Torcetrapib

Torcetrapib (CP-529,414, Pfizer) was a drug being developed to treat hypercholesterolemia (elevated cholesterol levels) and prevent cardiovascular disease. Its development was halted in 2006 when phase III studies showed excessive all cause mortality in the treatment group receiving a combination of atorvastatin and the study drug.

Mechanism
Torcetrapib acts (as a CETP inhibitor) by inhibiting cholesteryl ester transfer protein (CETP), which normally transfers cholesterol from HDL cholesterol to very low density or low density lipoproteins (VLDL or LDL). Inhibition of this process results in higher HDL levels (the "good" cholesterol-containing particle) and reduces LDL levels (the "bad" cholesterol).

Development
The first step in the synthesis was a recently created reaction of amination to p-chlorotrifluoryltoluene, a reaction that was created by Dr. Stephen Buchwald at MIT.

Development of the drug began around 1990; it was first administered in humans in 1999, and manufacturing at production scale began in Ireland in 2005.

Pfizer had previously announced that torcetrapib would be sold in combination with Pfizer's statin, atorvastatin (Lipitor); however, following media and physician criticism, Pfizer had subsequently planned for torcetrapib to be sold independently of Lipitor.

Clinical trials
A 2004 trial (19 subjects, non-randomised) showed that torcetrapib could increase HDL and lower LDL with and without an added statin.

Nine phase III studies were completed.

Early termination of study
On December 2, 2006 Pfizer cut off torcetrapib's [phase III] trial because of "an imbalance of mortality and cardiovascular events" associated with its use. This was a sudden and unexpected event and as recently as November 30 Jeff Kindler, Pfizer’s chief executive, was quoted as saying "This will be one of the most important compounds of our generation." In the terminated trial, a 60% increase in deaths was observed among patients taking torcetrapib and atorvastatin versus taking atorvastatin alone. Pfizer recommends that all patients stop taking the drug immediately.

Six studies were terminated early. One of the completed studies found it raised systolic blood pressure and concluded "Torcetrapib showed no clinical benefit in this or other studies, and will not be developed further."

The drug cost $800m+ to bring into Phase III development.