Torcetrapib
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2008-06-24T00:14:53Z
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'''Torcetrapib''' (CP-529414, [[Pfizer]]) was a [[medication|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 [[High density lipoprotein|HDL cholesterol]] to [[Very low density lipoprotein|very low density]] or [[low density lipoprotein]]s (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.<ref>{{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
}}</ref>
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.<ref>{{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 }}</ref>
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.<ref>{{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}}</ref>
==Clinical trials==
A 2004 trial showed that torcetrapib could increase HDL and lower LDL with and without an added statin.<ref>{{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
}}</ref>
==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.<ref name="Berenson 20061203">{{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)</ref>
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.''"<ref name="Berenson 20061203"/> In the terminated trial, a 60% increase in deaths was observed among patients taking torcetrapib and atorvastatin versus taking atorvastatin alone.<ref>{{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]])</ref>
Pfizer recommends that all patients stop taking the drug immediately.<ref>{{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]])</ref>
The drug cost $800m+ to bring into Phase III development.<ref>{{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 }}</ref>
==See also==
*[[Anacetrapib]], another CETP inhibitor currently studied by [[Merck & Co.|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===
<References/>
==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]
{{Lipid modifying agents}}
[[Category:Hypolipidemic agents]]
[[pl:Torcetrapib]]