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
Rumors of Tumors
In April 1976, Boyd Woodruff, then executive administrator of Merck, heard through the pharmaceutical network that Sankyo had a patent application covering mevastatin, and he inquired about obtaining a sample for evaluation under a confidentiality agreement. Sankyo assented and provided samples of the compound together with a report on its properties.
During the next couple of years, Merck studied mevastatin in cultured mammalian cells and in rats and dogs. By October 1978, they had obtained results that largely confirmed those of Endo and colleagues. Impressed by its efficacy, Alfred W. Alberts, a lipidologist at Merck, initiated fungal-culture screens to find another statin, one that Merck could call its own. In a matter of only two weeks, Alberts and colleagues found one. Sample number 18—derived from the common soil fungus Aspergillus terreus—contained lovastatin, which is structurally identical to mevastatin except for a single methyl group. Better still, at least for Merck, lovastatin proved every bit as effective as mevastatin.
By then, Sankyo was running clinical trials on mevastatin, but it hit a deadly snag. Rumor—and that is all that we have to this day—had it that some of the dogs treated with mevastatin developed intestinal tumors. So in the fall of 1980, Sankyo halted its trials.
Knowing that only a methyl group distinguished lovastatin from mevastatin, Merck, too, immediately halted its testing on people, recalling all outstanding samples from clinical investigators and notifying the U.S. Food and Drug Administration (FDA). Although only a few patients had received lovastatin, and only at low doses, Merck still advised the physicians who were conducting the trials to check very carefully for signs of cancer in their subjects.
Merck then set out to determine the exact nature and extent of the problems that Sankyo had seemingly encountered. Failing to track down any solid evidence of harm, P. Roy Vagelos, then president of Merck Research Laboratories, and Barry Cohen, Merck's head of international business, flew to Japan. As he was to relate years later in his 2004 autobiography (coauthored with historian Louis Galambos of Johns Hopkins University), Vagelos took aim at getting to the bottom of the problem by making a business proposition to Sankyo: "If you help us solve this problem, we'll share Mevacor [trade name for lovastatin] with you in Japan, and you can share your second-generation product with us when you're ready." Sankyo executives said that they wanted to cooperate, but couldn't. Apparently, their bosses at Sankyo saw it as bad for business.
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