The Future Hopes for CETP Inhibition

In recent years, cholesteryl ester transfer protein (CETP) inhibition has become contentious in lipidology and cardiology circles. Many believe that we have reached the end of the CETP inhibition class, and not without good reason—many drug makers have failed to bring the class to market.

Pfizer’s CETP inhibitor, torcetrapib, was the first to be discontinued in 2006 due to excess mortality in phase 3 trials. Then in 2012, Hoffman-La Roche discontinued dalcetrapib when the drug failed to show clinically meaningful success in efficacy. Eli Lilly & Company discontinued evacetrapib in 2015 due to insufficient efficacy as well. Amgen decided to discontinue obicetrapib last year after conducting a failed phase 2 trial that concluded in 2015.

Then, just months ago, Merck abandoned anacetrapib after it failed to show significant benefit in trials. Despite 5 attempts in more than a decade, little progress has been made that validated the CETP inhibition class of medicines.

However, for Brian Ference, MD, MPhil, MSc, the associate chief of translational research and clinical epidemiology, director of the Cardiovascular Genomic Research Center, and assistant professor of medicine at Wayne State University School of Medicine in Detroit, Michigan, there is still hope for the future of CETP inhibition.

A Simple Misunderstanding

“I think there’s a clear path forward, actually,” Ference told MD Magazine^â. “I think there are a number of players in the industry who clearly have an idea of if CETP inhibition is viable as a therapeutic agent, and if that’s going to be clinically efficacious and reduce risk enough to get approval by the FDA, that there is a path forward.”For Ference, it boils down to a misunderstanding of CETP inhibitors. In an early terminated study, the first of the class, Pfizer’s torcetrapib, showed an increase of blood pressure of 5 mm Hg as well as a 60% increase in mortality among patients taking the therapy in conjunction with atorvastatin compared with atorvastatin alone.

“It was only an 18-month trial—that’s very, very important because that high increase in blood pressure during that time (and possibly some other events) and the fact that it was stopped so soon, most likely exaggerated the increased morbidity effect,” Ference said. “But clearly, that 18 months was, in retrospect, was not enough to demonstrate a reduction in the risk of cardiovascular events.”

Ference noted that with most of these studies, there exists a caveat that could explain the poor outcomes. One of those is the length of the trials, as CETP inhibitors have shown positive results, but tend to take time to do so. Another is the way cardiologists examine cholesterol content in patients.

Cholesterol is clinically measured as the total cholesterol content of the low-density lipoprotein (LDL) particles. CETP blocks the transfer of cholesterol through high-density lipoprotein (HDL) to LDL and the other apolipoprotein beta (apoB) particles, which in turn creates HDL particles with more cholesterol, thus increasing the HDL cholesterol concentration without increasing the HDL particles.

“More importantly, it creates LDL particles that have less cholesterol on them without decreasing the LDL particle or apoB concentration, and the practical effect is it lowers LDL cholesterol, without lowering the particles,” Ference said.

In a similar breadth, the consensus regarding the results of the ACCELERATE trial, Eli Lilly & Company’s test of evacetrapib, was that it suggested that LDL cholesterol does not cause atherosclerosis, and that it should not be an adequate surrogate for US Food and Drug Administration (FDA) approval.

“With the European Atherosclerosis Society, I happened to have written the consensus statement on LDL causality,” Ference said. “In that document, we clearly state that it is the LDL particles, not the cholesterol content, that causes atherosclerosis. Now, that’s very important, but we didn’t have a lot of proof until very recently.”

Which leads to the final caveat—trial design.

“In every single study that has ever been conducted with CETP inhibition, when it is used alone, CETP reduces LDL cholesterol and apoB by approximately the same amount—about what statins do,” Ference said. “Which means that, in addition to just lowering the cholesterol content of the LDL particles, it also inhibits [proprotein convertase subtilisin/kexin type 9 (PCSK9)], which up-regulates the LDL receptor and decreases LDL particles.”

