Results from the just-concluded studies of the Eli Lilly drug candidate evacetrapib by the Cleveland Clinic in Ohio, USA, have underscored other findings that industry watchers have called disappointing.

The latest advanced research, unveiled at the beginning of this week, showed that the compound reduces levels of low-density lipoprotein (LDL, or “bad” cholesterol) by 37% while raising levels of high-density lipoprotein (HDL, or “good” cholesterol) by 130%.

Despite this, in clinical trials it up to now has failed to reduce rates of major cardiovascular events, including heart attack, stroke, angina or cardiovascular death. The researchers said they observed a borderline significant reduction in all-cause mortality in the evacetrapib group, but this was not driven by a decrease in cardiovascular death.

Lilly discontinued its phase 3, multi-center ACCELERATE clinical trial with evacetrapib in October 2015, on the recommendation of the independent Data Monitoring Committee – after preliminary data from clinical trials suggested the study would not meet its primary endpoint of a reduction in major cardiovascular events.

“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,” said Steve Nissen, chairman of Cardiovascular Medicine at Cleveland Clinic.

“These findings,” he said, “illustrate the importance of performing large, high-quality outcome trials,” adding: “Just looking at the effects a therapy has on cholesterol levels doesn't always translate into clinical benefits.”

The trial involved more than 12,000 patients who were at high risk for serious cardiovascular problems. The participants were randomized to receive either 130 milligrams of evacetrapib or a placebo daily, along with standard medical therapy.

Study participants either had an acute coronary syndrome 30 days to a year before enrolling, had cerebrovascular atherosclerotic disease, peripheral vascular disease or both diabetes and coronary artery disease.

“We were certainly hoping for different results, and are trying to understand why we didn't see a benefit from this drug,” said A. Michael Lincoff, director of the Cleveland Clinic Coordinating Center for Clinical Research (C5Research) and a principal investigator on the study.

The trial raises questions about the benefits of raising HDL and the future of this class of drugs,” Lincoff said, noting that considerable efforts have been put into investigating whether the protective benefits of HDL cholesterol could be targeted as a form of therapy.

Evacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor, which works by disrupting the process that normally transfers cholesterol from HDL cholesterol to LDL cholesterol in the body. Animal and genetic studies have suggested that CETP deficiency is cardioprotective, the Cleveland researchers remarked, but noted that this is the third failure in this class of drugs.

Other drugmakers who have tested drug candidates in the class include Pfizer (2006) and Roche (2012). US Merck and Amgen are still pursuing the development of CETP inhibitors, but the news from Cleveland “will likely prove fatal for the whole class,” said the biotech journal Fierce Pharma.

Safety concerns were not raised by the trial, and the study, which was funded by Lilly, did not reveal any major side effects, the clinic said. Cleveland stressed that its consultants do not accept honoraria, consulting fees or other compensation from commercial entities.