Straight Talk | Steven E. Nissen, MD, MACC

In July 2015, the FDA approved a PCSK9 inhibitor, the first major new class of lipid-modulating medications since the introduction of the statins in 1987. During the last 28 years, many promising therapies entered initial clinical development, but each failed to demonstrate either safety or efficacy (or both) during pre-clinical studies or human trials. Some development programs collapsed dramatically due to unexpected toxicity (torcetrapib), whereas others (darapladib, dalcetrapib) simply failed to show evidence of meaningful clinical benefit. Even previously accepted therapies such as niacin have come under scrutiny as a consequence of contemporary clinical trials that showed both lack of effectiveness and significant adverse effects. Arguably, even the PCSK9 inhibitors have yet to demonstrate a reduction in major cardiovascular events, although most knowledgeable observers consider a near certainty the likelihood of favorable conclusions from ongoing clinical trials.

Now that nearly 3 decades of drought has finally ended, what will the next few years bring? Are any other major new approaches to treatment of lipids likely to succeed? Currently available preclinical and genetic data suggest the distinct possibility that one or more additional new therapies will demonstrate significant clinical benefits. Two new approaches are current under investigation in ongoing Phase III clinical trials and several studies are likely to report results within the next 12-18 months. Here’s a summary of two of the most promising therapeutic targets.

CETP Inhibition

Cholesterylester Transfer Protein (CETP) transfers cholesterol from HDL to VLDL and LDL particles. Inhibiting this protein raises HDL substantially, typically > 100%, while reducing LDL moderately, approximately 25%-35% for the potent CETP inhibitors currently under development. Torcetrapib, the first of these drugs to reach Phase III, failed catastrophically, but the drug’s demise was eventually linked to an off-target adrenal toxicity that increased aldosterone levels, resulting in substantial increases in blood pressure. Pfizer terminated development in 2006 after the Data Monitoring Committee recommended halting a large Phase III clinical outcome trial due to an increase in adverse cardiovascular events, including death. However, soon after the failure of torcetrapib, evidence accumulated that other CETP inhibitors did not share adrenal toxicity and three other compounds entered advanced stages of development (dalcetrapib, anacetrapib, and evacetrapib).

Dalcetrapib was a weak CETP inhibitor that yielded only modest increases in HDL and no decrease in LDL. A definitive Phase III regulatory trial was halted in 2012 after a pre-specified interim analysis showed futility (neither benefit nor harm). The other two CETP inhibitors, anacetrapib and evacetrapib, are considerably more potent and both have large, fully-enrolled Phase III trials currently underway. These two drugs have not demonstrated torcetrapib-like toxicity and both increase HDL more than 100%, while lowering LDL by > 25%. The evacetrapib outcome trial results are expected in 2016 and completion of the anacetrapib clinical trial is likely to occur about the same time. Anacetrapib may face significant regulatory headwinds due to the unexpected finding of a very long terminal half-life with measureable drug levels still detectable 2-4 years following the last dose. Such a long half-life is worrisome to regulators because the drug persists in the circulation of patients for many years, even those who have an allergic reaction or other adverse effect.

Why might these drugs succeed? Several observations are encouraging. Patients with genetic variants that result in lowered CETP activity show a reduced lifelong propensity for developing coronary disease. Recent data in patients administered evacetrapib also shows a reduction of LDL particle number and the concentration of highly atherogenic small dense LDL. Other evacetrapib studies show an increase in pre-ß HDL by immunofixation and enhanced cholesterol efflux in cell cultures, both of which have been associated with benefit in epidemiological studies.

Triglycerides

Triglycerides have been a kind of step-child in the world of lipidology. While epidemiological studies have consistently shown an association between hypertriglyceridemia and the risk of coronary disease, no intervention to lower triglycerides (including fish oil or fibrates) has proven beneficial in a contemporary well-designed prospective clinical outcome trial that enrolled statin treated patients. Older studies showed reduced cardiovascular events for patients treated with the fibric acid derivative gemfibrozil, but these were placebo controlled, and gemfibrozil subsequentially fell into disuse due to a major pharmacokinetic interaction with statins that resulted in increased risk of rhabdomyolysis. The more commonly used agent fenofibrate has failed to show an overall benefit in several clinical trials enrolling a wide spectrum of statin-treated patients. However, strikingly, these trials virtually all demonstrated a clinical outcome benefit is a subgroup of patients with high triglycerides (generally > 200 mg/dL) and a low HDL (generally < 35-40 mg/dL).

What do the genetic data show? Again, as with CETP inhibitors, patients with genetic variants resulting in lower triglyceride levels also show markedly decreased likelihood of developing coronary disease. Importantly, hypertriglyceridemia is increasing in frequency as a consequence of the obesity and diabetes epidemic and the increased triglyceride levels are associated with higher concentrations of atherogenic small dense LDL. A constellation of abnormalities, obesity, insulin resistance, low HDL, and associated hypertension are commonly described as the cardiometabolic syndrome.

A least two triglyceride lowering therapies are now in large Phase III clinical outcomes trials, both derivatives of fish oil (omega 3 fatty acids). One of these drugs is ethyl eicosapentaenoic acid (EPA) and the other is a mixture of the free fatty acids docosahexaenoic acid (DHA) and EPA. Both drugs were approved by FDA to treat extremely high levels of triglycerides (> 500 mg/dL) but not the more common abnormality (triglycerides 200-500mg/dL) in the absence of evidence for a reduction in major cardiovascular events in a prospective clinical outcome trials.

Whether CETP inhibitors or triglyceride-lowering therapies succeed remains a debatable question, but I remain cautiously optimistic.

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Disclosure: Dr. Nissen is the study chairman for one of the CETP inhibitor trials and one of the fish oil studies.

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Steven E. Nissen, MD, is Chair of the Department of Cardiovascular Medicine at the Cleveland Clinic and co-author of Heart411: The Only Guide to Heart Health You’ll Ever Need.

Keywords: CardioSource WorldNews, Benzaldehydes, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipids, Niacin, Oximes, Quinolines, Sulfhydryl Compounds

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