Albireo announced initiation of a phase II trial with A4250, the company’s lead compound for cholestatic liver diseases and NASH. A4250 acts locally in the gut to inhibit the ileal sodium dependent bile acid transporter (IBAT, also referred to as ASBT).

The phase II study, which is a cross-over study to demonstrate the efficacy and safety of A4250 in patients with primary biliary cirrhosis (PBC) and cholestatic pruritus, is being conducted at the Sahlgrenska Academy, Göteborg, Sweden and is led by Professor Hanns-Ulrich Marschall, a world leading expert in the field of liver diseases and bile acid modulation.   

“There is a real need for novel therapies in this area and A4250 clearly has the potential as a novel hepatoprotective drug that may help improve liver function in patients with a variety of chronic liver diseases”, said Professor Marschall. “In phase I studies, A4250 has shown to be safe and shown clear effects on a number of key pharmacodynamic markers, including significant, dose-dependent lowering of serum bile acids.  Serum bile acids are commonly increased in cholestatic liver diseases. I am excited about the possibility to test A4250 in patients with PBC having severe pruritus/itching”

Dr. Hans Graffner, chief medical officer at Albireo commented that “The safety and efficacy of A4250 in both preclinical and phase I studies are encouraging and strongly support development of A4250 in cholestatic liver diseases. A4250 decreases the re-absorption of bile acids and will reduce the toxic levels of bile acids in the liver cells of patients, and studies in disease areas such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC)  and hereditary causes of cholestasis, such as progressive familial intrahepatic cholestasis (PFIC), are all planned or in process.  Given the mode of action, A4250 should also be beneficial in liver diseases due to metabolic disturbances such as NASH (nonalcoholic steatohepatitis). In addition to the effects on bile acids, the beneficial effects on LDL cholesterol and GLP-1 should be of importance in the treatment of NASH.

The phase II study is a cross-over study to demonstrate the efficacy and safety of once daily dosing of A4250 in patients with primary biliary cirrhosis and cholestatic pruritus. In addition to evaluation of changes in pruritus (itching), the study will focus on changes in liver parameters known to be predictors of disease progression in liver diseases in general.

A4250 is a highly potent inhibitor of the ileal bile acid transporter (IBAT or apical sodium dependent bile acid transporter (ASBT)).  A4250 decreases the re-absorption of bile acids and will thereby reduce the toxic levels of bile acids in the liver cells of patients with cholestatic liver disease.  Importantly, A4250 also will reduce the increased levels of serum bile acids seen in these patients. A4250 has shown excellent effects in animal models of cholestatic liver disease.  A4250 acts locally in the gut with no systemic exposure; thereby the risk for potential systemic side effects will be reduced.

The A4250 phase I study was a double-blind single and multiple ascending dose study to assess safety, pharmacokinetics and pharmacodynamics of A4250 in healthy subjects.  There were no serious adverse events reported and no subjects discontinued the trial. There was no systemic exposure of A4250 detected at dose levels producing appropriate IBAT inhibition.

The mode of action – inhibition of bile acid re-absorption in the distal small bowel – was clearly demonstrated by biomarker analysis, such as increased levels of the bile acid synthesis marker C4 ( 7a-hydroxy-cholesten-3-one) and dose dependent increase of fecal bile acids.

A hallmark of many liver diseases is elevated bile acid levels. In this study, A4250 significantly and dose-dependently decreased serum bile acids.

In addition to the phase II PBC study, plans for 2015 include moving the compound into studies in pediatric cholestatic liver disease patients and into a program for evaluation of A4250 in NASH.  A4250 has received orphan drug designation for PBC and PFIC both from the US Food & Drug Administration and the European Medicines Agency.

PBC (Primary Biliary Cirrhosis) is an autoimmune liver disease that may progress to cirrhosis and liver failure, and it is currently the fifth leading indication for liver transplant in the United States. It is primarily a female disease, afflicting approximately one in 1,000 women over the age of 40. Ursodeoxycholic acid is the only approved drug treatment for PBC and studies have shown that up to 50% of PBC patients fail to respond adequately, thereby remaining at risk for adverse outcomes.

Albireo is a Swedish biotechnology company focused on the development of novel therapeutics for the treatment of gastrointestinal and liver diseases.