Open-label study of ademetionine for the treatment of intrahepatic cholestasis associated with alcoholic liver disease

BACKGROUND: The effect of oral and/or parenteral ademetionine (500 mg intravenous [IV] and tablet formulation) on clinical symptoms and biochemical markers of intrahepatic cholestasis (IHC) was investigated in subjects with alcoholic liver disease (ALD) and compensated liver function. METHODS: Prospective, multicenter, open-label study consisting of a screening period and an 8-week treatment period and performed in subjects (18-75 years) with compensated ALD and confirmed IHC. Subjects with a baseline serum conjugated bilirubin value above normal range were initially treated with IV ademetionine for two weeks (500-800 mg daily) and continued with oral ademetionine 1500 mg daily for a further six weeks. Subjects with a baseline serum conjugated bilirubin value within normal range were treated with oral ademetionine for eight weeks. RESULTS: A total of 72 subjects were treated; 41 initially with IV ademetionine and 31 with oral ademetionine. Clinical symptoms status improved from baseline to end of treatment with an increase in the proportion of subjects with no symptoms. Ademetionine showed significant improvements in primary efficacy parameters alkaline phosphatase (ALP) and γ-glutamyltransferase (γGT) (P<0.0001). Although decreases of ALP were higher for subjects initially treated with IV ademetionine, these subjects also had higher baseline values. No safety concerns with ademetionine arose with respect to the severity or frequency of adverse events (AEs) during the treatment period, laboratory parameters, and vital signs. CONCLUSIONS: Administration of oral or IV/oral ademetionine step-therapy for 8 weeks to subjects with IHC due to ALD was safe and provided a significant improvement of disease burden.