So what might the next wave of successful anticholesterol agents look like? Will any achieve the therapeutic success of statins? One new class of drug candidates is cholesterol ester transfer protein (CETP) inhibitors, but there has already been one major clinical failure, with Pfizer’s torcetrapib failing in Phase III. The firm spent $800 million developing the drug, which was dubbed one of pharma’s biggest flops.
CETP normally moves cholesterol from high-density lipoproteins (HDL) to very low density or low density lipoproteins (VLDL or LDL). Inhibition of this transfer process is expected to increase HDL levels, the good cholesterol, and reduce the bad cholesterol, or LDL levels.
While Pfizer was expected to win approval for torcetrapib in 2008 and assuage declining Lipitor sales, it was forced to stop development in 2006 after the occurrence of major cardiovascular events among trial participants. The study called Illuminate involved 15,067 patients with coronary heart disease (CHD) or CHD risk equivalent (type 2 diabetes) given torcetrapib and atorvastatin or only atorvastatin.
The primary endpoint of the trial, a composite of first major cardiovascular event defined as CHD death, nonfatal myocardial infarction, stroke, or hospitalization for unstable angina, diverged between the treatment groups early in the trial. At termination, the torcetrapib group showed a 25% increased risk over the groups that received atorvastatin alone. Overall, 82 patients taking the combination of torcetrapib and atorvastatin died compared with 51 deaths among those taking only atorvastatin.
In a post-hoc analysis of the halted trial, investigators concluded that the reasons for the adverse outcome were uncertain. They said that torcetrapib administration was associated with undesirable off-target effects that could have contributed to and increased mortality/morbidity. These included heightened blood pressure, increased sodium bicarbonate and aldosterone levels, and decreased potassium levels.