Seladelpar

Seladelpar

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:

  • Fibrates target PPARα, which is predominately expressed in hepatocytes. They are effective in treating hyperlipidemia but are also anti-cholestatic by their suppression of bile acid synthesis. Although sometimes used as an unapproved treatment for PBC, they lack the additional anti-inflammatory and anti-fibrotic activity of delpars. Fibrates also carry a warning on their label against use in chronic liver disease.
  • Glitazones (or thiazolidines) are a class of drugs that target PPARγ, a PPAR subtype expressed at high levels in fat cells. They are effective in treating high blood sugar in patients with diabetes by acting to overcome resistance to insulin. However, they do not have the liver-directed, anti-cholestatic and anti-inflammatory effects of delpars. Activation of PPARγ is also known to result in concerning side effects, including weight gain, exacerbation of risk for heart failure, and increased risk of bone fracture in post-menopausal women.

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