Torcetrapib

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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 drug.

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. [cite website
last = Buchwald | first = Stephen | authorlink =
title = Research Projects
url = http://mit.edu/chemistry/buchwald/research/projects.html
date = July 23 2004 | accessdate = 2007-10-4]

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. [cite press release | title = Pfizer Begins Production at Torcetrapib/Atorvastatin Manufacturing Facility | publisher = Pfizer | date = June 22 2005 | url = http://www.pfizer.com/pfizer/are/investors_releases/2005pr/mn_2005_0622.jsp | accessdate = 2006-12-03 ]

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. [cite news | first = Alex | last = Berenson | title = Heart Pill to Be Sold by Itself | url = http://www.nytimes.com/2006/07/26/business/26drug.html | work = Business | publisher = The New York Times | date = July 26 2006 | accessdate = 2006-12-03]

Clinical trials

A 2004 trial showed that torcetrapib could increase HDL and lower LDL with and without an added statin. [cite journal
last = Brousseau | first = ME | authorlink =
coauthors = Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, Mancuso JP, Rader DJ
date = April 8 2004
title = Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol
journal = New England Journal of Medicine
volume = 350 | issue = 15 | pages = 1505–1515
doi = | pmid = 15071125
url = http://content.nejm.org/cgi/content/abstract/350/15/1505
accessdate = 2006-12-03
format = abstract ]

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.cite news
first = Alex | last = Berenson | authorlink =
title = Pfizer Ends Studies on Drug for Heart Diseas
url = http://www.nytimes.com/2006/12/03/health/03pfizer.html?_r=1&th&emc=th&oref=slogin
publisher = The New York Times
date = December 3 2006 | accessdate = 2006-12-03 (registration required)] 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. [cite news
author = Theresa Agovino (Associated Press) | title = Pfizer ends cholesterol drug development
url = http://news.yahoo.com/s/ap/20061203/ap_on_he_me/pfizer_cholesterol_drug_5&printer=1
publisher = Yahoo! News | date = December 3 2006 | accessdate = 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)] Pfizer recommends that all patients stop taking the drug immediately. [cite news
author = Associated Press
title = Pfizer cuts off cholesterol drug trials | url = http://news.yahoo.com/s/ap/20061203/ap_on_he_me/pfizer_cholesterol_drug_1
work = Yahoo! News | publisher = Yahoo.com
date = December 2 2006 | accessdate = 2006-12-03 (Link dead as of 15 January 2007)]

The drug cost $800m+ to bring into Phase III development. [cite journal
last = Cutler
first = D. M.
authorlink = D. M. Cutler
title = The Demise of the Blockbuster?
journal = The New England Journal of Medicine
volume = 356
pages = 1292–1293
date = 2007-03-29
publisher = Massachusetts Medical Society
url = http://content.nejm.org/cgi/content/full/356/13/1292
format = HTML
id = ISSN: 1533-4406
accessdate = 2007-04-23
doi = 10.1056/NEJMp078020
pmid = 17392299 ]

ee also

*Anacetrapib, another CETP inhibitor currently studied by Merck

References

* cite journal
last = Clark | first = RW | authorlink =
coauthors = Sutfin TA, Ruggeri RB, Willauer AT, Sugarman ED, Magnus-Aryitey G, Cosgrove PG, Sand TM, Wester RT, Williams JA, Perlman ME, Bamberger MJ
date = January 22 2004
title = Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib
journal = Arteriosclerosis, Thrombosis, and Vascular Biology
volume = 24 | issue = 3 | pages = 490–497
doi = | pmid = 14739125 | url = http://atvb.ahajournals.org/cgi/content/full/24/3/490
accessdate = 2006-12-03

* cite journal
last = Clark | first = RW | authorlink =
coauthors = Ruggeri RB, Cunningham D, Bamberger MJ
year = 2006 | month = March
title = Description of the torcetrapib series of cholesteryl ester transfer protein inhibitors, including mechanism of action
journal = Journal of Lipid Research
volume = 47 | issue = 3 | pages = 537–552
doi = | pmid = 16326978 | url = http://www.jlr.org/cgi/content/full/47/3/537
accessdate = 2006-12-03

* cite journal
last = Davidson | first = MH | authorlink = | coauthors = McKenny JM, Shear CL, Revkin JH
date = November 7 2006
title = Efficacy and safety of torcetrapib, a novel cholesteryl ester transfer protein inhibitor, in individuals with below-average high-density lipoprotein cholesterol levels
journal = Journal of the American College of Cardiology | volume = 48 | issue = 9 | pages = 1774–1781
doi = | pmid = 17084249 | url = http://patient-research.elsevier.com/patientresearch/displayAbs?key=S0735109706019917
accessdate = 2006-12-03

* cite journal
last = McKenny | first = JM | authorlink = | coauthors = Davidson MH, Shear CL, Revkin JH
date = November 7 2006
title = 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 = Journal of the American College of Cardiology
volume = 48 | issue = 9 | pages = 1782–1790
doi = | pmid = 17084250 | url = http://patient-research.elsevier.com/patientresearch/displayAbs?key=S0735109706019905
accessdate = 2006-12-03

Notes

External links

* [http://www.medscape.com/viewarticle/548725_print Medscape / HEARTwire : Torcetrapib Torpedoed: Increased Risk of Mortality, Cardiovascular Events Ends Development.]
* [http://www.cholesteroldoc.com/cetp-inhibitors.htm#news latest news about CETP Inhibitors]