THERAPY WITH THE THYROID HORMONE RECEPTOR AGONIST EPROTIROME IN PATIENTS WITH FAMILIAL HYPERCHOLESTEROLEMIA: A RANDOMISED, DOUBLE BLIND, PLACEBO-CONTROLLED STUDY

Objectives: Eprotirome is a liver selective thyroid hormone receptor agonist that effectively lowered plasma low-density LDL-C levels in previous phase I and II studies. We set out to assess the long-term safety and efficacy of 50 and 100 μg eprotirome in patients with familial hypercholesterolemia (FH). This randomised placebo controlled phase III study was prematurely terminated because of the concurrent recognition of cartilage damage in canines. Methods: Although it was impossible to meet the predefined study outcomes, we analyzed the changes in lipid levels, liver parameters, thyroid hormone levels and adverse effects after treatment with eprotirome or placebo after the initial 6 weeks of therapy. Results: Sixty-nine randomised patients reached the 6 weeks time point. LDL-C levels in the placebo (n=23), 50 (n=24) and 100 μg eprotirome (n=22) groups changed by +9% (95% CI -2 to +20%), -12% (-28 to +4%) (p=0.0677 vs. placebo), and -22% (-32 to -13%) (p=0.0045 vs. placebo), respectively. In the 50 and 100 μg eprotirome-treated patients, significant increases in AST (+62% (+32 to +85%) and +114 (+83 to +146%); p<0.0001), ALT (+114% (+101 to +187) and +183% (+137 to +229%); p<0.0001), conjugated bilirubin (+47% (+22 to +72%) and +60% (+22 to +72%); p=0.0006), and gamma-GT (+48% (+30 to +65%) and +81% (+55 to +107%); p<0.0001) were observed, respectively (all p-values for eprotirome groups vs. placebo). Four patients had to discontinue or interrupt study medication prior to trial termination due to AST elevations between the upper limit of normal (ULN) and 6xULN as well as ALT levels between 3 and 7xULN. Conclusion: Eprotirome lowered LDL-C levels, but increased liver enzymes. Along with the observed cartilage damage in canines, the results of this study raise serious doubts about selective thyroid mimetics as a therapeutic approach to lower LDL-C levels in man.