April 22, 2017, Amsterdam, The Netherlands: Results presented today from a study of a novel ileal bile acid transport inhibitor, A4250, demonstrated that it reduced levels of blood (serum) bile acids, which are characteristic of many liver diseases and often associated with severe liver damage, in children with cholestatic liver diseases. The data, presented at The International Liver Congress™ 2017 in Amsterdam, The Netherlands, showed that oral treatment with A4250 also improved pruritus (itching) in 74% of patients and was well tolerated, with mostly mild and transient side effects.
"There is a real need for novel and effective therapies for paediatric cholestatic diseases," said Dr Ulrich Baumann, Hannover Medical School, Germany, and lead author of the study. "The safety and efficacy data from this study show the potential for A4250 to become a significant and novel advance for the treatment of paediatric cholestatic liver diseases."
This study evaluated five doses of A4250 (0.01-0.2 mg/kg), with the dataset including four patients who received each dose. Patients with cholestatic disease and intractable itching were initially administered a single dose of A4250. As there were no safety issues, patients were then given the drug in tablet form for four weeks. If needed, therapy with ursodeoxycholic acid (UDCA) or rifampicin could also be given during the study. The dataset included nineteen patients aged 1-17 years and itching was measured by a visual itch score using patient reported diary data.
Pruritus improved in 14 of 19 cases. Mean levels of serum bile acids were reduced at all doses. In particular, there were substantial reductions in serum bile acids in seven out of nine patients with progressive familial intrahepatic cholestasis, ranging from a 43% to 98% reduction. Most side effects were mild and transient and considered to be unrelated to the drug, and there were no serious side effects.
"The study results are crucial as they address pruritus, a significant issue in chronic cholestatic diseases. Currently, there are few therapeutic options with limited efficacy, so new treatment strategies for pruritus are of great importance for clinical practice," said Prof Marco Marzioni, Professor of Gastroenterology, Università Politecnica delle Marche - "Ospedali Riuniti" University Hospital of Ancona, Italy and EASL Governing Board Member.
Grants, speaker fees, and consultancy work for Astellas, Novartis, Alexion, Alnylum, Nestle.
1 Baghdasaryan A, et al. Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis. J Hepatol. 2016;64(3):674-681.
2 Hanns-Ulrich M, et al. The ileal bile acid transporter inhibitor A4250 modulates bile acid synthesis and decreases serum bile acids. Presented at the Liver Meeting® 2015, San Francisco, CA, USA, November 13-17, 2015. Abstract 810.
3 Graffner H, et al. The ileal bile acid transporter inhibitor A4250 decreases serum bile acids by interrupting the enterohepatic circulation. Aliment Pharmacol Ther. 2016;43:303-310.