Earlier this week, Merck announced that Vytorin, a combination pill made up of Zetia and a statin, Zocor, reduced heart attacks and strokes more than Zocor alone in high-risk heart disease patients. These results came from the IMPROVE-IT clinical trial, which involved 18,000 patients studied over seven years. The 6% decrease in cardiovascular events was attributed to Vytorin’s superior LDL-lowering ability as those treated with Vytorin had an average LDL of 53mg/dL compared to those on Zocor who had an average of 70mg/dL.
Many view these results as a confirmation of the hypothesis that, when it comes to LDL cholesterol, “lower is better”. Others further speculated that these results would cause the FDA to become more lenient in approving all LDL-lowering drugs in advance of having to prove by way of an IMPROVE-IT-style outcome study that such a new LDL-lowering agent would share Vytorin’s risk-reducing profile. It is not at all certain that the FDA will move in such a direction.
Merck has yet another cardiovascular outcome study underway called REVEAL (“Randomized EValuation of the Effects of Anacetrapib through Lipid-modification”). The purpose of this study is to determine whether anacetrapib, a CETP inhibitor that has profound effects in raising HDL (the so-called “good cholesterol”), when combined with atorvastatin (the generic version of Lipitor), can further reduce heart attacks and strokes over atorvastatin alone in at-risk patients. This is a very big study with more than 30,000 patients enrolled. REVEAL began in 2011 and the estimated completion date, as reported on ClinicalTrials.gov, is January, 2017. For those concerned with the cost of developing new drugs, the REVEAL study is likely costing Merck as much as a half a billion dollars.
For the most part, people have dismissed REVEAL and other studies involving experimental drugs that elevate HDL. This is due to the fact that a variety of HDL elevating drugs including two other CETP inhibitors –
But beyond its HDL effects, anacetrapib also lowered LDL in the DEFINE patients well over the effects of atorvastatin. Those on atorvastatin alone had an average LDL of 77 mg/dL and those on anacetrapib plus atorvastatin had an average LDL of 49mg/dL. This 40% drop in LDL is better than that seen in IMPROVE-IT both in magnitude and degree of lowering. Does this mean that REVEAL will be as positive as IMPROVE-IT? That’s not easy to predict since it is hard to gauge the impact that anacetrapib’s HDL elevation will have. To date, experimental drugs that raise HDL have not shown long-term benefits.
Despite the fact that anacetrapib lowers LDL at least as well as Vytorin did in IMPROVE-IT, the FDA would never approve anacetrapib based solely on LDL lowering. This is a new experimental agent and the results of REVEAL are needed before the FDA can act. This is not an unreasonable position. It will be interesting to see how the FDA will respond to other experimental LDL-lowering agents. Will the results of outcome studies be needed for those drugs as well?
Regardless of how REVEAL turns out, the world of cardiovascular medicine should be appreciative of Merck’s efforts. Sure, Merck has a lot to gain if REVEAL is successful, as anacetrapib will become a major new drug. However, in the IMPROVE-IT and REVEAL studies, Merck probably invested close to a billion dollars with no assurance that either study would have a favorable outcome. Yet the knowledge gained in understanding the consequences of lipid modulation is invaluable to cardiologists and the patients that they are treating. It must be stated that such studies can only be done by a big pharmaceutical company like Merck. These type of studies cannot be funded by the NIH nor small to midsize companies. They simply can’t afford them.
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