The failure of Lilly's evacetrapib may prove the final nail in the coffin for CETP

There may be good and bad cholesterol, but today there is only bad news for Eli Lilly ($LLY) and rivals Merck ($MRK) and Amgen ($AMGN) after the full extent of the failure for CETP inhibitor evacetrapib is revealed--and will likely prove fatal for the whole class.

Lilly announced last year it was to discontinue studies of its drug after it failed to reduce rates of major cardiovascular events, including heart attack, stroke, angina or cardiovascular death.

Over the weekend the Cleveland Clinic released further analysis of the Phase III trial Accelerate study of 12,000 patients--and the results were damning.

The researchers found that not only did it not reduce CV events, but that this came despite reducing levels of low-density lipoprotein (LDL, or "bad" cholesterol) by 37% and raising levels of high-density lipoprotein (HDL, or "good" cholesterol) by 130 percent. The data also revealed that hypertension was significantly increased with evacetrapib--a highly concerning AE given the patient population.

Improving HDL via CETP inhibition had been seen as the great hope of this next-gen class of statins, but Steve Nissen, chairman of cardiovascular medicine at Cleveland Clinic, said: "Here we have a paradox. The drug more than doubled HDL and lowered LDL levels by as much as many statins--but had no effect on cardiac events. These findings illustrate the importance of performing large, high-quality outcome trials. Just looking at the effects a therapy has on cholesterol levels doesn't always translate into clinical benefits."

Dr. A. Michael Lincoff, director of the Cleveland Clinic Co-ordinating Center for Clinical Research (C5Research) and a principal investigator, added:  "The trial raises questions about the benefits of raising HDL and the future of this class of drugs."

Lilly has already moved on from this failure, but these data will be a kick to the stomach for Merck and Amgen, who are both continuing to develop their versions of cholesteryl ester transfer protein (CETP) inhibitors, despite three huge failures in the area from Pfizer ($PFE) all the way back in 2006 after deaths were reported, and more recently from Roche ($RHHBY) in 2012 and Lilly last year.

The idea is that CETP deficiency is cardioprotective, but these three late-stage studies just have not backed this up. In fact, evacetrapib was thought to be the most promising approach because it is a potent CETP inhibitor that lacks the toxicity of former failed meds, but it too still did not help CV patients and increased hypertension.

The study's researchers concluded: "Despite widespread use of statins, many patients continue to experience cardiovascular events. Therefore, considerable efforts have been put into investigating whether the protective benefits of HDL cholesterol could be targeted as a form of therapy."

Merck's ongoing Reveal study for anacetrapib may just reveal something many are already expecting: failure. "Merck's drug is the fourth shot on goal for CETP inhibitors, but with disappointment or lack of success for the other agents you have to be increasingly pessimistic" about the class of drugs, said Dr. Stephen Nicholls, deputy director of the South Australian Health and Medical Research Institute in Adelaide, Australia, and lead investigator for the failed trial of Lilly's drug.

The same goes for Amgen, whose CETP inhibitor TA-8995, acquired from its $1.6 billion deal with Dezima in 2015, is undergoing mid-stage testing. Analysts at Leerink say the latest data from Lilly will be the writing on the wall: "We do not expect Amgen to take the asset forward," the firm said in a note to clients.

And their prediction for Merck? "We believe Merck's Reveal trial is likely to fail either clinically or commercially." Final data for the drug is expected to be released next year.

The latest top prospect in the class--PCSK9 inhibitors--may also now be under increased scrutiny, with Amgen's Repatha and Praluent, which is being developed by Sanofi ($SNY) and Regeneron ($REGN), the main players in this field.

Tim Anderson, an analysts at Bernstein, said in a note to clients that PCSK9 inhibitors should not be adversely affected by these data sets, however, as this class "clearly work differently from CETP inhibitors, and from what has been published, have not been shown to have off-target effects. We continue to think an outcomes benefit will be shown with this class of medicines. If these trials were to fail, it would be viewed as a major setback."

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