THERAPY WITH THE THYROID HORMONE RECEPTOR AGONIST EPROTIROME IN PATIENTS WITH FAMILIAL HYPERCHOLESTEROLEMIA: RESULTS OF THE AKKA TRIAL

Background: Eprotirome is a liver selective thyroid hormone receptor agonist that effectively lowered plasma low-density lipoprotein cholesterol (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). The 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 randomized patients reached the 6 weeks timepoint. LDL-C levels in the placebo, 50 and 100 μg eprotirome groups changed by +9±25%, -12±38% (p=0 0853 vs. placebo), and -22±22% (p=0 0059 vs. placebo), respectively. In the 50 and 100 μg eprotirome-treated patients, significant increases in aspartate aminotransferase (AST; 62±54% and 114±71%; p<0 0001), alkaline aminotransferase (ALT; 144±102% and 183±104%; p<0 0001), conjugated bilirubin (47±58% and 60±62%; p=0·0003), and gamma-glutamyl transpeptidase (gamma-GT; 47±42% and 81±58%; p<0 0001) were observed, respectively (all overall 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. None of these patients had a concomitant increase in bilirubin. There were no changes in serum thyroid stimulating hormone (TSH) and free trijodothyronine (FT3). However, free tetrajodothyronine (FT4) decreased by 19±9% and 27±9% (both p<0 0001 vs. placebo) in the 50 and 100 μg eprotirome groups, respectively. Conclusions: Eprotirome lowered LDL-C levels, but increased liver enzymes and lowered FT4. Along with the observed cartilage damage in canines, the results of this study have raised serious doubts about the potential role of developing sufficiently selective thyroid hormone receptor agonists as a therapeutic approach to lower LDL-C levels in man.