Can any drug be better than Atorvastatin in improving the cholesterol profile of patients? The industry was betting on a class of drugs known as CETP inhibitors until it got burnt by Pfizer’s (PFE) Torcetrapib. But Merck may have given this class of drugs a new life.
CETP stands for cholesterol ester transfer proteins. These proteins transfer cholesterol from high density lipoproteins (HDL, the “good” cholesterol) to low density lipoproteins (LDL, the “bad” cholesterol). Under natural circumstances, the transferred cholesterol in LDL either gets oxidized (after being converted sequentially to LDL 1, 2, 3, and 4) or is converted to intermediate density lipoprotein (IDL) and then to very low density lipoprotein (VLDL), then taken up by the liver and degraded. CETP’s role is curious, since those with a genetic defect resulting in a congenital abnormality or absence of CETP actually live longer, with a lower incidence of cardiovascular events and a decreased incidence Alzheimer’s Disease. Naturally, inhibiting CETP became a logical target for drug development.
Pfizer was the first out of the gate with Torcetrapib. Data from two important phase III studies included
- ILLUMINATE study (18 months or approximately 78 weeks) in subjects on background Atorvastatin that showed greater than 20% decrease in LDL and a more than 60% increase in HDL. Unfortunately, it also showed an increase in BP (4.6 mm systolic) and an increase in mortality (of about 60%) over atorvastatin alone.
- ILLUSTRATE study that showed no difference in atheroma volume as measured by ultrasound between subjects who were treated with Atorvastatin alone compared to the combination of the statin with Torcetrapib.
Needless to say, the results were discouraging – falling into the category of the surgery being successful but the patient dying. The cause for this outcome was unclear – especially since those with congenital CETP deficiency live longer and don’t have high BP. An editorial in the New England Journal of Medicine (Alan R. Tall, N Engl J Med 2007; 356:1364-1366 March 29, 2007) speculated that the results were most probably drug and not mechanism related, with possible culprits including an effect on the rennin angiotensin system. It was also speculated that the dose of Torcetrapib was actually too low – something we will probably never know for sure since it is very unlikely that this drug will be given to humans again.
Many had given up on this class of drugs, but Merck (MRK) recently announced the results of its own CETP inhibitor. At the American Heart Association meeting on Nov 17, 2010, results of the Phase III DEFINE study was released. At a dose of 100 mg a day for 76 weeks, AnacEtrapib (on a back ground statin) decreased LDL by 39% and increased HDL by 130%. It also increased ApoA1 by 45%, decreased ApoB by 21% and Lp(a) by 36% compared to placebo. In marked contrast to the Pfizer study, there was no increase in BP or mortality. There was no increase in serious adverse events or adverse events compared to placebo. The two year long term follow up ends in 2012.
The data are certainly encouraging. So will Merck succeed where Pfizer did not? It is still too early to say, but there are two key reasons to think it may:
- In phase II studies, Torcetrapib showed an increase in BP, whereas AnacEtrapib has not shown any such effect in any study.
- By approximately 78 weeks, Torcetrapib had already shown a statistically significant effect on BP and mortality. In contrast, by 76 weeks, AnacEtrapib has shown no such effects.