Anacetrapib for Increasing HDL—New Hope for CETP Inhibitors?

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In mid-2017, Merck announced favorable results with their REVEAL trial, a pivotal outcomes study with their investigational drug, anacetrapib. Anacetrapib is designed to increase  HDL cholesterol (“good” cholesterol) levels. Merck’s press release stated that, when added to  statin therapy, anacetrapib significantly reduced the incidence of cardiovascular events in patients who were at  elevated risk for heart disease.

The announcement came as a big surprise to most cardiologists.

Why a Surprise?

Anacetrapib is cholesterol ester transfer protein (CETP) inhibitor, a class of drugs specifically designed to greatly increase blood levels of HDL cholesterol. Because elevated HDL cholesterol levels have long been associated with reduced cardiovascular risk, experts long believed that drugs that inhibited CETP would prove to be highly beneficial in people whose cardiovascular risk is high.

Accordingly, since the 1990s various drug companies have spent billions of dollars developing and testing several CETP inhibitors. Cardiovascular experts and investors alike were nearly unanimous in thinking that at least a few of the CETP inhibitors would become blockbusters.

It has not turned out that way. In fact, for several years before the 2017 Merck announcement, the CETP inhibitors had come to be universally regarded as one of the most costly “busts” in pharmaceutical history.

Even with Merck’s preliminary declaration of success with anacetrapib, many experts remain skeptical that the CETP inhibitors in general, or anacetrapib in particular, will have much of a positive impact on people’s lives, or on any drug company’s profits.

A Brief History of CETP Inhibitors

Inhibiting the CETP enzyme became an attractive target for drug makers in the 1990s, when it was learned that rodents lacking CETP had high HDL levels and resistance to  atherosclerosis.

Soon thereafter (once researchers began looking for them), several people were also identified who had mutations in their CETP gene that turned out to be associated with high HDL levels and a greatly reduced risk of  coronary artery disease (CAD).

The implication was obvious: Simply design drugs that inhibit CETP, and you will elevate HDL levels and thereby reduce cardiovascular disease. With great effort and at great expense, several drug companies launched major programs to do just that. And by the mid-2000s, clinical testing with several promising CETP inhibitors was begun, to great fanfare and the enthusiastic counting of pre-hatched chickens.

So the surprise was real when, for over a decade, the results of clinical trials with CETP inhibitors were (to say the least) disappointing.

The first drug to fail was torcetrapib (Pfizer), in 2006. In the ILLUMINATE trial, people from a high-risk population were randomized to receive either torcetrapib or placebo (along with a statin). The CETP inhibitor seemed to do what everyone wanted it to do: people receiving torcetrapib had a 72 percent increase in HDL levels, and a 24 percent decrease in LDL cholesterol—so a great reduction in cardiovascular events was anticipated.

However, the opposite happened. By the end of the study, people randomized to torcetrapib actually had a 25 percent  increase  in cardiovascular events, and a 58 percent increase in deaths. Pfizer quickly abandoned torcetrapib.

Experts expressed widespread, stunned surprise at this negative result. The surprise turned to resignation over the following years, as other CETP inhibitors under development also failed to improve outcomes, despite producing very large increases in HDL cholesterol.

In 2012, Hoffman-La Roche stopped development of their CETP inhibitor, dalcetrapib, when an interim analysis of their large clinical trial showed no clinical benefit.

And in 2015 Eli Lilly stopped their development of evacetrapib, for the same reason.

By 2015, almost everyone believed that pursuing CETP inhibitors had become a blind alley. Indeed, Merck considered stopping their REVEAL trial with anacetrapib at that time, but finally elected to keep going.

By the time Merck made its June, 2017 announcement, it was the apparent success of a CETP inhibitor, not its failure, that turned out to be the surprise.

Either Way, Nobody Should Really Be Surprised

If we were to take a close look at what is known about HDL  lipoproteins  and CETP, the “surprising” outcomes seen with the various CETP inhibitors would not be so much of a surprise.

It turns out that the actions of the CETP enzyme are very complex, and it has various effects on not only HDL cholesterol, but also LDL cholesterol, and on other aspects of lipid metabolism. Due to this complexity, it really can’t be predicted ahead of tome what effect a reduction in the CETP enzyme will have on clinical outcomes. The research literature actually provides plenty of evidence that CETP inhibition might make things worse under certain circumstances.

For instance, while (as we have noted) some people with a genetic reduction in CETP activity have a high HDL levels and a reduced risk of cardiovascular disease, it turns out that others who have a different type genetic reduction in CETP have high HDL levels but an  increased  risk of heart disease. It appears that the CETP enzyme can sometimes promote, and sometimes protect from, accelerated atherosclerosis, depending on a person’s genetic profile, on their metabolic state, and probably on other factors. 

To illustrate this point, researchers appear to have identified a subset of people from the ILLUMINATE trial who had a certain genetic profile, in whom torcetrapib reduced cardiovascular risk (despite the fact that this drug worsened outcomes in the overall population). Perhaps the successful use of CETP inhibitors will require the careful selection of patients, using genetic and/or metabolic profiling.

The point is, the success or failure of CETP inhibition is complex and multifactorial, and anyone claiming to be “surprised” by clinical outcomes with any of these drugs probably fails to understand how complicated this problem is turning out to be.

Will Anacetrapib Turn Out to Be a Big Deal?

In the REVEAL trial, over 30.000 people with atherosclerotic vascular disease were randomized to receive either anacetrapib plus high-dose atorvastatin or atoravstatin alone. After four years, there was a 9% reduction in cardiovascular risk in those receiving anacetrapib. The outcome measured in the REVEAL study was a composite of death from CAD,  heart attack, and a requirement for coronary artery revascularization (that is,  bypass surgery  and/or a  stent ). There was no reduction in overall mortality, however. 

In a press release, Merck indicated that they will “consider whether to file” for drug approval with the FDA. This apparent reticence is unusual for a drug company press release announcing a successful clinical trial. It is likely a tacit acknowledgement that the magnitude of benefit from anacetrapib appears somewhat marginal, at least when compared with unknown risks from long-term therapy with this drug. 

Anacetrapib is stored for long periods of time in fat cells, and thus remains in the body for a long time. This might turn out to be a major concern if, say, rare but serious toxicity is eventually discovered. This factor is one which the company will have to “consider” as it decides whether to move forward.

So it seems questionable that Merck expects big things from this drug, and it seems particularly unlikely that anacetrapib will at last become the blockbuster CETP inhibitor that everybody once expected.

Right now it seems more likely that anacetrapib may become, if anything, a niche agent in the management of cardiovascular risk.

A Word From Verywell

Merck’s announcement of a successful outcome in their clinical with the CETP inhibitor anacetrapib, while encouraging, should be regarded circumspectly at this time. 

Given the disappointing history of other CETP inhibitors, some of the peculiarities of this particular drug, and the fact that Merck itself seems undecided about the drug, we should not become too excited at this point about anacetrapib as an important new way to reduce cardiovascular risk.

Sources:

Kosmas CE, DeJesus E, Rosario D, et al. CETP Inhibition: Past Failures and Future Hopes. Clinical Medicine Insights: Cardiology 2016:10 37-42 doi: 10.4137/CMC.S32667.

The HPS3-TIMI55-REVEAL Collaborative Group. Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease (REVEAL). N Engl J Med 2017;doi:10.1056/HEJMoa170664.

 

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