Clinical Trials

Date: 2017-04-22

Type of information: Presentation of results at a congress

phase: 2

Announcement: presentation of results at The International Liver Congress 2017

Company: Albireo (Sweden)

Product: A4250

Action mechanism: 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.

Disease: primary biliary cirrhosis, cholestatic pruritus

Therapeutic area: Autoimmune diseases - Hepatic diseases - Liver diseases

Country: Sweden

Trial details: 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. (NCT02360852)

Latest news:

• • On April 22, 2017, Albireo Pharma announced that data from a Phase 2 clinical trial of its lead product candidate A4250 in children with cholestatic liver disease will be presented  at The International Liver Congress™ 2017 in Amsterdam . The data demonstrated improvement in pruritus and reduction in serum bile acids (sBA) in most patients, particularly patients with progressive familial intrahepatic cholestasis (PFIC), after four weeks of treatment with A4250. Albireo is currently engaging with regulatory authorities in the United States and Europe with the objective to design a coordinated Phase 3 program in patients with progressive familial intrahepatic cholestasis. The company expects to initiate this trial in the second half of 2017. The open label, multicenter, dose finding Phase 2 trial assessed the safety and tolerability of A4250 and explored changes in sBA levels and pruritus. Nineteen patients aged one to 17 years old with a pediatric cholestatic liver disease, including PFIC (subtype 1, 2 or 3), Alagille syndrome, biliary atresia or intrahepatic cholestasis, were enrolled in the trial's first five cohorts. Five different doses of A4250 were evaluated, ranging from 10 µg/kg to 200 µg/kg. A4250 reduced mean levels of sBA in all five dose groups, with substantial sBA reductions observed in seven of nine PFIC patients (ranging from 43 percent to 98 percent). In addition, 14 of 19 patients showed improvement in pruritus using a visual analogue scale (VAS-Itch 0-10). The dose with the greatest improvement showed a mean decrease of 2.86 points from baseline. The trial was not powered for formal statistical analyses. The data showed a significant correlation between reduction in sBA and improvement of pruritus. In addition, no treatment-related serious adverse events were observed, and A4250 was well tolerated. Subsequent to the submission date for ILC, the trial's remaining patients completed the study.
• • On February 5, 2015, 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. 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 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 ( 7?-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 FDA and the European Medicines Agency.

Is general: Yes