Pharmaceutical companies that are developing compounds in the ACAT inhibitor class will be alarmed at a Phase III trial of Daiichi Sankyo's pactimibe which suggests the drug not only fails to prevent progression of atherosclerotic plaque but also appears to promote, rather than reduce, atherosclerosis.

The results, from ACTIVATE, the first Phase III study of an ACAT inhibitor, were announced yesterday at the American Heart Association annual meeting in Dallas.

Daiichi Sankyo had already announced that the trial was a failure and it had discontinued pactimibe last month.

The ACAT inhibitors are a new class of drug designed to slow or reduce the build-up of plaque in the artery walls (atheroma volume). ACTIVATE examined pactimibe's effects on atheroma volume using intravascular ultrasound. The study was not designed to investigate the drug's effects on patients' risk of death, but there was no difference in the rate of death, heart attack, stroke or other cardiovascular disease endpoints.

ACTIVATE's results will cause disappointment beyond Daiichi Sanyko. There has not been a major new treatment for atherosclerosis since the introduction of statins in 1987, and the ACAT inhibitors seemed promising new options for the two thirds of patients who experience a coronary event despite taking a statin.

It is possible that a different dose of pactimibe or a different ACAT inhibitor might have produced a more positive result in ACTIVATE, but companies will be carefully considering the further development of this class of drug.

Source: Sue Lyon at the AHA in Dallas, USA.