Whitehouse Station, NJ - The first clinical trials with Merck's new cholesteryl ester transfer protein (CETP) inhibitor, anacetrapib, have shown impressive effects on raising HDL and lowering LDL, with no signs of any increase in blood pressure, raising hopes that this drug may not suffer from the toxicity seen with the first CETP inhibitor developed—Pfizer's torcetrapib.

The two phase 1 studies, published in the December 8, 2007 issue of the Lancet, were conducted by Merck researchers. They conclude: "Anacetrapib seems to exhibit HDL-C increases greater than those seen with other investigational drugs in this class and LDL-C-lowering effects similar to statins. Despite greater lipid-altering effects relative to other members of this class, anacetrapib seems not to increase blood pressure, suggesting that potent CETP inhibition by itself might not lead to increased blood pressure."

The results have been greeted with cautious optimism from experts in the field, who are urging that further trials should now be conducted with this agent, although they are still wary of other possible adverse effects of CETP inhibition. Dr Prediman Shah (Cedars-Sinai Medical Center, Los Angeles, CA) commented to heartwire: "Most of us in this field are concerned about CETP as a strategy, but the upside is so good that it does deserve further study."

In the first study, 50 patients with dyslipidemia (LDL-C 100-190 mg/dL) received anacetrapib at doses of 0, 10, 40, 150, or 300 mg orally or placebo once a day for 28 days. The drug was given with a meal, as it appears to be more effective when taken with food. Anacetrapib produced dose-dependent increases in HDL and reductions in LDL, with maximum effects of a 129% increase in HDL and a 38% decrease in LDL seen at the 150-mg and 300-mg doses. The researchers say that a dose of 150 mg with a meal seemed to be "at or near the plateau for these pharmacodynamic effects."

In the second study, which had a crossover design, 22 healthy participants received either 150 mg of anacetrapib once a day or matching placebo with a meal for 10 days in each crossover period. Continuous 24-hour ambulatory blood-pressure monitoring was done the day before treatment started and on day 10 of each treatment period. Results showed that anacetrapib had no significant effect on ambulatory 24-hour mean systolic and diastolic blood pressure compared with placebo.

The researchers write: "Despite the small sample size, the apparent lack of increase in blood pressure with anacetrapib is relevant in the context of its relatively higher lipid-altering effects compared with either torcetrapib or JTT-705 [a CETP inhibitor in development by Japan Tobacco/Roche]. These results are consistent with our preclinical investigations comparing the blood-pressure effects of anacetrapib and torcetrapib in rhesus monkeys, where it seemed that torcetrapib was associated with increased blood pressure, whereas anacetrapib was not."

They note, however, that the complete molecular mechanism behind torcetrapib's negative effects on blood pressure and mortality are still not completely understood. But they add: "Given no reported association between CETP deficiency and hypertension, our findings support the hypothesis that CETP inhibition itself might have no detrimental effects on blood pressure and that the blood-pressure-raising effect reported with torcetrapib in humans is perhaps compound-specific. Only continued assessment of anacetrapib in larger clinical studies can confirm the apparent lack of blood-pressure finding seen in our study."

In an editorial accompanying the paper [2], Dr Patrick Duriez (INSERM, Lille, France) says, "The short-term safety of anacetrapib . . . (which needs to be confirmed in the longer term) opens new perspectives in the study of the effect of CETP inhibition on atherogenesis and cardiovascular risk and may resuscitate the hope that CETP inhibitors could be an important new class of drugs that normalize lipidemia."

But he also points out that long-term studies in larger populations will be necessary to confirm the absence of an off-target effect on blood pressure with anacetrapib. "This prudence is necessary because torcetrapib and anacetrapib are in the same structural class and because the effect of torcetrapib on systolic blood pressure was found in large long-term studies; the effect was lower and even not statistically significant in phase 2 studies," he writes.

Noting that part of torcetrapib's toxicity is now believed to be due to aldosterone production, Duriez states: "An important proof of absence of toxic effects with anacetrapib on blood-pressure regulation would involve having data on aldosterone production and the expression of genes coding for mineralocorticoid biosynthesis in the adrenal glands. If anacetrapib truly lacks such off-target effects, this molecule would be a good tool to study whether CETP inhibition decreases or increases cardiovascular risk."

Duriez also warns that although it has been shown that HDL from torcetrapib-treated patients induced a modestly higher in-vitro efflux of cellular cholesterol compared with controls, which indicates that the first step of reverse cholesterol transport may be improved by torcetrapib, the relevance of this in-vitro test for human disease is unknown, and modified HDL produced by CETP inhibition could still have deleterious effects via many other mechanisms.

Commenting on the new data for heartwire, Dr Alan Tall (Columbia University, New York) said that these studies suggest that anacetrapib does not have hypertensive side effects and is more potent than other reported CETP inhibitors, in terms of HDL raising and LDL lowering. "Therefore, they provide considerable encouragement for carrying out further clinical evaluation of the safety and efficacy of this class of drug."

Dr Daniel Rader (University of Pennsylvania School of Medicine, Philadelphia) told heartwire that he does not believe anacetrapib will have any adverse effect on blood pressure. "This is the first published peer-reviewed study that shows that effective CETP inhibition in humans does not raise blood pressure. That is a very important finding. This and many animal studies with this drug that have also not shown any effect on blood pressure support the concept that the blood-pressure increases seen with torcetrapib were not mediated by inhibition of CETP, but by some other mechanism. Yes, the numbers of patients in these current Lancet studies are small, but I've seen quite a lot of data with anacetrapib, and I'm quite confident that this compound does not affect blood pressure."

Rader was also enthusiastic about the lipid changes seen with anacetrapib. "The lipid changes in these studies—an increase in HDL of more than 100% and a reduction in LDL of almost 40%—are very impressive. That is more than what was seen with the dose of torcetrapib selected for large-scale trials. The LDL lowering alone is similar to that of a medium-dose statin and would probably be additive to a statin. So you could make a case for using a drug with this profile just for its LDL lowering to add on to statin therapy, even without the 100% increase in HDL levels."

Rader explained that the LDL lowering would probably be beneficial, as it is believed that lowering LDL is antiatherogenic no matter how it is reduced. But the same thing is not known for raising HDL. "The big issue for me is whether the HDL increase brought about by CETP inhibition with this compound and others will be antiatherogenic," he said. "But I am encouraged by these data, and I hope that Merck does move forward with this drug now. I would love to see whether the lipid changes associated with a 'clean' CETP inhibitor, which this appears to be, would be protective," he added.

Shah also believes larger-scale trials are warranted, although patients would have to be monitored very closely for adverse effects. "Whether the HDL produced by CETP inhibition is protective or harmful is still not known and is a critical issue. I am worried about the excess of deaths from infection and cancer seen with torcetrapib in ILLUMINATE. It hasn't been ruled out that these were not caused by a CETP effect. There are many proteins carried on the HDL molecule that play a role in the immune system, and changing the composition of HDL could affect this. The only way to know for sure is to go ahead with a large clinical event trial. But the stakes are so high and the rewards would be so great if it were successful that I would not discard the whole class of drugs at this point. I think another trial with a different drug needs to be done." He believes Merck will now go ahead with larger studies, and he noted that Roche is also moving ahead with its CETP inhibitor.

Shah added that he would like to know what happens to CRP with anacetrapib. "In the early trials with torcetrapib, despite good lipid changes, CRP did not go down. That was a red flag for me," he said.