A Novel Therapy Aspiring to Help Patients Live Longer and Feel Better
Seladelpar is the first potent, selective peroxisome proliferator-activated receptor (PPAR) delta agonist, or delpar, in development for PBC. In clinical studies of patients with PBC, it reduced biomarkers associated with adverse clinical outcomes (liver-related complications, transplantation, and death) while also improving pruritus (itching).
PPARδ is a ligand-activated transcription factor that regulates gene expression in multiple cell types in the liver that are important in PBC. Seladelpar decreases bile acid synthesis, a key mediator of cholestatic toxicity, in both hepatocytes and in patients. It also has important anti-inflammatory activity, inhibiting activation of resident and recruited macrophages and their release of inflammatory mediators. In multiple animal models, and in patients with non-alcoholic steatohepatitis, seladelpar was found to decrease fibrosis. In patients with PBC, it increases serum markers of fatty acid oxidation while decreasing elevated levels of low-density lipoprotein cholesterol (LDL or “bad” cholesterol) and triglycerides. In addition, seladelpar treatment has been shown to improve pruritus in some patients with PBC in two clinical studies.
As a delpar, seladelpar uniquely acts on multiple liver cell types leading to effects on processes important in the pathobiology of PBC. Seladelpar' mechanism of action is distinct from the other drug classes that target the PPARα and PPARγ subtypes in the following way: