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 nonalcoholic steatohepatitis (NASH).
We continue to evaluate opportunities to expand the development of seladelpar in liver and other chronic diseases. Primary Sclerosing Cholangitis (PSC) is an orphan, chronic cholestatic liver disease characterized by diffuse inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts. There are currently no approved treatments for PSC. We intend to initiate a Phase 2, dose-ranging proof-of-concept study of seladelpar in patients with PSC in the second half of 2019.
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.
ENHANCE, the Phase 3 registration trial to evaluate the safety and efficacy of seladelpar for the treatment of PBC, began enrolling patients in Q4 2018. This 52-week, placebo-controlled, randomized study is enrolling approximately 240 PBC patients in more than 20 countries over five continents. Patients who have shown an inadequate response to ursodeoxycholic acid (UDCA) will be randomized to seladepar 10 mg/day, seladelpar 5/10 mg/day (starting treatment at 5 mg with the possibility to escalate dose to 10 mg after six months), or placebo. Seladelpar is being developed as a drug candidate for PBC patients who have an inadequate response to, or are intolerant of, UDCA, the first-line treatment for PBC.
The primary outcome measure for the trial is the responder rate after 52 weeks. A responder is defined as a patient who achieves an alkaline phosphatase level <1.67X the upper limit of normal with at least a 15% decrease from baseline and has a normal level of total bilirubin. Previous Phase 2 studies of seladelpar established proof of concept in PBC. In these studies, seladelpar demonstrated anti-cholestatic and anti-inflammatory effects with no indication that it was associated with drug-induced pruritus (severe itching).
PBC primarily affects women; 1 in 1000 women over the age of 40 lives with PBC. It is rare, chronic, progressive autoimmune disease of the liver characterized by impaired bile flow and accumulation of toxic bile acids. Accompanying inflammation and destruction of the intrahepatic bile ducts may cause progression to fibrosis, cirrhosis and liver failure. Other clinical symptoms of PBC include fatigue and pruritus, which can be quite disabling in some patients.
We are 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.
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
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, cirrhosis and hepatocellular carcinoma.