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==Overview==
==Overview==
Dalcetrapib or JTT-705 is a [[CETP inhibitor]] which was being developed by Hoffmann–La Roche until May 2012.  The drug was aimed at raising the blood levels of "good cholesterol" (cholesterol carried in HDL particles, ''aka'' HDL-C).  Prevailing observations indicate that high HDL levels correlate with better overall cardiovascular health, though it remains unclear whether raising HDL levels consequently leads to an increase in cardiovascular health.


'''Dalcetrapib''' or '''JTT-705''' is a [[CETP inhibitor]] which was being developed by [[Hoffmann–La Roche]] until May 2012.<ref name=pmid12444911/><ref name=bennett2012/> The drug was aimed at raising the blood levels of "[[good cholesterol]]" (cholesterol carried in HDL particles, ''aka'' HDL-C).<ref name=cortez2012/> Prevailing observations indicate that high HDL levels correlate with better overall cardiovascular health, though it remains unclear whether raising HDL levels consequently leads to an increase in cardiovascular health.<ref name=NIH2011/>
==Development and Research==
A 24 week [[clinical trial]] showed that dalcetrapib did increase HDL-C levels, supporting the agent's desired effect.  Further, the dal-PLAQUE phase IIb trial found evidence of [[Atheroma|plaque]] reduction.  Plaque reduction is an anticipated observation following an increase in HDL.


As of 2010 five phase II trials had started and there was no evidence of the raised blood pressure seen with [[torcetrapib]].


dal-VESSEL phase IIb trial found no evidence of flow-mediated dilatation improvement.  A 17% increase of [[Lipoprotein-associated phospholipase A2|Lp-PLA<sub>2</sub>]] mass level was noted.  Lp-PLA<sub>2</sub> is associated with [[coronary heart disease]] and [[stroke]].<ref name="pmid23126252">{{cite journal |author=Schwartz GG, Olsson AG, Abt M, ''et al.'' |title=Effects of dalcetrapib in patients with a recent acute coronary syndrome |journal=[[The New England Journal of Medicine]] |volume=367 |issue=22 |pages=2089–99 |year=2012 |month=November |pmid=23126252 |doi=10.1056/NEJMoa1206797 |url=}}</ref><ref name="pmid23400900">{{cite journal |author=Phelan M, Anzures-Cabrera J, Carlile DJ, ''et al.'' |title=Effect of hepatic and renal impairment on the pharmacokinetics of dalcetrapib : altered distribution of the active thiol? |journal=[[Clinical Pharmacokinetics]] |volume=52 |issue=4 |pages=255–65 |year=2013 |month=April |pmid=23400900 |doi=10.1007/s40262-013-0035-z |url=}}</ref>


A 24 week [[clinical trial]] showed that dalcetrapib did increase HDL-C levels, supporting the agent's desired effect.<ref name=Roth2010/>  Further, the dal-PLAQUE phase IIb trial found evidence of [[Atheroma|plaque]] reduction.<ref name=fayad2011/>  Plaque reduction is an anticipated observation following an increase in HDL.{{citation needed|date=November 2012}}
dal-OUTCOMES phase III trial passed its first interim review in July, 2011, however, development was halted on May 7, 2012 “due to a lack of clinically meaningful efficacy”. The results of dal-OUTCOMES III were published in November, 2012.<ref name="pmid23317399">{{cite journal |author=Bochem AE, Kuivenhoven JA, Stroes ES |title=The Promise of Cholesteryl Ester Transfer Protein (CETP) Inhibition in the Treatment of Cardiovascular Disease |journal=[[Current Pharmaceutical Design]] |volume=19 |issue=17 |pages=3143–9 |year=2013 |pmid=23317399 |doi= |url=}}</ref>
 
 
 
{{As of|2010}} five phase II trials had started and there was no evidence of the raised blood pressure seen with [[torcetrapib]].<ref name=Roth2010/>
 
 
 
dal-VESSEL phase IIb trial found no evidence of flow-mediated dilatation improvement.  A 17% increase of [[Lipoprotein-associated phospholipase A2|Lp-PLA<sub>2</sub>]] mass level was noted.<ref name=tfl2012/>  Lp-PLA<sub>2</sub> is associated with [[coronary heart disease]] and [[stroke]].{{citation needed|date=November 2012}}
 
 
 
dal-OUTCOMES phase III trial passed its first interim review in July, 2011,<ref name=parziale/> however, development was halted on May 7, 2012 “due to a lack of clinically meaningful efficacy.”.<ref name=bennett2012/>
 
 
 
The results of dal-OUTCOMES III were published in November, 2012.<ref>{{cite pmid|23126252}}</ref>
 
 
 
==See also==
 
* [[CETP inhibitor]], which contains links to related agents; as of November 2012: Torcetrapib, Anacetrapib, Dalcetrapib and Evacetrapib
 
 


==References==
==References==
 
{{reflist|2}}
{{reflist|2|refs=
 
 
 
<ref name=pmid12444911>{{cite journal |author=Huang Z, Inazu A, Nohara A, Higashikata T, Mabuchi H |title=Cholesteryl ester transfer protein inhibitor (JTT-705) and the development of atherosclerosis in rabbits with severe hypercholesterolaemia |journal=[[Clin. Sci.]] |volume=103 |issue=6 |pages=587&ndash;594 |year=2002 |month=December |pmid=12444911 |doi= |url=http://www.clinsci.org/cs/103/0587/cs1030587.htm }}</ref>
 
 
 
