FEATURE ARTICLE
Statins: From Fungus to Pharma
The curiosity of biochemists, mixed with some obvious economic incentives, created a family of powerful cardiovascular drugs
Philip A. Rea
Merck Moves Ahead
Knowing Sankyo's concerns over the tumors that mevastatin allegedly induced, and given the general lack of cooperation that they encountered in Japan, Merck executives didn't know what to do with lovastatin. Their ultimate decision proved to be a wise one. Instead of pursuing a drug to treat the general population, they focused their efforts on the small fraction with a condition called heterozygous familial hypercholesterolemia, which afflicts approximately 1 in 500 people. In this genetic disease, a person carries two different copies of a gene, hence the term heterozygous. One copy works normally, and one does not. The possession of one aberrant copy of the gene in this autosomal-dominant disease is sufficient to cause problems because of a deficiency in the cellular receptors responsible for the removal of circulatory LDLs. As a result, people with this disease have a severe elevation of LDLs, and they typically develop cardiovascular disease between the ages of 30 and 40 if left untreated.
Since Sankyo had already used mevastatin on similar patients with some favorable results, the case was compelling: After all, people with hypercholesterolemia faced a great and certain danger, whereas the cancer potential of mevastatin remained only speculation. For this reason, many of the clinicians involved in the early trials of lovastatin urged Merck to continue. Merck, therefore, did what had to be done: It presented all of its data to the FDA and sought approval for further studies on patients with this condition.
The FDA consented, and Merck's clinical trials on lovastatin resumed in 1982. The early results suggested that this compound dramatically reduces LDL levels with few side effects. The company continued its work, moving through the drug-development process. By 1987, the FDA approved Mevacor (alias lovastatin) for use in patients whose cholesterol levels could not be adequately controlled by diet or by using other drugs, such as inhibitors of the intestinal resorption of cholesterol derivatives or absorption of the parent compound from dietary sources.
Despite the FDA's approval, Merck still faced a fundamental question: Although it was clear that statins decreased the level of blood LDL-cholesterol, did these drugs necessarily protect against cardiovascular disease? To find out, Merck sponsored the Scandinavian Simvastatin Survival Study (the "4S study" for short), which was completed in 1994. In a group of patients diagnosed with "moderate" hypercholesterolemia (defined at the time as a total blood cholesterol level of 200-300 milligrams per deciliter), 2,223 patients received a placebo, and 2,221 took simvastatin, a second-generation statin from Merck produced by the synthetic modification of lovastatin. The results of this study, a milestone in cardiology and evidence-based medicine, were conclusive. The group of patients taking simvastatin not only showed statistically significant decreases in total blood cholesterol and LDL cholesterol of 25 and 35 percent, respectively, but also a 42 percent decrease in death rate.
These stunning results and the successful trials with Mevacor drew other pharmaceutical companies into the statin market. Sankyo, for instance, eventually teamed up with Bristol-Myers Squibb to distribute and sell a derivative of mevastatin with increased efficacy, pravastatin (marketed as Pravachol).
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