Merck announced this morning that anacetrapib, a cholesterol-lowering medicine, reduced heart problems and strokes in a 30,000-patient clinical trial, giving the drug giant a success where Pfizer, Eli Lilly and Roche have all failed.
The full details of the study will be revealed at the annual meeting of the European Society of Cardiology on August 29. Merck signaled that it is not sure whether the data, though positive, are strong enough to result in a regulatory approval. "Merck plans to review the results of the trial with external experts, and will consider whether to file new drug applications with the U.S. Food and Drug Administration (FDA) and other regulatory agencies," the company said in a statement.
Merck's anacetrapib trial was very large, and very long. Patients were followed for five years. It would have been able to pick up a very small benefit from the drug. For comparison, Merck's study of Zetia showed a 7% reduction in heart problems and strokes, according to Umer Raffat, an analyst at Evercore/ISI. Anacetrapib's benefit could conceivably be smaller, perhaps just a 5% reduction. Whereas many recent heart drug trials have looked at only heart attacks, strokes and cardiovascular deaths, Merck's study also included stenting procedures to open blocked arteries. Exactly what the drug prevented will be important. Also, anacetrapib has a liability: the molecule stays in the body, in fat tissue, for years after patients take it. The could make the drug more effective, but it also means that any side effects could last even after patients stop taking the drug.
Timothy Anderson, an analyst at Bernstein Research, who had long said success for anacetrapib was possible and forecasts sales of $1.6 billion for the drug, warns that the medicine is "not out of the woods" and that the full results in August will matter. It could be that the medicine won't be commercially viable against generic versions of Merck's own Zetia.
Still, it's hard to overstate the magnitude of the upset here. Merck seemed to put anacetrapib into development as a hedge against a rival project from Pfizer, only to succeed as rivals spent literally billions of dollars to no avail.
"It's a shock," tweeted Sekar Kathiresan, director of the Center for Genomic Medicine at Massachusetts General Hospital. "Where else have three drugs in a class failed in large-scale [randomized controlled trials] but the fourth succeeds! Drug development is a tough business."
All the drugs targeted the cholesterol ester transfer protein (CETP), which controls how cholesterol moves in the body. Some genetic studies of the patients who don't have CETP showed that they had not only low levels of low-density lipoprotein (LDL), the so-called "bad cholesterol," but also high levels of high-density lipoprotein (HDL), the "good cholesterol" that was thought to help prevent heart attacks. The idea was that a drug to block CETP could lower LDL and boost HDL, adding to the benefits of potent statin drugs like Pfizer's Lipitor and Merck's Zocor.
Pfizer was the first to rush a CETP inhibitor into clinical trials. The idea was that by combining it with Lipitor, then the best-selling drug in the world, it could preserve those sales for an extra decade or more. Wall Street analysts forecast that if it worked, the Lipitor-CETP inhibitor combo would become the best-selling drug in the world. But when results of Pfizer's clinical trial were revealed in 2006, it was found that the people who got the CETP inhibitor were more likely to die than those who received Lipitor alone. The failure helped push Pfizer into its $68 billion purchase of Wyeth later on.
But the multibillion-dollar potential of new heart drugs kept other companies from giving up. The Pfizer drug raised blood pressure; that might be why it proved deadly. Roche had a CETP inhibitor that it licensed from Japan Tobacco. In 2012, it stopped a 15,000-patient study of the drug because there was no chance of success. Some researchers blamed the fact that the Roche drug seemed to have little effect on LDL. Eli Lilly rushed forward with its own CETP drug, which had a strong profile in both increasing HDL and cutting LDL. It failed in 2015.
Merck made several choices that could lead to a different result. Its trial contained twice as many patients as those of other drug companies. While other firms had bet to some degree on the benefit of raising HDL, Merck designed it's study so that the LDL-lowering effect of anacetrapib would be enough to reach statistical significance. That's why many experts expect a small benefit: Merck was just willing to wait longer and look harder. Genetic data reveal another worry: people with genes that mimic CETP inhibition may have a higher risk of macular degeneration. That's another reason the full data in August will matter so much.
Still, the news of the success is actually good news for drug development in general. The CETP story had stood out as an example of the difficulty of using genetic data to develop new medicines. The genetic data seemed to say that a CETP inhibitor would lower the risk of heart disease. The fact that it never seemed to work called into question the whole, increasingly important, strategy of using genes to create drugs. If it turns out the strategy did work, but that the effect was small, that's a positive sign for researchers trying to invent medicines. After all, a tiny success is still better than a gigantic failure.
