Albert Einstein never said that the definition of insanity is doing the same thing over and over again and expecting a different result. But whoever did say it was probably talking about a pharmaceutical executive.
This morning, Eli
In its release, Lilly wrote that that the largest study of evacetrapib, was being stopped because of “insufficient efficacy.” Steven Nissen, the Cleveland Clinic cardiologist who ran the study, says that the results can’t be explained because the study was too small or because too few heart attacks and strokes occurred. “The drug didn’t work,” Nissen says.
That harsh reality will be felt across the pharmaceutical industry. It creates big doubts over whether another similar drug, from
Evacetrapib is a drug designed to boost levels of “good cholesterol” in HDL particles by blocking the cholesterol ester transfer protein, or CETP. For years, doctors largely believed that any HDL-boosting drug would prevent heart attacks and strokes. People with low HDL, after all, seemed to be at higher risk.
But the genetic data on people who had high levels of HDL because of changes in their CETP genes were mixed. People in Japan who had no CETP function – and super-high HDL levels – didn’t seem to have fewer heart attacks. Caucasian people with slight defects in CETP, and slight boosts in HDL, seemed to have a 4% reduction in their risk of heart attacks and strokes – significant, but not very big.
Three times, CETP-blocking drugs failed to help patients.
“We now have three different CETP inhibitors that have all failed,” says Sekar Kathiresan, a Harvard geneticist. “The odds of the fourth one succeeding are low.”
In fact, Kathiresan’s work seems to show that the whole idea that boosting HDL prevents heart attacks may just be wrong. In a 2012 study published in the Lancet, he showed people with genetic mutations that boosted HDL didn’t have fewer heart attacks and strokes. Clinical trials of other HDL-raising drugs have failed, too.
The hope for CETP inhibitors was that they also lowered LDL cholesterol. Investors were becoming more optimistic, according to polls conducted by ISI Evercore analyst Mark Schoenebaum. Amgen even bought the rights to a CETP inhibitor for $300 million last month. Oh, well.
The new cholesterol-lowering shots, Praluent and Repatha, represent an alternative approach to developing drugs. These drugs target a protein called PCSK9, and people whose genes don’t make it have much lower levels of heart disease. That strategy – creating drugs where genetics are clear – may represent a way to prevent expensive failures.
But such genetic data doesn’t exist for every new medicine. For instance, it doesn’t exist for the drug being developed by tiny Esperion, code-named ETC-1002. The stock has been hammered because Esperion told investors that the Food and Drug Administration might ask it to do a big study like the one evacetrapib failed in to prove ETC-1002 prevents heart attacks and strokes. Previously, Esperion claimed that the study wouldn’t need to finish until after the drug hit the market.
There are other factors that matter. In contrast to drugs that raise HDL, medicines that lower LDL cholesterol and do nothing else all seem to have prevented heart attacks and strokes. Even a weak drug, Merck’s Zetia, recently showed such a benefit in a large clinical trial. Esperion shares, by this logic, look cheap: an effective cholesterol-lowering drug with an enterprise value of just $350 million.
The bigger question is whether investors should take the CETP story as a cautionary tale about other big, risky drug development programs. For instance, Lilly’s other big pipeline asset, solanezumab for Alzheimer’s disease, has scary parallels to today’s failure. The genetics here are better. But a similar medicine from Pfizer failed, and solanezumab itself failed in a previous study. Sure, things might be different next time. But do we really want to bet on that?
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