Can HDL-raising drugs be a big field after all?

 

Atherosclerosis. From Nephron. http://bit.ly/jL6Zos

 

In the April 29, 2011 issue of Cell, there is a Leading Edge review entitled “Macrophages in the Pathogenesis of Atherosclerosis”, by Kathryn J. Moore (New York University Medical Center, New York, NY ) and Ira Tabas (Columbia University, New York, NY). This 15-page  review (including 4 pages of references) covers a big subject–the central role of the macrophage in the pathogenesis of atherosclerosis, and of the resulting acute thrombotic vascular disease, including myocardial infarction, stroke, and sudden cardiac death. The review will be helpful to those who wish to update their knowledge of the mechanistic basis of atherothrombotic disease, or to those who want an introduction to the subject.

Included in the review is a discussion of the role of high-density lipoprotein (HDL), or “good cholesterol” in promoting regression of atherosclerotic plaques. HDL, as well as the protein component of HDL, apolipoprotein A1, are key players in the process of cholesterol efflux, or removal of cholesterol from macrophages in atherosclerotic plaques. HDL may also have other beneficial roles, including prevention of subendothelial apolipoprotein B-lipoprotein (apoB-LP) retention (which starts the atherosclerotic process in the first place), decreasing activation of endothelial cells, and reducing LDL oxidation. (ApoB is the protein component of low-density lipoprotein [LDL], or “bad cholesterol”.) In human populations, low HDL is generally recognized as a major cardiovascular risk factor, and high HDL is recognized as being protective.

In its discussion of therapeutic strategies based on our current picture of the mechanistic basis of atherosclerosis, the authors of the review state that the most effective way to treat the condition would be to decrease subendothelial apoB-LP retention by lowering apoB-LPs in the blood via lifestyle changes and drugs. In order to completely prevent atherosclerosis, serum apoB-LPs (i.e., mainly LDL and VLDL [very low-density lipoprotein]) would need to be lowered below the threshold level required for subendothelial apoB-LP retention in the arteries. However, in Western societies (and in other societies that have been rapidly adopting Western lifestyles), initiation of atherosclerotic lesions occurs in the early teens; thus this preventive approach is not currently feasible.

The leading drugs for lowering serum LDL are the statins, such as atorvastatin (Pfizer’s LIpitor, which is the largest-selling statin; Lipitor will go off-patent in November 2011), pravastatin (Bristol-Myers Squibb’s Pravachol, generics), simvastatin (Merck’s Zocor, generics), and rosuvastatin (AstraZeneca’s Crestor). Statins are generally accepted as being effective in decreasing mortality in patients with cardiovascular disease (CVD). These drugs are also widely prescribed for patients with a high risk of developing CVD; i.e., patients with high LDL, type 2 diabetes, and/or other risk factors. However, some researchers question the value of statins in primary prevention in patients without preexisting CVD but at high risk of developing the disease. For example, a 2010 meta-analysis published in the Archives of Internal Medicine did not find evidence that statin therapy was beneficial in primary prevention of all-cause mortality in patients at high risk of developing CVD. Moreover, although statins are highly effective in decreasing cardiovascular events (up to 60%) and cardiovascular deaths in patients with pre-existing CVD, a large percentage of patients with or at high risk of developing CVD, despite statin treatment, still experience cardiovascular events and cardiovascular death. Therefore, researchers and companies would like to develop other, complementary drugs that work via different mechanisms from the statins.

HDL raising has long been a key target for pharmaceutical and biotechnology companies in their quest to develop CVD drugs that would be complementary to the statins. In the early-to-mid 2000’s, companies had several candidate drugs, of different types, in development. In an article published by Pharmaceutical Executive in 2006, I was quoted as saying that raising HDL was a big field. However, most of the drugs being developed at that time fell by the wayside, mainly due to failure in the clinic.

A particular focus of pharmaceutical companies has been the development of cholesteryl ester transfer protein (CETP) inhibitors. CETP catalyzes the transfer of cholesteryl esters and triglycerides between LDL/VLDL and HDL, and vice versa. In vivo (in animals and in humans), CETP inhibitor drugs raise HDL and lower LDL.

The leading CETP inhibitor in the early to mid-2000s was Pfizer’s torcetrapib. Pfizer had placed high hopes on torcetrapib, as a potential blockbuster to replace anticipated lost revenues from Lipitor when it went off-patent in 2011. However, in late 2006 Pfizer pulled the drug from Phase 3 trials, after finding that combination therapy with torcetrapib  and atorvastatin gave a 50 percent greater mortality rate that atrovastatin alone. This was not only a huge disappointment for Pfizer and its shareholders, but also cast a pall of gloom over the entire HDL-raising drug field, and especially over CETP inhibitors. Researchers speculated that inhibition of CETP might result in producing a form of HDL that is not cardioprotective, and might even be harmful. There were even calls for pushing the HDL field back to the basic research level, with the need to find just how (and what form of) HDL exerted its cardioprotective effects, in people with elevated HDL due to genetics, lifestyle, or treatment with high-dose niacin (the only drug approved to raise HDL).

