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Seladelpar

Our most advanced clinical program is for seladelpar (MBX-8025), a potent, selective, orally active peroxisome proliferator-activated receptor δ (PPARδ) agonist in development for the treatment of patients with the autoimmune liver disease, primary biliary cholangitis (PBC) and non-alcoholic steatohepatitis (NASH).


Mechanism Uniquely Suited for Liver Diseases

Seladelpar is uniquely suited as a potential treatment for inflammatory liver diseases. In the liver, PPARδ is expressed in multiple cell types including: hepatocytes, cholangiocytes, Kupffer cells and stellate cells. Preclinical and clinical data support its effect on regulating genes involved in bile acids synthesis, inflammation, fibrosis and lipid metabolism, storage and transport.


Established Proof-of-Concept in PBC

Phase 2 results with seladelpar in patients with PBC established proof-of-concept as a potential treatment by demonstrating significant reductions of serum alkaline phosphatase (AP), an established surrogate marker for disease progression. Favorable treatment effects were observed in an ongoing Phase 2 PBC study of seladelpar evaluated at doses of 2, 5 and 10 mg. It was found that seladelpar maintains potent and sustained anti-cholestatic and anti-inflammatory activity through 26 weeks of treatment and appears safe and well tolerated, with no apparent drug-induced pruritus.


An interim analysis of 71 patients with PBC receiving at least one dose of 2, 5, or 10 mg of seladelpar was presented at the International Liver Congress in Paris in April of 2018.

  • At 12 weeks, a dose response was observed with meaningful decreases in AP:
    •  -21% for 2 mg
    •  -33% for 5 mg
    •  -45% for 10 mg
  • After the first 12 weeks, the dose of seladelpar was increased to 10 mg for select 5 mg patients who investigators determined could benefit from additional reductions in AP to reduce the risk of disease progression.
  • At 26 weeks, a dose response was observed with even greater decreases in AP:
    • -45% for 5 mg
    • -43% for patients whose dose increased from 5 mg to 10 mg after week 12
    • -43% for 10 mg
  • After 26 weeks, responder rate for the composite regulatory endpoint (comprised of an AP less than 1.67 times the upper limit of normal), with at least a 15% decrease in AP from baseline and normal bilirubin was:
    • 69% for 5 mg
    • 68% for up-titration from 5 to 10 mg after week 12
    • 79% for 10 mg
  • Overall, 29% of patients achieved the important goal of having normal AP levels at 26 weeks.
  • Having a significant proportion of patients achieve the composite response, which is largely dependent on AP, is important for potentially obtaining regulatory approval.


In the interim analysis, seladelpar did not appear to be associated with drug-induced pruritus. Baseline median pruritus as measured using the visual analogue scale (VAS) was 10 and 37 in the 5 mg and 10 mg groups, respectively, and patients in the 10 mg group experienced consistent decreases during treatment suggesting the potential for anti-pruritic activity. Seladelpar was generally safe and well tolerated, with no transaminase elevation safety signal. There were six serious adverse events and none were deemed related to seladelpar.


Ongoing Evaluation in PBC

Based on findings from the Phase 2 studies, CymaBay is planning to initiate a Phase 3 study evaluating seladelpar in patients with PBC in the second half of 2018.


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


Potential New Therapy in NASH

NASH, a disease linked to the metabolic syndrome which is associated with obesity and diabetes, is a growing global concern which has no approved treatment. The disease is manifested by the accumulation of fat in the liver that may lead to chronic liver inflammation and ultimately to fibrosis and cirrhosis. Seladelpar has demonstrated potent anti-inflammatory activities in the clinic and has also demonstrated beneficial effects in animal models on lipid and glucose metabolism, liver fat content, and the development of liver fibrosis, further supporting its potential for treating NASH.1, 2


CymaBay is conducting a Phase 2b proof-of-concept study of seladelpar for the treatment of patients with NASH. The Phase 2b study is a randomized, placebo-controlled, parallel, dose-ranging study that is intended to enroll approximately 175 patients with liver biopsy proven NASH. The primary efficacy outcome will be the change from baseline in liver fat content at 12 weeks, as measured by magnetic resonance imaging using the proton density fat fraction method (MRI-PDFF). A notable secondary outcome of efficacy will be the evaluation of histological improvement in NASH and fibrosis, to be assessed by comparing liver biopsy samples at baseline and 52 weeks.