzyme CYP7A1, thereby reducing cholestatic liver injury. A key differentiating feature of seladelpar is its dual benefit: pivotal Phase 3 clinical trials have demonstrated not only a statistically significant improvement in biochemical markers of liver health, including a high rate of alkaline phosphatase (ALP) normalization, but also a significant reduction in moderate-to-severe pruritus (itching), a common and debilitating symptom of PBC. This unique clinical profile contrasts with other second-line therapies that may improve liver biochemistry but can exacerbate pruritus.