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Our most advanced internal clinical program is seladelpar (MBX-8025), a potent, selective, orally active PPARδ agonist currently in development for the treatment of patients with the autoimmune liver disease, primary biliary cholangitis (PBC) and NonAlcoholic SteatoHepatitis (NASH).

Mechanism Uniquely Suited for Liver Diseases

Seladelpar is uniquely suited as a treatment for liver disease. Preclinical and clinical data support its effect on bile acids synthesis, inflammation, fibrosis and cellular metabolism. PPARδ has been shown to regulate genes in hepatocytes, cholangiocytes, Kupffer cells and stellate cells.

Established Proof-of-Concept in PBC

Phase 2 data in patients with PBC have established proof-of-concept for seladelpar by demonstrating significant reductions of serum alkaline phosphatase (AP). This includes recent data from a Phase 2 study of seladelpar at daily doses of 5 and 10 mg in patients with PBC, which was conducted to support dose selection for Phase 3.

After 12 weeks of treatment, a planned interim analysis of the first 24 patients in the study demonstrated a significant AP reduction from baseline of 39% and 45% for the 5 mg and 10 mg groups, respectively. AP is an established surrogate marker of disease progression in PBC, and reaching a level of < 1.67 x ULN is a key component in the composite endpoint used for regulatory approval.

Alongside substantial reductions in AP, patients in both dose groups experienced decreases in other liver markers of cholestasis including gamma glutamyl transferase and total bilirubin. Seladelpar also improved metabolic and inflammatory markers with patients experiencing decreases in low-density lipoprotein-C and high sensitivity C-reactive protein.  There were no serious adverse events and no safety transaminase signal was observed at either dose. Further, mean transaminase levels decreased over the course of treatment, supporting seladelpar’s anti-inflammatory activity. Consistent with prior studies, there was no signal for drug-induced pruritus.

Ongoing Evaluation in PBC

Based on these interim findings, the FDA has agreed to allow continuation of seladelpar treatment beyond six months for the 5 mg and 10 mg doses.  Cymabay intends to develop a phase 3 program for seladelpar in PBC. The company is very encouraged by the phase 2 results and the potential for seladelpar to improve treatment alternatives in PBC and other chronic liver diseases.

Seladelpar has also received U.S. Food and Drug Administration (FDA) orphan drug designation and European Medicines Agency (EMA) PRIority MEdicines (PRIME) designation for the treatment of PBC.

Potential New Therapy in NASH

There are currently no drugs approved for the treatment of NASH. However, several clinical studies have been carried out or are underway with drug candidates that may affect disease outcomes in patients with this serious disease.

Data from our Phase 2 clinical trial in patients with mixed dyslipidemia as well as evidence from other PPARδ agonists, suggest that seladelpar may have utility in treating patients with NASH. In this study, seladelpar treatment decreased the triglyceride content of serum lipoproteins, which because they are derived from the liver, strongly suggested that seladelpar lowers hepatic fat. Our clinical experience with seladelpar leads us to believe that it could potentially benefit patients affected with NAFLD who are further at risk of developing NASH. Recently, seladelpar was found to decrease fibrosis, inflammation, hepatic lipids and reverse insulin resistance in the foz/foz mouse which is a diabetic obese mouse model of NASH.