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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

A Phase 2 high-dose clinical study of seladelpar in patients with PBC has established proof-of-concept for seladelpar. The study was designed to enroll approximately 75 patients who had an inadequate response to ursodeoxycholic acid, a bile acid that is the first line treatment for PBC. Patients then received either placebo or seladelpar (50 mg or 200 mg) once-daily for 12 weeks.

Data from 35 patients evaluated for efficacy demonstrated that treatment with seladelpar resulted in statistically significant reductions in the primary endpoint of serum alkaline phosphatase (AP). The mean decreases from baseline in AP for the 50 and 200 mg dose groups were 53% and 63%, respectively, versus 2% for the placebo group (p < 0.0001 for both). These results were encouraging because AP is a biochemical marker that reflects the status and progression of impairment of the excretion of bile in the liver into the bile duct. It has been a key component of a composite surrogate for outcome that has been used recently for regulatory approval for a treatment in PBC.

In the study, three cases of asymptomatic, reversible transaminase elevations (two in the 200 mg and one in the 50 mg groups) were observed after a review of safety and efficacy data. While the study demonstrated proof-of-concept for activity based on cholestatic biomarkers, it was discontinued given the need to reduce the dose in order to optimize seladelpar clinical safety and efficacy.

Ongoing Evaluation in PBC

In December 2016, we initiated a low-dose Phase 2 study of seladelpar at daily doses of 5 and 10 mg in patients with PBC in order to support dose selection for Phase 3. An interim evaluation of the study will take place following the initial eight weeks of dosing, after which the study may enroll patients in an extension phase for an additional 18 weeks.

Seladelpar has 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.