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Inhibition of ASBT Improves Liver Function in an Animal Model of Cholestatic Liver Disease
Date:11/5/2013

SAN DIEGO, Nov. 5, 2013 /PRNewswire/ -- Lumena Pharmaceuticals, a company developing oral therapeutics for cholestatic liver diseases, today announced that inhibition of the apical sodium-dependent bile acid transporter (ASBT) improves liver function in animal models of cholestasis. The data will be presented at 11:15 a.m. EST today in an oral presentation titled "SC-435, an Oral Inhibitor of ASBT, Improves Liver Function in a Rat Partial Bile Duct Ligation Model of Cholestasis," at the 64th Annual Meeting of the American Association for the Study of Liver Diseases in Washington DC.

The study showed that inhibiting ASBT with SC-435, a close analog of LUM001, the company's lead drug candidate for the treatment of cholestatic liver disease, significantly improved markers of liver function in rats that had undergone partial bile duct ligation (pBDL) surgery to induce a state of cholestasis. Rats subjected to pBDL showed an impaired liver function as demonstrated by an increase in biomarkers of liver function, including serum liver alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin and ɤ-glutamyl transferase (GGT) over baseline at three days post-surgery. Rats that received SC-435 showed an increase in excretion of bile acids in the feces, a reduction of serum bile acids and improvements in biomarker profiles of liver function at seven days post pBDL. The benefits of treatment with SC-435 were maintained at 14 days post pBDL, and histology studies showed that livers from rats treated with the ASBT inhibitor had less cell death and inflammatory cell infiltration. Taken together, the results show that inhibiting ASBT reduces circulating bile acid levels and improves liver function in animal models, suggesting that ASBT inhibition may be an attractive approach to treating cholestatic liver disease.

"This study provides additional preclinical proof of concept for Lumena's approach to the treatment of cholestatic liver diseases currently being evaluated in multiple Phase II clinical studies," said Bradley T. Keller, Ph.D., vice president, research at Lumena Pharmaceuticals, who presented the data. "Inhibiting bile acid recirculation to the liver pharmacologically has the potential to improve liver function and dramatically impact patient health in a population in dire need of non-invasive treatment options."

Cholestatic liver diseases are characterized by elevated bile acids, progressive liver damage and severe itching, which is generally the most debilitating symptom afflicting adults and children with these diseases. Treatment with anti-pruritics typically provides only modest relief. Procedures that remove bile from the circulation can lower serum bile acids, reducing itch and improving liver function in some patients, but tend to be invasive in nature. ASBT recycles intestinal bile acids back into the circulation and blocking it with a once-daily oral presentation, such as LUM001, reduces serum bile acids and may offer a novel therapeutic approach for alleviating the severe itching and progressive liver damage associated with many cholestatic liver diseases.

LUM001 has been studied in 12 clinical trials in more than 1,400 subjects. In previous trials, LUM001 was shown to be generally well tolerated, the most common side effect, gastrointestinal disturbance, was usually mild and transient in nature. Clinical studies have demonstrated that LUM001 can reduce serum bile acid levels. Reductions in bile acids may be effective in alleviating symptoms and improving liver function in many patients with cholestatic liver disease. Lumena is currently evaluating LUM001 in Phase II studies in children with Alagille syndrome and adults with primary biliary cirrhosis. The company plans to initiate additional Phase II studies in patients with progressive familial intrahepatic cholestasis and primary sclerosing cholangitis in late 2013.

About Lumena Pharmaceuticals
Lumena Pharmaceuticals is a San Diego-based company developing oral therapeutics for patients with rare and debilitating liver diseases. Lumena's lead candidate, LUM001, has been studied in more than 1,400 patients in 12 different clinical studies and is being evaluated in Phase II studies in patients with Alagille syndrome and primary biliary cirrhosis. The company is privately held and has raised $23 million in Series A financing from Pappas Ventures, RiverVest Venture Partners and Alta Partners.


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