JTT-705: is there still future for a CETP inhibitor after torcetrapib? (wikipedia.org)
PARIS, France-The experimental agent dalcetrapib appears to raise high-density lipoprotein (HDL) cholesterol levels by inhibiting cholesterol ester transfer protein (CETP) activity without adversely affecting blood pressure or endothelial function, according to phase II trial data presented Sunday, August 28 at the European Society of Cardiology Congress 2011. (tctmd.com)
According to discussant Keith A. A. Fox, MD, of the University of Edinburgh (Edinburgh, Scotland), researchers were eager to find a CETP inhibitor that showed efficacy without dangerous side effects, because a previous agent, torcetrapib, reached phase III trials before being dropped because of an increase in deaths. (tctmd.com)
Dalcetrapib is a cholesteryl ester transfer protein (CETP) inhibitor - the first CETP inhibitor, Pfizer's torcetrapib, was a high-profile failure back in 2006, with trials stopped because the drug raised blood pressure. (chemistryworld.com)
We always knew dalcetrapib was an extremely weak inhibitor of CETP,' says Stanley Hazen, section head of preventive cardiology and cardiac rehabilitation at the Cleveland Clinic. (chemistryworld.com)
Dalcetrapib has clearly been hit a mortal blow, but I don't think the CETP inhibitor as a class of drug has yet. (chemistryworld.com)
With the presentation of the dal-OUTCOMES trial at the American Heart Association in Los Angeles andsimultaneous publication in the New England Journal of Medicine, dalcetrapib joins torceptrapib on the list of once-promising CETP inhibitors. (cardiobrief.org)
Roche announced today that it had ended development of dalcetrapib, its entry in the once-promising class of HDL-raising CETP inhibitors. (cardiobrief.org)
Evacetrapib4
These drugs have generally failed in clinical trials, either causing a marked increase in deaths (torcetrapib), or having no meaningful clinical improvement despite HDL increases (dalcetrapib, evacetrapib). (wikipedia.org)
Of the other two drugs, dalcetrapib was as ineffective as evacetrapib at preventing cardiovascular events, while torcetrapib increased risk. (upi.com)
He acknowledged that there were safety concerns torcetrapib, efficacy concerns with dalcetrapib, and investigations of evacetrapib were "stopped early" and represent a "wasted opportunity. (medscape.com)
Efficacy2
citation needed] Dalcetrapib, development halted in May 2012 when Phase III trials failed to show clinically meaningful efficacy. (wikipedia.org)
Beginning in 2015, the efficacy of dalcetrapib in the genetic sub-population was being investigated in the dal-GenE trial. (wikipedia.org)
Cardiovascular events1
In patients with the rs1967309 'AA' genotype, there was a significant reduction in the rate of cardiovascular events in the dalcetrapib arm whereas non-carriers were at increased risk. (wikipedia.org)
Roche2
Patients were randomized to receive 600-mg dalcetrapib (R. Hoffman-La Roche, Basel, Switzerland) or placebo for 36 weeks. (tctmd.com)
The failure of dalcetrapib, a drug from Roche designed to raise HDL, or 'good', cholesterol, has turned the spotlight again on such drugs. (chemistryworld.com)
Genetic1
In 2015, a pharmacogenomic sub-study of the dal-OUTCOMES clinical trial on 5,749 individuals identified a genetic variant in the ADCY9 gene which modulates response to dalcetrapib. (wikipedia.org)
Cholesterol2
Total cholesterol levels were 3.945 ± 0.665 mmol/L in dalcetrapib patients and 3.802 ± 0.563 mmol/L in placebo patients, while HDL cholesterol levels were 1.013 ± 0.190 mmol/L and 0.995 ± 0.185 mmol/L, respectively. (tctmd.com)
The HDL elevation is substantially lower with dalcetrapib and, more importantly, there was no LDL ['bad' cholesterol] reduction. (chemistryworld.com)
Patients2
Now dalcetrapib will be tested in a larger trial of 14,000 patients, Dr. Lüscher reported, with results expected by around 2013. (tctmd.com)
Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: The dal-VESSEL randomized clinical trial. (tctmd.com)
Drug3
Ray said that, in contrast, obicetrapib is the "most potent" drug in the class, has "none of the off-target effects of torcetrapib and, after stopping, is not retained in the body," making it a "viable option. (medscape.com)
Torcetrapib, at that time, the most expensive drug ever developed raised HDL just as promised, but failed to reduce heart disease. (thefastingmethod.com)
The drug dalcetrapib raised HDL an impressive 40%, but also failed to deliver any heart benefits. (thefastingmethod.com)
Failure1
The failure of torcetrapib: what have we learned? (wikipedia.org)
Rs19673093
In their genomewide-association study, which is published January 12, 2015 in Circulation: Cardiovascular Genetics , the researchers identified a single nucleotide polymorphism (SNP) on chromosome 16 in ADCY9 that was associated with cardiovascular events among patients treated with dalcetrapib (rs1967309). (medscape.com)
Again, individuals homozygous for rs1967309 showed a significant reduction in IMT when treated with dalcetrapib. (medscape.com)
In patients with the rs1967309 'AA' genotype, there was a significant reduction in the rate of cardiovascular events in the dalcetrapib arm whereas non-carriers were at increased risk. (wikipedia.org)
Investigators1
In a new genetic analysis of the dal-OUTCOMES trial , as well as the dal-PLAQUE-2 imaging study, investigators suggest a benefit of dalcetrapib might exist in a group of patients with a certain genetic profile. (medscape.com)
ADCY93
Indeed, several polymorphisms in the ADCY9 gene influenced the effects of dalcetrapib on cardiovascular clinical outcomes and changes over time in carotid atherosclerosis . (medscape.com)
When they stratified by genotypes in the dalcetrapib arm, individuals homozygous with the AA genotype (minor allele) in ADCY9 had a statistically significant 39% relative reduction in the risk of the composite end point of coronary heart disease death, resuscitated cardiac arrest, nonfatal MI, nonfatal stroke , unstable angina , or urgent coronary revascularization compared with placebo. (medscape.com)
In 2015, a pharmacogenomic sub-study of the dal-OUTCOMES clinical trial on 5,749 individuals identified a genetic variant in the ADCY9 gene which modulates response to dalcetrapib. (wikipedia.org)
Clinical3
As reported previously by heart wire , the dal-OUTCOMES study, which was published in 2012 in the New England Journal of Medicine , showed dalcetrapib raised HDL-cholesterol levels 30% but did not reduce clinical events among the nearly 8000 ACS patients who received the drug. (medscape.com)
These drugs have generally failed in clinical trials, either causing a marked increase in deaths (torcetrapib), or having no meaningful clinical improvement despite HDL increases (dalcetrapib, evacetrapib). (wikipedia.org)
Failed: Torcetrapib, failed in 2006 due to excess deaths in Phase III clinical trials. (wikipedia.org)
Trial1
Next, the researchers evaluated samples from the dal-PLAQUE-2 study, an imaging trial showing that dalcetrapib did not positively alter atherosclerosis as measured by carotid intima-media thickness (IMT). (medscape.com)
Development1
citation needed] Dalcetrapib, development halted in May 2012 when Phase III trials failed to show clinically meaningful efficacy. (wikipedia.org)