Atherosclerosis - JTT-705

High plasma levels of low density lipoprotein cholesterol (LDL-C) are associated with an increased risk of coronary heart disease, and agents like statins have been very effective at reducing these levels.

However, this is insufficient for some patients, either because they struggle to achieve low LDL-C levels or because reducing LDL-C alone is insufficient to cut the risk of heart disease. One strategy that looks promising in such cases is to increase the levels of high density lipoprotein cholesterol (HDL-C), which has also been shown to have a cardioprotective effect.

The enzyme cholesterol ester transfer protein (CETP) promotes the transformation of HDL-C to LDL-C, and so inhibiting it has the effect of increasing HDL-C levels. Japan Tobacco has been developing a potent and selective CETP inhibitor, JTT-705,¹ licensed to Roche outside Japan and Korea.

Several clinical trials have been carried out, including three Phase I studies. It was given in

single doses of 100 to 1800mg/day to healthy subjects, and had no significant toxic effects. A crossover bioavailability study was carried out, and showed that the drug was more effective when taken after food than after fasting. And it was given in doses of 600 and 900mg a day in a 14 day multiple dose study, and it had the effect of lowering LDL-C and raising HDL-C.

A Phase II trial has also been carried out.² JTT-705 was given in doses of 300, 600 or 900mg in a randomised, double blind placebo-controlled trial to 198 subjects with hyperlipidaemia. The drug was well tolerated, and the only side effects were mild gastrointestinal disorders. None of these proved treatment limiting. After four weeks, those given the highest dose had a 37% reduction in CETP activity, a 34% increase in HDL-C, and a 7% drop in LDL-C. Trials continue to establish its potential as a preventative treatment for atherosclerosis.