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The Story Of Statins

Recounting the discovery of a class of drugs that revolutionized cardiovascular medical care

by John LaMattina
June 8, 2009 | A version of this story appeared in Volume 87, Issue 23

Credit: Newscom
Credit: Newscom

STATINS are the biggest selling class of pharmaceutical compounds of all time, with annual sales in excess of $22 billion. They are taken by hundreds of millions of people around the world as a way to ward off heart disease. Indeed, a recent article in Forbes magazine titled "Eat Your Statins" stated that to avoid a heart attack, people should stop taking vitamins and switch to cholesterol-lowering statins instead. The most popular member of the class, Lipitor, is a name that is now in the common vernacular. But where did statins come from? Why do so many patients take them? Are they really wonder drugs? These and many other questions are answered in a timely book from Jie Jack Li entitled "Triumph of the Heart: The Story of Statins."

TRIUMPH OF THE HEART: The Story of Statins,
by Jie Jack Li, Oxford University Press, 2009, 201 pages, $29.95 hardcover (ISBN: 978-0-19532-357-3)
by Jie Jack Li, Oxford University Press, 2009, 201 pages, $29.95 hardcover (ISBN: 978-0-19532-357-3)

Li, a medicinal chemist, has written a number of books concerning synthetic chemistry as well as more recent efforts in telling the stories around the discovery and development of important medicines. His recent book "Laughing Gas, Viagra, and Lipitor: The Human Stories Behind the Drugs We Use" attempts to humanize the R&D process. He has done the same with his new book. It is a story that he is well qualified to tell because during his career he has been a scientist at both Warner-Lambert Parke-Davis and Pfizer, where a good part of this history occurred.

While the story of statins is the focus of the book, Li also provides a veritable history of pharmaceutical science particularly around cholesterol. It is amazing to read about the number of Nobel Prizes that have been awarded for work in the cholesterol field, ranging from the identification of the molecular structure of cholesterol to the total synthesis of cholesterol, its biosynthesis, and the regulation of LDL (low-density lipoprotein) cholesterol through the liver. In covering almost a century of research on this topic, Li brings to life the great work in the 1940s and '50s of some of the early giants of synthetic organic chemistry such as Robert Robinson and Robert Burns Woodward. It is also striking how much has changed in science over the past several decades. For example, the elegance of natural products synthesis, so crucial in elucidating biological mechanisms, is now taken for granted.

Where did statins come from? Why do so many patients take them? Are they really wonder drugs?

Li correctly focuses on the famous Framingham Heart Study, which has been ongoing since 1948 and which highlighted for the American public the major risk factors for heart attacks, such as smoking, hypertension, obesity, and high cholesterol. But even with the publication of the Framingham Study, the market for cholesterol-lowering drugs remained small. There were a number of reasons for this. People were reluctant to take drugs for the rest of their lives when they were asymptomatic. In addition, the drugs available at the time—specifically, bile acid sequestrants, niacin, and fibrates—were not ideal. Finally, no one really knew how low one's LDL cholesterol needed to be. Thus, in 1982, the market for these drugs was less than $200 million.

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This all changed with the advent of statins, which first reached the market in 1987. Li justifiably gives a great deal of credit to the father of this field, biochemist Akira Endo, who isolated the first statin, mevastatin, from fermentation broths while at Sankyo, a Japanese pharmaceutical company. Endo was searching for inhibitors of the enzyme HMG-CoA reductase, a key to the biosynthesis of cholesterol, as it was envisioned that blocking the synthesis of cholesterol would result in lower cholesterol levels in plasma. In yet another example of a compound being used to elucidate biological processes, Michael S. Brown and Joseph L. Goldstein, doctors in the department of medicine at the University of Texas Southwestern Medical Center, demonstrated that blocking HMG-CoA reductase results in an upregulation of LDL receptors on the liver, thereby draining plasma of LDL. Brown and Goldstein won the Nobel Prize in 1985 for this work. Ironically, Sankyo never developed statins commercially.

Li devotes an entire chapter to Merck, the company that did in fact develop the first two statins (Mevacor and Zocor) to reach the market. The reader gets a clear sense of the tremendous admiration that the author has for Merck. This respect is not unfounded. Merck in the late 1980s and early '90s was the world's most admired company according to Fortune. Merck achieved this status through innovative R&D, and the architects who created this wonderful pipeline of products are given their due in the book.

WHEN MERCK STARTED its research into the statin field, it wasn't a given that a successful product would emerge from its efforts. In fact, Merck shut down the statin program when it saw toxicity in long-term animal studies. One of the failings of this chapter is the lack of detail and credit given to the subsequent studies that Merck toxicologists did to resurrect this class of compounds. (Merck toxicologists had also accomplished a similar feat with a class of agents used to treat ulcers called proton-pump inhibitors—again rescuing a very valuable franchise from initial adverse animal toxicology findings.) The commitment of Merck's P. Roy Vagelos to this field is what made these wonderful medicines a reality.

But the best part of this book is the account of the discovery and development of the most successful drug product of all time, Lipitor. Li's access to both Parke-Davis and Pfizer scientists provides an insider's view of how this compound was discovered—and almost not developed. It outlines the years of struggle that Parke-Davis endured in trying to discover its own statin. It also tells of the serendipity involved in discovering a new molecule as revealed by the lead chemist, Bruce Roth, who made the core pyrrole piece of the Lipitor molecule. Roth didn't have any initial insight; rather, he made this analog simply because he knew how to make pyrroles as a result of his Ph.D. thesis work.

The most memorable part of this story, however, involves how Parke-Davis management at a key internal meeting was getting ready to stop development of atorvastatin (generic name of Lipitor) because they believed that at best it would be the fifth statin to market and would be difficult to market against existing agents. What saved the day was the head biologist for the program, Roger Newton, getting on one knee and crooning to the tune of Al Jolson's "You Made Me Love You": "You've got to let us do the human tests. I know it's the right thing to do, and I'm begging you to do it." Management was impressed by the passion of Newton and the team. It also helped Newton's cause that the Parke-Davis pipeline was pretty bare at the time.

"Triumph of the Heart" has its flaws, particularly when Li steps away from his expertise as a medicinal chemist. He spends too little time on the toxicology issues that almost sunk statins at the start. In addition, the elegant work by Brown and Goldstein that revealed the mechanism of action of statins is given too little attention. He also understates the importance of the clinical studies with Lipitor in homozygous familial hypercholesterolemia patients. These studies gave the first clinically meaningful demonstration that the higher LDL-lowering ability of Lipitor had any clinical benefit over the competitive agents. Finally, more coverage of the Phase IV trials of Lipitor would have been very helpful. These trials changed medical practice in terms of the real value of getting LDL cholesterol levels to below 100 mg/deciliter, the importance of lower LDL cholesterol in people who are diabetic and hypertensive, and so on. These studies drove the expansion of the use of statins and established Lipitor as an extremely important medicine.

These criticisms are relatively minor, however. This is a lively book and one that captures the essence of the tribulations of the drug discovery and development process. Furthermore, it provides a valuable historical account of the pharmaceutical industry that should be of interest to anyone who wants to get a flavor of how tenuous the discovery of medicines truly is.

John LaMattina is the former president of global R&D at Pfizer.


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