Last week, Merck announced that it would not pursue the approval of anacetrapib for clinical use. The entire program for commercialization of the drug was scrapped.
You probably did not notice the announcement. And if you did, you probably didn't care. But the demise of anacetrapib speaks volumes.
Maybe you thought that Merck killed anacetrapib because it was not effective. If you thought that, you would be wrong.
Anacetrapib is an inhibitor of cholesteryl ester transfer protein (CETP). The drug lowers LDL cholesterol and nearly doubles HDL cholesterol. It was tested in a trial of 30,449 patients who were already taking a statin and were followed for an average of 4.1 years.
The trial succeeded. Patients treated with anacetrapib had a lower risk of the composite of coronary death, myocardial infarction or coronary revascularization (P=0.004). Furthermore, the drug was well tolerated; there were no important safety issues.
Anacetrapib is given as a single oral tablet once daily. There are no injections.
Why would a company abandon a drug that was safe, effective and easy to use and improved cardiovascular outcomes?
The problem: Anacetrapib emerged at the wrong place and at exactly the wrong time.
After many halcyon years, the field of lipid lowering drugs is in sharp decline.
Lipidologists burst into the limelight with the advent of statins, which many thought were miraculous. Statins reduced LDL cholesterol and prevented cardiovascular events. With each passing year, the target level of LDL cholesterol was lowered. That meant higher doses of statins, and the need for more drugs to achieve low target levels of LDL cholesterol.
Then the field was rocked by a series of earthquakes.
First, many people simply hated statins. Some developed side effects, but many simply viewed statins as a symbol of medical disempowerment. If taking a statin became more important than watching your diet or taking natural supplements, then you no longer had personal control of your health. And people resented it.
Second, a new class of drugs emerged to be added to statins -- the PCSK9 inhibitors. Statins were given orally, were cheap and reduced the risk of cardiovascular events by 30-40% (depending on the analysis). The PCSK9 inhibitors had a dramatic effect on LDL cholesterol, but they reduced cardiovascular risk by only 15%. Furthermore, they were really expensive and required periodic injections. Payers objected to their price, and the drugs languished. The most recent trial with bococizumab yielded disappointing results, and the sponsor never sought approval.
Third, another class of lipid lowering drugs was introduced -- the CETP inhibitors. They were effective modulators of a high-risk lipid profile. But several large-scale trials produced disappointing results. Torcetrapib harmed people; two other agents yielded no benefits.
Then came the trial with anacetrapib, and amazingly, the drug worked. It reduced cardiovascular risk -- but by only 9%.
How much could Merck charge for a drug that had such a small effect, when other lipid lowering agents had failed in clinical trials or floundered in the marketplace? Obviously, the answer was: not enough.
I have never been interested in lipids. But some of my good friends are totally devoted to lipid research. Billions of dollars have been spent to make everyone's lipid profile look good. But I fear that we have now reached the point of diminishing returns.
When sponsors decline to pursue the results of a positive trial after an extraordinary investment, it means that the field is dying.
My friends who are experts in lipids should not feel terribly sad.
No one makes new drugs for hypertension, angina or arrhythmias any more either.
Disclosures
Packer has recently consulted for Amgen, Boehringer Ingelhim, Cardiorentis and Sanofi. He was one of the two co-principal investigators for the PARADIGM-HF trial (sacubitril/valsartan) and currently chairs the Executive Committee for the EMPEROR trial program (empagliflozin).