Treatment of primary biliary cirrhosis with tetrathiomolybdate: results of a double-blind trial

The results of a double-blind trial of tetrathiomolybdate therapy and standard of care, versus placebo and standard of care treatment, in primary biliary cirrhosis patients are presented. Baseline studies of liver function, various safety variables, ceruloplasmin, a liver biopsy for histologic analysis, and for various cytokine analyses were carried out. Patients were observed every 4 months for up to 2 years of treatment by a hepatologist for clinical evaluation and repeat of all the baseline studies except liver biopsy, which was repeated at 2 years. The primary end points were improvement in 2 liver function tests and in 1 inflammatory cytokine. Fifteen placebo patients were followed for an average of 13 months, and 13 tetrathiomolybdate patients were followed for an average of 14 months. The predefined primary end points for efficacy were met. Tetrathiomolybdate was well tolerated. Because tetrathiomolybdate has been shown in numerous animal studies to inhibit autoimmune and inflammatory processes, and because primary biliary cirrhosis is an autoimmune attack on bile ducts, these positive findings on efficacy of tetrathiomolybdate therapy in primary biliary cirrhosis fit with the animal studies and suggest the need for a longer clinical trial to examine transplant-free survival.

Abbreviations: alk phos, alkaline phosphatase, ALT, alanine amino transferase, AMA, antimitochondial antibody, ANA, antinuclear antibody, AST, aspartate aminotransferase, bili, bilirubin, CLIA, Clinical Laboratory Improvement Amendments, CRP, C-reactive protein, IL-1β, interleukin-1β, INR, international normalized ratio, PBC, primary biliary cirrhosis, SE, standard error, TGF-β, transforming growth factor beta, TM, tetrathiomolybdate, TNF-α, tumor necrosis factor alpha