Albireo liver treatment on verge of human testing

A4250 shown to protect against bile acid-mediated cholestatic liver injury in mice

Lloyd Dunlap
GOTHENBURG, Sweden—Albireo, a biotechnology company focused on the development of novel therapeutics for the treatment of gastrointestinal and liver diseases, has announced that inhibition of ileal bile acid transport by A4250, the company’s lead compound for cholestatic liver diseases, protects against bile acid-mediated cholestatic liver injury in mice. The data was presented last month in an oral presentation titled “Inhibition of Intestinal Bile Acid Absorption by Bile Acid-Mediated Cholestatic Liver Injury in Mice” at the 49th annual meeting of the European Association for the Study of the Liver (EASL) in London.
 
“We are currently performing Phase 1 studies with A4250,” notes Albireo’s Chief Operating Officer and Managing Director Dr. Jan P. Mattsson, “and plan to move into patients with cholestatic liver disease later this year.” The study reported on at EASL was performed in the laboratory of Prof. Michael Trauner of the Medical University of Vienna, a world-leading expert in cholestatic liver diseases, using the mice Mdr2-/- model, a well-established animal model of cholestatic liver injury. In the four-week study, A4250 significantly decreased key cholestatic liver disease biomarkers, such as ALT, ALP and serum bile acids. In line with the biomarker findings, A4250 also reduced portal inflammation, as revealed by histological examination, and reduced pro-inflammatory biomarkers such as TNF-α, Mcp-1 and Vcam-1.
 
“The data in this trial clearly indicate that A4250 has beneficial effects on a broad range of biochemical liver function parameters and A4250 has potential as a novel hepatoprotective drug that may help preserve liver function in a number of chronic liver diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC),” according to Dr. Hans Graffner, chief medical officer at Albireo. A4250 decreases the reabsorption 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 PBC, PSC and hereditary causes of cholestasis, such as progressive familial intrahepatic cholestasis (PFIC), are planned. Given the mode of action, A4250 should also be beneficial in liver diseases due to metabolic disturbances such as nonalcoholic steatohepatitis, the company stated in a release.
 
A4250 is a highly potent inhibitor of the apical sodium dependent bile acid transporter (ASBT). A4250 decreases the reabsorption 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 acts locally in the gut with only minimal systemic exposure, thereby reducing the risk for potential systemic side effects. A4250 has received orphan drug designation for PBC and PFIC both from the U.S. Food and Drug Administration and the European Medicines Agency.
 
Albireo has extensive experience in the development of ASBT modulators and currently has two ASBT inhibitors in clinical development, elobixibat and A4250. Elobixibat is in Phase 3 trials in chronic constipation and is also in development for irritable bowel syndrome (IBS) with constipation. “Phase 2 clinical trials with elobixibat in patients with chronic constipation conducted in USA and Europe have demonstrated clinically meaningful, statistically significant and dose-dependent improvement on key constipation and IBS-C symptoms such as bowel movement frequency, straining, stool consistency and bloating,” notes Mattsson. Elobixibat is in Phase 3 in chronic constipation and is also in development for IBS with constipation. Elobixibat is partnered with Ferring Pharmaceuticals and with Ajinomoto, Mattsson explains.
 
In addition to ASBT inhibitors, Albireo has a pipeline of drug candidates for the development in areas such as inflammatory bowel disease. The Albireo management team has a broad experience in drug development and has an extensive network in the international scientific and clinical communities. The company was created as a spinout of AstraZeneca in 2008, financed by a syndicate of leading healthcare investors, led by Phase4 Ventures and joined by TPG Biotech, TVM Capital and Scottish Widows Investment Partnership.

Lloyd Dunlap

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