Data Behind Eli Lilly's Decision to Halt Potential Cholesterol Blockbuster Released Last Weekend

April 4, 2016
By Mark Terry, BioSpace.com Breaking News Staff

It was back in October 2015 that Indianapolis-based Eli Lilly and Company announced it was halting development of its late stage cardiovascular drug evacetrapib. Now that the data for the study has been released, cardiac experts are stunned at the results, wondering if they need to reevaluate the role LDL, HDL and cholesterol play on heart disease.

The Phase III study involved 12,095 patients at 540 sites in 37 countries. The issue wasn’t safety, nor was it the drug’s ability to reduce LDL cholesterol, the one associated with poor health outcomes. The drug seemed to do a very good job of cutting LDL levels and improving HDL levels.

The problem is that the drug didn’t show any health benefits in terms of decreasing the risk of a heart attack or stroke.

Data was presented yesterday at the American College of Cardiology’s annual meeting. Patients on the drug had a decrease in LDL by an average of 55 milligrams per deciliter from 85. HDL levels, the good kind of cholesterol, rose from 46 milligram per deciliter to an average of 104. That’s the good news.

The bad news was that out of the participants, 256 of the patients taking the drug had heart attacks compared to 255 patients in the group on placebo. Of those on the drug, 92 patients had a stroke compared to 95 taking placebo. The mortality figures were similar as well, with 434 patients on the drug dying from cardiovascular disease like a heart attack or stroke compared to 444 deaths in the placebo group.

“We had an agent that seemed to do all the right things,” said Stephen Nicholls, the trial’s principal investigator and deputy director of the South Australian Health and Medical Research Institute in Adelaide, to The New York Times. “It’s the most mind-boggling question. How can a drug that lowers something that is associated with benefit not show any benefit?”

Two other drugs that have the same mechanism of action, CETP inhibitors, have also failed in trials. One decreased LDL levels by 20 percent, but had toxic side effects. The other drug increased HDL levels but didn’t affect LDL levels. The two drugs were Pfizer ’s torcetrapib and Roche ’s dalcetrapib.

Evacetrapib’s method of action is different than the more common statins. Evacetrapib removes cholesterol from HDL so it can then be excreted in bile. Statins remove cholesterol from LDL, into the liver, where the body removes it.

No one is certain why this didn’t affect cardiac outcomes. “It may be that the LDL level is less important than how it gets changed,” said Paul Thompson, a cardiologist at Hartford Hospital, to The New York Times. “But we don’t know that.”

There’s another class of cholesterol medications that have given cardiologists hope, known as PCSK-9 inhibitors. They have the same effect as statins, involving the liver in removing cholesterol. To date, they have been approved by the U.S. Food and Drug Administration (FDA) in patients who don’t respond well to statins.

One problem, however, is that PCSK-9 inhibitors come with hefty price tags of more than $14,000 annually, while statins cost about $50 per month. At the moment, Amgen ’s Repatha (evolcumab) and Sanofi and Regeneron Pharmaceuticals ’s Praluent (alirocumab) are the two PCSK-9 inhibitors on the market.

Now that Lilly has pulled evacetrapib, the only company working with CETP inhibitors in Phase III trials is Merck . Roche (RHHBY)’s dalcetrapib and Pfizer (PFE)’s torcetrapib all failed in late-stage trials.