A CETP Phoenix Rising from the Ashes of Torcetrapib?
Posted Feb 02 2009 10:53pm
Gene investigation and pharmaceutical research may be working together to revive cholesterol ester transfer protein (CETP) inhibition as a means of combating heart disease. The failure (both therapeutic and financial) of Pfizer's novel CETP inhibition agent "torcetrapib" literally pushed Pfizer off the heart drug development cliff and with it perhaps the finest heart drug research team in existence.
But recently, the Women's Genome Health Study led by Dr. Paul M Ridker has discovered variants in the gene for CETP that impact heart attack risk. They note that the risk is partially but not completely reduced by a rise in HDL. Torcetrapib was found to raise blood pressure (BP) along with other adverse effects such as effects on aldosterone. It was thought that these effects overwhelmed the postive effect of raising HDL. This new study raises the hope that the negative effects were only peculiar to torcetrapib but not other similar agents.
Merck's anacetrapib and Roche's dalcetrapib are two potentional CETP inhibitors in Phase 2 and Phase 3 trials repectiviely that do not exhibit the toxic effects found with torcetrapib. Dr. John Kastelein, who is involved with both trials added, "When you have a number of patients in different clinical studies and there is still doubt about whether the mechanism works at all, research such as this by Ridker et al is good . . . torcetrapib was about the worst choice Pfizer could have made. They thought a few millimeters of mercury were nothing compared with the immense power of a 70% increase in HDL-C. But everyone was lulled to sleep—no one understood at the time that the elevation of blood pressure was only the tip of the iceberg and below that was a whole metabolic derangement that was extremely harmful."
The Women's Genome Health study was divided into two parts. First, they looked for common genetic variants associatied with HDL. Baseline HDL was measured among the 18,245 particpants (caucasion females at or above 45 years of age) who were followed for ten years. They discovered nine locations in the genome with at least one genetic variant or SNP (single nucleotide polymorphism) that were associated with HDL. Eight of these locations were already known to influence HDL, but one was new.
The second and most important part of the work found that among all the SNPs associated with raising HDL, all those linked to lowering heart attack risk were found on the CETP gene sequence. Whenever a CETP SNP raised HDL it also reduced heart attack risk. One such CETP SNP (rs708272) was associated with a 3.2 mg/dL increase in HDL and a 24% lower risk of heart attack. Such as small HDL increase should not produce such a profiund reduction in risk. Something else is clearly going on!
Perhaps this is not the end of the line for CETP agents that some had predicted. The Phoenix may be rising!