But something “quite strange,” as Ference puts it, occurs when CETP is added to a statin: a discordance between the LDL cholesterol reduction and the LDL particle reduction.

The Case for Monotherapy

“What that means is that CETP is still working—it’s causing LDL particles that have less cholesterol—but it’s not removing the LDL particles,” he said. “So, one gets a discordance between the decrease in LDL cholesterol and the decrease in apoB, the measure of the LDL particles. That’s true in every single study that has ever been conducted with a CETP inhibitor added on to a statin.”Shortly before the REVEAL trial, which tested anacetrapib, was published by Merck, Ference and colleagues published late-breaking clinical trial in JAMA, detailing the interactions of genetic instruments that mimicked CETP inhibitors and statins. When used alone, the CETP inhibitor variants, like the molecules they mimic, reduced LDL cholesterol and apoB by the same amount, concordantly, and reduced the risk of cardiovascular events.

“But even in our genetic study, when we combined genetic variants that mimic CETP inhibitors with genetic variants that mimic statins, we found exactly the same thing that happens once CETP inhibitors are actually added to statins: you get a large reduction in LDL cholesterol, but a much less reduction in apoB,” Ference said. “The corresponding risk of cardiovascular events is proportional to the reduction in apoB, not the LDL cholesterol.”

Meanwhile, REVEAL showed that anacetrapib lowered LDL cholesterol by 24 mg/dL in patients with a directly measured atherosclerosis. However, it only reduced the risk of the primary composite of cardiovascular death, myocardial infarction, and revascularization by 9%.

That 24 mg/dL decrease in LDL would lead one to expect “at least” a 15% reduction in risk after a period of 4 years, Ference said, but REVEAL showed a much lower reduction. Although, he added, that reduction of risk was exactly proportional to the expected effect per unit change in ethyl ß.

“That’s really important because what it implies is that the causal effect of LDL is not related to its cholesterol content measured by LDL cholesterol, but instead it is caused but the reduction in LDL particles, as measured by apoB,” Ference said. “In fact, we did another study to test that hypothesis directly, where we found genetic variants that had naturally occurring discordance between LDL cholesterol with large LDL reductions, but very small apoB reductions—exactly like what happens when we add a CETP inhibitor onto a statin.”

“In every case, the risk of coronary disease was proportional not to the LDL cholesterol, but instead to the apoB containing apoliprotein concentration,” he added.

This difference, though, only becomes apparent when LDL cholesterol and apoB become discordant. Ference noted there are 2 ways to observe that discordance, either by genetic variants or by adding a CETP inhibitor onto a statin.

“In that case, both in the genetics and the trials, the risk is exactly proportional to the expected effect per unit change in apoB , but much less than expected per unit change in LDL cholesterol,” he said.

Thus, taking CETP inhibitors plus statins forward is futile. In addition to seeing only a small reduction of apoB and of risk, the LDL cholesterol measurement itself becomes unreliable.

That would only continue to confuse people.

“However, what the data also suggest, both the clinical trial data—not the outcomes data but the phase 2 trial data with dose responses—and the genetic data, is if one simply takes a CETP inhibitor as a monotherapy, then one would get concordant reductions in LDL cholesterol and apoB, and a corresponding reduction in the risk of cardiovascular events that was proportional to either the LDL cholesterol or the apoB because they have essentially the same inclination,” Ference said.

This is also shown in the context of the REVEAL data. In that trial, baseline concentrations of LDL and apoB were 59 mg/dL and 62 mg/dL, respectively— “extraordinarily low levels,” Ference said.

“If we use CETP as a monotherapy in people, for example, who were statin intolerant because we would in no way want to add a CETP inhibitor to a statin because of this discordance between LDL and apoB,” Ference said. “What we could do is get large proportional reductions in both LDL cholesterol and apoB, and correspondingly large reductions in the risk of cardiovascular disease. The future of CETP is clearly as a potential monotherapy as an alternative to ezetimibe or other therapies, even PCSK9 inhibitors, in persons who are statin intolerant.”