Thursday, November 18, 2010


Back in 2006, Pfizer felt strongly that they had a blockbuster drug that will take the company for the next decade. That drug was Torcetrapid, and the clinical was Illuminate. Torcetrapid belong to a new class of drug called " Cholesteryl Ester Transfer protein inhibitor or CETP inhibitor. By inhibiting the CETP, we increase HDL-C ( the good cholesterol ), thereby protecting all of us from nasty CAD, and saving lives. So we thought. Well, 5years later, we know that Torcetrapid is removed from the market. The Illuminate study was terminated and withdrawn. Although the theory seemed straightforward and good, unexpectedly ( that is what clinical trials are for ), torcetrapid did increase HDL-C, but it also increase blood pressure and worse still, it also increase CV events including CV deaths and heart attacks. That was the end of torcetrapid. Pfizer's coffers took a big hit and they are still recovering, even as they see their lipitor and norvasc patency expire without another block-buster to fill the void.
Well, at this just concluded AHA, at their 17th Nov late breaking trial session in Chicago, Dr Christopher Cannon of Bringham and Women's hospital, Boston, presented the results of the DEFINE trial. Define stands for " Determining the Efficacy and tolerability of CETP inhibition with Anacetrapid. This trial is sponsored by MSD, on their CETP drug Anacetrapid. Well Dr Cannon ( a very senior researcher ) and colleagues studied 1,623 patients ( a modest number ), with CAD. As usual, half the patients were on placebo and the other half were on Anacetrapid. They wanted to know the effect of anacetrapid on LDL-C lowering ( primary end-point ) and HDL-C increase ( secondary end-point ). They were also observing for any adverse reaction ( having learned the lesson from ILLUMINATE ). They modest number I suppose was to limit the lost, in case it tuns out wrong again.
Well, the good news is that after 24 and 76 weeks of anacetrapid, LDL-C was reduced by about 36% and HDL-C was increased by about 138%. They were also no significant increase in blood pressure and no incrase with CV events. So yes, it is a CETP inhibitor, but without the bad CV effects of torcetrapid. This is very much a biochemistry mandated trial on surrogate CV endpoints of LDL-C and HDL-C, not truly a CVS trial on hard CV end-points of CV death, heart attacks and need for revascularisation.
Following DEFINE, MSD is planning the next big trial called " REVEAL HPS-3 TIMI-55 " to study the effects of anacetrapid on CV end-points, besides their effect on blood lipids. This will be keenly watched.
We are keen on HDL-C raisers, as this will afford CV protection, which is better then CV mitigation with lowering of LDL-C. At the moment, the only effective HDL-C raisers are the naicin group of drugs, and even with this, you have to go to high doses of naicin ( running the risk of side effects ), before you can see appreciable HDL-C increase.
Well DEFINE is certainly one of the more important clinical trials presented at AHA 2010 Chicago. Needless to say, MSD has also timed the presentation to coincide with the publication of DEFINE in the Nov 17th issue of NEJM.

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