Why Pfizer's torcetrapib failure might not thwart other CETP inhibitors
drug tree, but when torcetrapib failed, other pharma firms
developing similar drugs looked on nervously to see if their drugs
were also doomed. A new study suggests they might have nothing
to worry about.
Researchers at the Cleveland Clinic have been investigating the impact of Pfizer's drug on levels of high-density lipoprotein (HDL), or 'good cholesterol' and think they may now know where torcetrapib went wrong. Last December, the drug spectacularly failed a large Phase III clinical trial (called ILLUMINATE) when it was found to actually increase the risk of death. Billions of dollars were wiped off Pfizer's value in the aftermath, and many were left wondering if the adverse events were just related to torcetrapib, or would there a problem with other drugs that targeted cholesteryl ester transfer protein (CETP). In fact, Merck & Co. and Roche halted research on their own CETP inhibitors - anacetrapib (MK-0859) and R1658 (Phase II) / R1664 (Phase I) respectively - until more was known about why torcetrapib failed. Roche also had at least two CETP inhibitors in clinical trials. However, the companies may now have got the news they wanted to hear. Speaking at the American Heart Association (AHA) conference, being held in Florida this week, Dr Steven Nicholls, said that although adverse events with all CETP inhibitors cannot be ruled out, other drugs in the same class do still warrant further investigation. "In this study, we also examined the effect of torcetrapib on blood pressure and electrolyte changes in order to investigate the potential mechanisms of toxicity," he said. "What we found was that the increased blood pressure and changes in electrolytes signal the potential activation of the renin-angiotensin-aldosterone system (RAAS) by torcetrapib. The greater RAAS activation may weaken the benefit of raising HDL." This off-target RASS effect might explain both why torcetrapib didn't work as well as expected and also its toxicity. Therefore, if Merck can prove that Zocor and BMS can prove that Pravachol doesn't interact with RASS, the drugs may still been able to make it to market. Dr Nicholls' research is published in the latest edition of the New England Journal of Medicine (NEJM). The research also provides strong evidence that raising HDL predicts a drug's benefit. Finding compounds that raise HDL has been a priority of drug developers as many patients on drugs that lower low-density lipoprotein (LDL, or 'bad cholesterol) still experience heart attacks, stroke or sudden cardiac death. The initial results from this secondary trial, called ILLUSTRATE - comprising 1,188 people - showed that although torcetrapib markedly increased good cholesterol levels, it also substantially raised blood pressure and failed to significantly slow the buildup of plaque. The trial used intravascular ultrasound (IVUS) technology to determine the findings. IVUS is a technique in which a tiny ultrasound probe is inserted into the coronary arteries, providing a precise and reproducible method for determining the change in plaque, or atheroma, burden during treatment. Dr Steven Nissen, Chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic, said: "These observations offer new hope that raising HDL by inhibiting CETP may ultimately succeed in slowing the progression of coronary heart disease and reducing cardiovascular events. "New studies with agents other than torcetrapib seem warranted."
