The Swedish biotech company Karo Bio (Reuters: KARO.ST) announced the publication of results from a clinical phase II trial evaluating the company's liver selective thyroid hormone receptor agonist eprotirome and its ability to further reduce serum LDL cholesterol levels in statin-treated patients. The results are published in the March 11, 2010 edition of the New England Journal of Medicine (NEJM).

The study was a randomized, placebo-controlled, double-blind multi-center trial of three months duration, performed between November 2007 and June 2008. It was designed to assess the safety and efficacy of the liver selective thyroid receptor agonist eprotirome (KB2115) in lowering the serum concentration of LDL cholesterol and other atherogenic lipids in hypercholesterolemic patients already taking simvastatin or atorvastatin.

Eprotirome is the first liver selective thyroid hormone receptor agonist that has demonstrated pronounced effects on several atherogenic serum lipids. These beneficial effects were observed at doses where no extra-hepatic thyroid hormone-like effects were evident. Eprotirome is mainly distributed to the liver where it exerts its beneficial effects on LDL-cholesterol and other atherogenic lipoproteins. This is in contrast to the natural hormone triiodothyronine (T3) and thyroxine (T4), which are widely distributed throughout different tissues. Eprotirome's liver-selectivity is important for the avoidance of side effects related to extra-hepatic thyroid hormone-receptor activation. A slight selectivity for the thyroid hormone receptor (TR)-beta may also contribute to the avoidance of side effects such as the TR-alpha mediated effects on the heart.

The results published in the NEJM show that in statin-treated patients, eprotirome substantially lowers serum LDL cholesterol, non-HDL cholesterol and apo B and also reduces a number of other risk factors for cardiovascular disease including serum triglycerides and lipoprotein(a) (Lp(a)). Furthermore, these favorable changes in atherogenic lipids were achieved without evidence of adverse thyroid hormone-like effects.

"We are very excited by the results. Eprotirome has the potential to be a useful drug in high-risk patients currently on statins but not able to reach their LDL-goals. This is an area with a high unmet medical need", commented Jens Kristensen, VP Clinical Development and Chief Medical Officer of Karo Bio.

In all, 329 patients were screened for the study, of which 189 were randomized and included in the trial. In addition to statin treatment, they received either eprotirome 25, 50, or 100 mcg per day or placebo. Secondary outcomes were changes in serum apo B, triglyceride, and Lp(a) concentrations. Safety monitoring included assessments of potential adverse thyroid hormone-like effects on the heart, bone, and pituitary.

The addition of eprotirome to statin treatment for 12 weeks resulted in placebo-adjusted reductions in serum LDL-cholesterol concentrations of -15%, -20%, and -26% with daily 25 mcg, 50 mcg and 100 mcg eprotirome, respectively. Similar reductions were seen in serum apo B (-14%, -19%, and -24%), triglycerides (-20%, -20%, and -37%), and Lp(a) (-17%, -22%, and -34%). These effects on atherogenic lipid variables were similar in magnitude to those found in a previous study where eprotirome was given as monotherapy, indicating a full additive effect on top of statins. Eprotirome therapy was clinically very well tolerated without adverse cardiac or bone effects. No change in serum Thyroid Stimulating Hormone (TSH) or T3 was detected although the thyroxine (T4) concentration decreased.

In eprotirome-treated patients, no significant changes were seen in body weight, serum markers of bone turnover, heart rate, or blood pressure; no abnormal cardiac rhythm or electrocardiography changes, including QTc interval, were detected; and no pattern of symptoms suggesting clinical thyrotoxicosis or hypothyroidism was observed. The frequency, pattern and intensity of adverse events were similar in placebo and eprotirome-treated patients. Mild and reversible increases in serum alanine aminotransferase were observed, and two patients had confirmed ALT levels of more than three-fold the upper limit of the normal range.

In conclusion, this randomized, placebo-controlled, double-blind trial has demonstrated eprotirome's ability to further reduce serum LDL cholesterol levels in statin-treated patients. Eprotirome also possesses potent non-HDL cholesterol, apo B, triglyceride and Lp(a) lowering properties. Eprotirome's actions are exerted at doses where no adverse effects on the heart, bone, or pituitary are evident. The therapeutic promise and safety of eprotirome as a novel drug for treatment of dyslipidemia will need to be confirmed in longer-term studies.

About Dyslipidemia and LDL cholesterol

The association of elevated circulating LDL cholesterol with increased atherosclerotic cardiovascular disease risk is well established, as are the reductions in both serum cholesterol and cardiovascular risk that occur with statin therapy. However, the remarkable efficacy of statin therapy is limited by patients failing to achieve their serum LDL cholesterol goals when treated with these agents alone, and by patients suffering from side effects requiring dose reduction or treatment discontinuation. Furthermore, statins show less efficacy in lowering levels of other lipoproteins associated with increased atherosclerotic vascular disease risk, i.e. hyper?¬triglyceridemia and elevated Lp(a).

The cholesterol-lowering effect of thyroid hormone therapy in patients with hypothyroidism was described already in 1930. LDL-cholesterol is the principal lipoprotein fraction reduced, an action brought about by increased hepatic LDL receptor gene expression. In rodents, thyroid hormone receptor agonists also accelerate hepatic cholesterol disposal by increasing the HDL-receptor SR-B1, elevating cholesterol 7a-hydroxylase activities and increasing fecal excretion of cholesterol through bile acids.

Previous studies with naturally occurring thyroid hormone metabolites and synthetic thyroid hormone receptor agonists have confirmed their cholesterol lowering properties. However, development of some of these drugs has ceased due to thyroid hormone-related adverse effects, such as effects on the heart with D-thyroxine, and on bone with tiratricol. Karo Bio's aim with eprotirome has been to develop a liver-selective thyroid hormone receptor agonist to avoid these side effects.

Source
Karo Bio