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
Improving on Nature
Although Sankyo and Merck both originally isolated valuable statins from natural sources, their later efforts were directed at manufacturing them synthetically. In the early 1980s, Merck filed a patent that showed that some of the complexities of the fungal metabolites were superfluous and could be eliminated without compromising biological activity.
At about this time, five years before the FDA approved Mevacor, Bruce D. Roth, then a 28-year-old postdoc in the chemistry department at the University of Rochester, started tinkering with statins, exploring their synthetic chemistry. In the spring of 1985, he succeeded in synthesizing one of the fungal statins that Endo and Kuroda had isolated a few years before.
Within only two years, Roth found himself heading up an 18-scientist atherosclerosis group at Parke-Davis Pharmaceutical Research. And while they made remarkable progress in fabricating their first synthetic HMG-CoA-reductase inhibitor, this was scuttled when they were notified that Sandoz AG, a Swiss drug company that is now part of Novartis, had obtained a patent for the very same compound. Parke-Davis was left with no other option but to turn its efforts toward what started out as a second-tier drug called atorvastatin—now known better by its trade name, Lipitor.
By the time Parke-Davis had Lipitor ready to present to the FDA, it was late 1989, and three statins—Mevacor, Zocor and Pravachol—were already approved for sale. Did this mean that the market was already saturated? According to Ron Winslow, later writing in the Wall Street Journal, the decision Parke-Davis made arose from economic rather than scientific considerations. First, the patent for Parke-Davis's Lopic—a treatment for high serum-triglyceride levels, which was also the company's most-successful drug with annual sales of about $600 million—was about to expire. Second, the statin market looked likely to grow into one of the biggest pharmaceutical boons of all time. In short, if Parke-Davis could capture even a small piece of the action, Lipitor could become the company's best seller.
These considerations were to be the tipping point. Parke-Davis moved the compound into clinical trials to show that doses of Lipitor of 10 milligrams and 80 milligrams per day decreased LDL-cholesterol levels by 40 and 60 percent, respectively. These were decreases in LDL-cholesterol levels that beat every other available statin—at any dose—by at least 40 percent.
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