Livdelzi (Seladelpar) effects and benefits

The main ingredient of Livdelzi (Seladelpar), Seladelpar, is a PPAR-delta agonist; however, the mechanism by which Livdelzi exerts its therapeutic effect in patients with primary cholangitis (PBC) is unclear. Pharmacological activities potentially relevant to therapeutic efficacy include inhibition of bile acid synthesis through activation of PPARδ. Published studies have shown that seladelpar activates PPARδ to reduce bile acid synthesis by inducing fibroblast growth factor 21 (FGF21) to activate the c-Jun N-terminal kinase (JNK) signaling pathway, indicating that the inhibitory effect of seladelpar on bile acid synthesis is independent of the farnesoid X receptor (FXR) pathway, another molecular pathway that regulates hepatic bile acid synthesis.

Peroxisome proliferator-activated receptors(PPARs) belong to the nuclear hormone receptor superfamily and have three members - PPARα (α), PPARδ (δ) and PPARγ (γ). Each PPAR plays a role in maintaining energy homeostasis and metabolic functions such as fatty acid metabolism, bile acid synthesis, and adipocyte differentiation. In chronic liver diseases such as PBC and non-alcoholic steatohepatitis [NASH], changes in bile acid composition and increases in systemic bile acids are observed.

Seladelpar reduces total bile acid levels and reduces bile acid synthesis in patients with PBC. Studies have shown that increased bile acid concentrations in hepatobiliary diseases, including PBC, can lead to elevated alkaline phosphatase (ALP) levels. In patients with PBC treated with seladelpar 10 mg once daily, greater reductions in mean ALP from baseline were observed as early as one month post-treatment compared with placebo, and lower ALP levels were generally maintained through month 12. In another study, a dose-dependent decrease in mean alkaline phosphatase was observed in patients with PBC treated with 2, 5, or 10 mg of Seladelpar once daily.