CHICAGO (EGMN) – The experimental oral agent anacetrapib increased HDL cholesterol levels by a staggering 138%, compared with placebo, in high-risk patients and did so without the negative side effects that plagued another drug in the same class.

When compared with placebo at 24 weeks, once-daily anacetrapib increased HDL levels from 40 mg/dL to 101 mg/dL and decreased LDL levels by 40% from 81 mg/dL to 45 mg/dL in the double-blind phase III Determining the Efficacy and Tolerability of CETP Inhibition With Anacetrapib (DEFINE) trial.

“This is a total change in what lipids can be,” said senior investigator Dr. Christopher Cannon, who went one step further in a statement describing anacetrapib as having a “knock-your-socks-off effect on HDL and a jaw dropping effect on LDL” among 1,623 patients already taking a cholesterol-lower statin and had LDL levels consistent with recommended guidelines.

Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor designed to fight hypercholesterolemia by raising levels of HDL. The strategy was called into question, however, after the experimental CETP inhibitor torcetrapib was found to have off-target effects in the adrenal glands, leading to increased blood pressure, mortality and cardiovascular events.

Anacetrapib had an acceptable side-effect profile, with no effects on blood pressure electrolytes or aldosterone through 76 weeks of follow-up, Dr. Cannon, with Brigham and Women’s Hospital, Boston, reported at a press briefing at the annual scientific sessions of the American Heart Association.

The prespecified, adjudicated composite end point of death from cardiovascular causes, MI, hospitalization for unstable angina or stroke occurred in 16 anacetrapib-treated patients and in 21 placebo-treated patients.

Although the trial was not designed as an outcome study, a Bayesian analysis indicated a 94% predictive probability that anacetrapib would not increase cardiovascular events by 25% as seen with torcetrapib.

In addition, anacetrapib reduced the need for revascularization by two-thirds, compared with placebo (8 patients vs. 28 patients), a finding that Dr. Cannon said convinced him that the strategy of CETP inhibition works.

Invited discussant Dr. Thomas Luscher, professor and chair of cardiology at University Hospital, Zurich, said anacetrapib results in impressive changes in lipid profiles beyond that achieved by statins and that these changes are likely to provide prognostic benefit. It remains to be shown whether the larger HDL particles generated with CETP inhibition by anacetrapib are biologically normal.

The REVEAL follow-up trial of anacetrapib vs. placebo is being launched in Europe, North America and Asia in 30,000 patients with occlusive arterial disease, with a primary end point of coronary death, MI or coronary revascularization, Dr. Cannon announced during the press conference.

Dr. Mariell Jessup, who moderated the conference, said, “With 30,000 [patients], we’ll learn a lot more, but it’s really exciting news for patients and the potential for lowering morbidity and mortality.”

Reporters questioned whether increasing HDL really matters, to which Dr. Jessup remarked that HDL is a potent marker of risk and that older data showed that niacin, which also works by increasing HDL, decreased the need for revascularization. Two trials of niacin are also underway that may provide more contemporary data.

Although niacin, which can be hard for some patients to tolerate, had pronounced effects on LDL and HDL, they “paled in comparison to DEFINE,” said Dr. Jessup of the University of Pennsylvania, Philadelphia.

There is some concern that the drug might be too powerful and potentially push levels too low, as 18% of patients had to discontinue treatment after their LDL cholesterol level fell below 25 mg/dL.

“It’s an ongoing question in every lipid trial we do whether it could get too low, and we’ve not seen it yet,” Dr. Cannon said, adding that when managing patients on both drugs one could simply reduce the level of statin therapy. He does not foresee front-line monotherapy with anacetrapib, but rather using it as an add-on to statins or as an option in patients unable to tolerate statins.

But Dr. Suzanne Oparil said the question of whether anacetrapib could potentially replace statins as first-line treatment should be an open one. “Potentially, why not?” she remarked in an interview. “They’re being very cautious because statins are mandated for anyone with any hint of cardiovascular disease or risk. But working things out, and particularly if it’s shown that getting the LDL too low – as you can by combining this drug with a statin – is bad, then conceivably this could take over for a statin.” Dr. Oparil is professor of medicine, physiology, and biophysics and director of the vascular biology and hypertension program at the University of Alabama, Birmingham

Follow-up from REVEAL is planned in 4 years, which means that barring any new safety signals, anacetrapib would be submitted for approval in about 2015, Dr. Cannon said in an interview.

Results of DEFINE were published online simultaneously with Dr. Cannon’s presentation (N. Engl. J. Med. 2010 [doi:10.1056/NEJMoa1009744]).

DEFINE was supported by Merck Research Laboratories. Dr. Cannon and his co-authors report financial relationships with several pharmaceutical firms including Merck. Dr. Cannon also serves as an advisor and holds equity in Automedics Medical Systems.

Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

芝加哥(EGMN)——波士顿布赖海姆妇女医院的Christopher Cannon博士在美国心脏学会科学年会上报告称，试验新药anacetrapib与安慰剂相比，可使高危患者高密度脂蛋白胆固醇(HDL-C)水平升高138%，且未见同类药物的副作用(N. Engl. J. Med. 2010 [doi:10.1056/NEJMoa1009744])。

Anacetrapib为胆固醇酯转运蛋白(CETP)抑制剂，通过升高HDL以治疗高胆固醇血症。但此前对同类药物torcetrapib的研究发现，由于其对肾上腺具有脱靶效应，可导致血压升高等副作用。为考察 anacetrapib的有效性和耐受性，研究者对1,623例已经服用他汀药物且LDL水平达到推荐指南的患者进行了DEFINE试验。

结果显示，与安慰剂相比，每日服用1次anacetrapib 持续24周，可使患者HDL-C从40 mg/dL 升至101 mg/dl，而使低密度脂蛋白胆固醇(LDL-C)从81 mg/dl降至 45 mg/dl，降低40%。Anacetrapib的副作用尚可接受，在76周的随访过程中未见对血压、电解质或醛固酮产生影响。Anacetrapib组和安慰剂组分别有16例和21例患者达到预先设定、调整后的复合终点，即心源性死亡、心肌梗塞、因不稳定心绞痛住院或卒中。贝叶斯分析显示，Anacetrapib不增加心血管事件的预测概率为94%，而torcetrapib为25%。此外，与安慰剂组相比，anacetrapib组患者需要血运重建的例数降低2/3(8 例对 28 例)。但是，18%的患者当LDL-C低于25 mg/dl时不得不停药。

研究表明， anacetrapib可显著升高 HDL-C和降低LDL-C，且安全性良好，有望成为他汀类药物的附加药物或作为他汀类药物不耐受患者的另外选择。

DEFINE试验由默克研究实验室资助。研究者声称与多家制药公司存在经济关系。

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