<ref name=bennett2012>{{cite web |author=Simeon Bennett and Naomi Kresge |title=Roche Drops After Halting Cholesterol Drug Development |url=http://www.bloomberg.com/news/2012-05-07/roche-halts-testing-on-dalcetrapib-cholesterol-treatment-1-.html }}</ref>
 
 
 
<ref name=cortez2012>{{Citation |author=Michelle Fay Cortez |publication-date=November 5, 2012 |title=Roche’s Good Cholesterol Drug Shows Negative Side Effects |magazine=[[Bloomberg Businessweek]] |url=http://www.businessweek.com/news/2012-11-05/roche-s-good-cholesterol-drug-shows-negative-side-effects |accessdate=November 6, 2012 }}</ref>
 
 
 
<ref name=fayad2011>{{cite journal |author=Zahi A Fayad |author2=Venkatesh Mani |display-authors=1 |title=Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial |journal=[[The Lancet]] |volume=378 |issue=9802 |pages=1547&ndash;1559 |year=2011 |doi=10.1016/S0140-6736(11)61383-4 |url=http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61383-4/abstract }}</ref>
 
 
 
<ref name=NIH2011>{{cite web<!--statement lifted from [[High-density lipoprotein]]--> |title=NIH stops clinical trial on combination cholesterol treatment |url=http://www.nih.gov/news/health/may2011/nhlbi-26.htm |work=National Institute of Health |publisher=[[NHLBI]] |accessdate=June 2, 2011 }}</ref>
 
 
 
<ref name=parziale>{{cite web |author=Gail Parziale |title=Dalcetrapib and Anacetrapib: a Tale of Two CETPs |url=http://www.pharma-share.com/dalcetrapib-anacetrapib-tale-cetps }}</ref>
 
 
 
<ref name=Roth2010>{{cite journal |doi=10.1093/eurheartj/ehp601 |author=Stein |url=http://eurheartj.oxfordjournals.org/content/31/4/480.full |journal=[[Eur. Heart J.]] |last2=Roth |first2=EM |last3=Rhyne |first3=JM |last4=Burgess |first4=T |last5=Kallend |first5=D |last6=Robinson |first6=JG |title=Safety and tolerability of dalcetrapib (RO4607381/JTT-705): results from a 48-week trial |volume=31 |issue=4 |pages=480&ndash;4888 |year=2010 |pmid=20097702 |pmc=2821630 |display-authors=1 |unused_data=author-Stein et al. }}</ref>
 
 
 
<ref name=tfl2012>{{cite journal |author=Thomas F. Lüscher |author2=Stefano Taddei |display-authors=1 |title=Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-VESSEL randomized clinical trial |journal=[[Eur. Heart J.]] |year=2012 |doi=10.1093/eurheartj/ehs019 |url=http://eurheartj.oxfordjournals.org/content/early/2012/02/16/eurheartj.ehs019.abstract }}</ref>
 
 
 
}}
 
 


{{Lipid modifying agents}}
{{Lipid modifying agents}}


[[Category:Anilides]]
[[Category:Anilides]]
[[Category:Thioesters]]
[[Category:Thioesters]]
 
[[Category:Drugs]]
[[Category:Hoffmann-La Roche]]

Latest revision as of 13:10, 26 April 2013

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]

Overview

Dalcetrapib or JTT-705 is a CETP inhibitor which was being developed by Hoffmann–La Roche until May 2012. The drug was aimed at raising the blood levels of "good cholesterol" (cholesterol carried in HDL particles, aka HDL-C). Prevailing observations indicate that high HDL levels correlate with better overall cardiovascular health, though it remains unclear whether raising HDL levels consequently leads to an increase in cardiovascular health.

Development and Research

A 24 week clinical trial showed that dalcetrapib did increase HDL-C levels, supporting the agent's desired effect. Further, the dal-PLAQUE phase IIb trial found evidence of plaque reduction. Plaque reduction is an anticipated observation following an increase in HDL.

As of 2010 five phase II trials had started and there was no evidence of the raised blood pressure seen with torcetrapib.

dal-VESSEL phase IIb trial found no evidence of flow-mediated dilatation improvement. A 17% increase of Lp-PLA2 mass level was noted. Lp-PLA2 is associated with coronary heart disease and stroke.[1][2]

dal-OUTCOMES phase III trial passed its first interim review in July, 2011, however, development was halted on May 7, 2012 “due to a lack of clinically meaningful efficacy”. The results of dal-OUTCOMES III were published in November, 2012.[3]

References

  1. ↑ Schwartz GG, Olsson AG, Abt M; et al. (2012). "Effects of dalcetrapib in patients with a recent acute coronary syndrome". The New England Journal of Medicine. 367 (22): 2089–99. doi:10.1056/NEJMoa1206797. PMID 23126252. Unknown parameter |month= ignored (help)
  2. ↑ Phelan M, Anzures-Cabrera J, Carlile DJ; et al. (2013). "Effect of hepatic and renal impairment on the pharmacokinetics of dalcetrapib : altered distribution of the active thiol?". Clinical Pharmacokinetics. 52 (4): 255–65. doi:10.1007/s40262-013-0035-z. PMID 23400900. Unknown parameter |month= ignored (help)
  3. ↑ Bochem AE, Kuivenhoven JA, Stroes ES (2013). "The Promise of Cholesteryl Ester Transfer Protein (CETP) Inhibition in the Treatment of Cardiovascular Disease". Current Pharmaceutical Design. 19 (17): 3143–9. PMID 23317399.

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