Sunday, February 1, 2009

A CETP Phoenix Rising from the Ashes of Torcetrapib?

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!

Looking out for your heart health,



Anonymous said...

HH- If Roche is already in Phase 3 clinical studies doesn't that suggest that its cetp agent could be on the market relatively soon? If they got past Phase 2 that should indicate that dalceptrapib was found not to be harmful to humans who took it in clinical studies? Phase 3 is designed to determine efficacy and dosage so it would seem as though we are somewhat close to having a cetp agent on the market. Any idea when Roche might introduce this to the market?

That is really interesting stuff about one SNP being responsible for an increase of 3.2 mg/dL of HDL-C yet reducing heart attack risk by 24%. I wonder whether someone will develop an easy test to determine who has these variants and whether the drug companies will target treatments designed to simulate the effect of such a SNP for those people who lack the variant.

HeartHawk said...

Dear Anonymous:

The dalcetrapib Phase III trial is scheduled for completion in February of 2012.

Regarding gene testing, the market is exploding! I have no doubt this one wil find its way into the home test market!


roaminghermit said...

Yea and the simple stuff like getting on thyoid 1 1/2 gr is still ignored...too cheap at $11 pre month...66 is getting old...50's still young...LOL

Indian Pharmacy said...

I hope that there can be found very positive results after the gene investigation and pharmaceutical research so that many people can benefit from them, in the health sense of course

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