Torcetrapib

Torcetrapib (CP-529414, 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 mortality in the treatment group receiving a combination of atorvastatin and the study group.

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Mechanism

Torcetrapib acts by inhibiting cholesterylester 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-chlorotriflouryltoluene, a reaction that was created by Dr. Stephen Buchwald at MIT.^[1]

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.^[2]

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 torcetraipib to be sold independently of Lipitor.^[3]

Clinical trials

A 2004 trial showed that torcetrapib could increase HDL and lower LDL with and without an added statin.^[4]

End of study

On December 2 2006 Pfizer cut off torcetrapib's trial because of "an imbalance of mortality and cardiovascular events" associated with its use.^[5] 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."^[5] In the terminated trial, a 60% increase in deaths was observed among patients taking torcetrapib and atorvastatin versus taking atorvastatin alone; there was no suggestion that the results called into question the safety of atorvastatin.^[6] Pfizer recommends that all patients stop taking the drug immediately.^[7]

The drug cost $800m+ to bring into Phase III development.^[8]

References

• Clark, RW; Sutfin TA, Ruggeri RB, Willauer AT, Sugarman ED, Magnus-Aryitey G, Cosgrove PG, Sand TM, Wester RT, Williams JA, Perlman ME, Bamberger MJ (January 22 2004). "Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib". Arteriosclerosis, Thrombosis, and Vascular Biology 24 (3): 490–497. PMID 14739125. Retrieved on 2006-12-03.

• Clark, RW; Ruggeri RB, Cunningham D, Bamberger MJ (March 2006). "Description of the torcetrapib series of cholesteryl ester transfer protein inhibitors, including mechanism of action". Journal of Lipid Research 47 (3): 537–552. PMID 16326978. Retrieved on 2006-12-03.

• Davidson, MH; McKenny JM, Shear CL, Revkin JH (November 7 2006). "Efficacy and safety of torcetrapib, a novel cholesteryl ester transfer protein inhibitor, in individuals with below-average high-density lipoprotein cholesterol levels". Journal of the American College of Cardiology 48 (9): 1774–1781. PMID 17084249. Retrieved on 2006-12-03.

• McKenny, JM; Davidson MH, Shear CL, Revkin JH (November 7 2006). "Efficacy and safety of torcetrapib, a novel cholesteryl ester transfer protein inhibitor, in individuals with below-average high-density lipoprotein cholesterol levels on a background of atorvastatin". Journal of the American College of Cardiology 48 (9): 1782–1790. PMID 17084250. Retrieved on 2006-12-03.

Notes

1. ^ Buchwald, Stephen (July 23 2004). Research Projects. Retrieved on 2007-10-4.
2. ^ Pfizer (June 22 2005). "Pfizer Begins Production at Torcetrapib/Atorvastatin Manufacturing Facility". Press release. Retrieved on 2006-12-03.
3. ^ Berenson, Alex. "Heart Pill to Be Sold by Itself", Business, The New York Times, July 26 2006. Retrieved on 2006-12-03. 
4. ^ Brousseau, ME; Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, Mancuso JP, Rader DJ (April 8 2004). "Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol". New England Journal of Medicine 350 (15): 1505–1515. PMID 15071125. Retrieved on 2006-12-03.
5. ^ ^{a b} Berenson, Alex. "Pfizer Ends Studies on Drug for Heart Diseas", The New York Times, December 3 2006. Retrieved on 2006-12-03.  (registration required)
6. ^ Theresa Agovino (Associated Press). "Pfizer ends cholesterol drug development", Yahoo! News, December 3 2006. Retrieved on 2006-12-03.  Each study arm (torcetrapib + atorvastatin vs. atorvastatin alone) had 7500 patients enrolled; 51 deaths were observed in the atorvastatin alone arm, while 82 deaths occurred in the torcetrapib + atorvastatin arm. (Link dead as of 15 January 2007)
7. ^ Associated Press. "Pfizer cuts off cholesterol drug trials", Yahoo! News, Yahoo.com, December 2 2006. Retrieved on 2006-12-03.  (Link dead as of 15 January 2007)
8. ^ Cutler, D. M. (2007-03-29). "The Demise of the Blockbuster?" (HTML). The New England Journal of Medicine 356: 1292–1293. Massachusetts Medical Society. ISSN: 1533-4406. Retrieved on 2007-04-23.