However, later studies of torceptrapib found that the toxicity of the compound was not due to an untoward effect of CETP inhibition or HDL raising, but was due to off-target effects of the drug. In animals and in humans, torceptrapib raised serum levels of aldosterone, via release of aldosterone from the adrenals. Aldosterone was responsible for the increase of blood pressure seen in animals and in humans treated with torceptrapib, and aldosterone has proatherogenic effects that go beyond its effects on blood pressure. The hypertensive and aldosterone-raising effects of torceptrapib were independent of its CETP inhibitor activity, and other CETP inhibitors (discussed below) do not raise aldosterone levels or blood pressure.

A March 2011 News and Analysis article in Nature Reviews Drug Discovery reviewed the history of the CETP inhibitor field after the demise of torcetrapib. Although the torcetrapib debacle caused several other companies to exit the CETP inhibitor field, Roche and Merck persisted. Roche has been developing the CETP inhibitor  dalcetrapib, and Merck’s CETP inhibitor is known as anacetrapib.

As mentioned in the Nature Reviews Drug Discovery mini-review, Dr. Alan Tall (Columbia University), working in collaboration with Merck researchers, showed in 2010 that niacin treatment in humans resulted in a 30% increase in HDL, while anacetrapib treatment resulted in a 100% increase in HDL. Niacin treatment in humans resulted in a moderate increase in the ability of HDL to promote net cholesterol efflux (measured in in vitro assays) while anacetrapib treatment caused a more dramatic increase. This was due not only to a higher level of HDL in anacetrapib-treated subjects, but also to enhanced ability of anacetrapib-induced HDL particles to promote cholesterol efflux, especially at high HDL concentrations. HDL from both niacin-treated and anacetrapib-treated subjects also exhibited anti-inflammatory activity. This study should help lay to rest the idea that pharmacological inhibition of CETP might result in abnormal pro-atherogenic HDL, as theorized by some researchers after the clinical failure of torceptrapib.

Currently, Roche’s dalcetrapib is in a 15,600-patient Phase 3 clinical trial known as dal-OUTCOMES; this trial was initiated in 2008, and efficacy results are expected in 2012-2013. As of the time of the Nature Reviews Drug Discovery article, Merck planned to initiate its 30,000-patient REVEAL trial of anacetrapib in April 2011. Efficacy results of REVEAL are anticipated in 2014-2016.

In December 2010, the results of Merck’s moderate-sized (1623 patients with or at high risk for CVD, who were already being treated with a statin) Phase 3 DEFINE trial of anacetrapib were published in the New England Journal of Medicine. The DEFINE trial was designed as a safety study. In this 76-week study, anacetrapib showed no significant differences from placebo in terms of safety, as measured by a pre-specified cardiovascular endpoint (defined as cardiovascular death, myocardial infarction, unstable angina or stroke). These cardiovascular events occurred in 16 anacetrapib-treated patients (2.0 percent) compared with 21 placebo-treated patients (2.6 percent). There were also no significant differences in blood pressure, serum electrolytes, or aldosterone levels between anacetrapib-treated and placebo-treated patients.

Anacetrapib treatment also decreased LDL by 40 percent (from 81 to 45 mg/dl vs. 82 to 77 mg/dl for placebo) and increased HDL by 138 percent (from 40 to 101 mg/dl vs. 40 to 46 mg/dl for placebo). Anacetrapib also had other favorable effects on lipid levels (e.g., 36.4% reduction in lipoprotein(a), and 6.8% reduction in triglycerides, beyond the changes seen with placebo treatment).

Although the DEFINE study was too small to provide definitive results regarding the safety of anacetrapib, it gave a 94% predictive probability that treatment with anacetrapib is not associated with the rate of cardiovascular events seen with torcetrapib. The trial also indicated that anacetrapib treatment does not result in the effects (especially raising of serum aldosterone levels) thought to be responsible for torcetrapib’s toxicity. Moreover, anacetrapib treatment resulted in a dramatic increase in HDL levels (beyond that seen with torcetrapib) in the DEFINE study, and the 2010 study by Dr. Tall and his colleagues indicates that anacetrapib-induced HDL is highly effective in promoting cholesterol efflux.

The results with anacetrapib have reignited enthusiasm for CETP inhibitors in the medical community. Even the often-critical Dr. Steven Nissen (Cleveland Clinic) expressed enthusiasm for anacetrapib. However, despite these promising results, the efficacy of CETP inhibitors, in terms of significantly reducing the rate of cardiovascular events, has not yet been demonstrated. Only large, adequately-powered Phase 3 clinical trials, such as dal-OUTCOMES for Roche’s dalcetrapib and REVEAL for Merck’s anacetrapib, can definitively establish both the efficacy and the safety of these drugs.

The development of CETP inhibitors represents a situation in which the leading drug in the class failed because of off-target effects. However, these off-target effects were not class effects, and targeting CETP in order to raise HDL now seems like a good idea after all. Pfizer ignored warning signs (especially the modest elevation in blood pressure induced by torcetrapib, which did not appear to be very significant) in pursuit of its commercial goals, while Roche and especially Merck pursued a more moderate and science-based approach to development of CETP inhibitors. Other companies stopped development of their CETP inhibitors, thus losing their opportunities in this field. Meanwhile, various companies and academic group have been developing other approaches to HDL raising, such as apolipoprotein A1 mimetics, which are in early stages of development.

Despite its early setbacks, HDL-raising drugs may turn out to be a big field after all.

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