Field of Science

An industrial tour de force laid bare

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Statins revolutionized the prevention and treatment of heart disease and saved hundreds of thousands of lives that may have been otherwise lost through heart attacks and stroke and millions of dollars that would have been paid by patients for surgery and other invasive treatments. The best selling molecule in this class(atorvastatin, Lipitor) is the best selling drug of all time and makes more than 12 billion dollars for its parent company, Pfizer. In this engaging and informative book Jie Jack Li, a scientist at Bristol-Myers Squibb company, tells us their story and drives home the importance of the pharmacautical industry at a time when much of the public has become cynical about its motives.

What makes the book valuable is that Li traces not just the history of the drugs themselves but the history of cardiovascular and obsesity research as well as the major players involved in this research. Li also spices up his accounts with amusing ancedotal information about scientists and companies. He narrates the famous Framingham study which definitively established the connection between high cholesterol and heart disease, a connection that has been tentatively explored for more than a hundred years. Also included are interesting historical accounts of several major pharmaceutical companies including Merck, Parke-Davies and Pfizer.

Cholesterol is a remarkable molecule that is the classic embodiment of a double edged sword. Michael Brown, a Nobel prize winning cholesterol researcher calls it a "Janus-faced" molecule, one which is critical in biological function while being harmful when employed incorrectly. No less than thirteen Nobel Prizes have been awarded to researchers who worked on this molecule. Lie traces the pioneering research of several chemists like R B Woodward and Konrad Bloch (Harvard), Lewis Sarrett and Max Tishler(Merck), Dorothy Hodgkin (Cambridge), John Cornforth (MRC, 91 and still going strong) and Wieland and Windhaus (Germany) who were key in elucidating both the pathway of cholesterol synthesis and metabolism, as well as the structures and syntheses of cholesterol and its analogs.

Most of the cholesterol in the body (~70%) is biosynthesized while the rest of it comes from the diet. It forms a crucial component of membranes and is a key signaling molecule. 23% of body cholesterol ends up in the brain where its critical functions are still being investigated. The connection between high cholesterol and heart disease was suspected early on but had to await much pioneering research in order to be deciphered in detail. The Framingham study in Massachusetts studied thousands of local subjects spread over almost 50 years and two generations and established the best correlation between heart disease and cholesterol to date. The study is a landmark because it also analyzed several of the now widely known risk factors for heart disease, including the effects of diet, smoking and exercise. It also established a critical standard; a 1% lowering of cholesterol can lead to a roughly 1% reduced risk of heart disease.

After the correlation was established, both academic and industrial scientists started looking for drugs that would reduce cholesterol. Key during this time was Michael Brown and Joseph Goldstein's discovery of the LDL receptor as a major player in cholesterol metabolism and the importance of LDL and HDL in causing heart disease. Today efforts are underway to both reduce LDL and increase HDL as strategies in combating heart disease. Lie talks about the three dominant pre-statin drugs that were widely used; niacin (vitamin B3), bile acid sequestrants and fibrates. All these drugs had unpleasant side effects although niacin is still seriously considered by companies like Merck as a possible cholestrol-lowering drug. It was in the 70s that research pioneered by Akiro Endo, P. Roy Vagelos and others suggested the initial steps in cholesterol synthesis as prime targets for possible drugs. The logic was rather simple; targeting later steps would lead to a buildup of high molecular weight lipophilic molecules that would cause problems. It was best to target early steps which would lead only small, relatively water soluble and easily excreted molecules to accumulate. Several studies finally settled on 3-hydroxy, 3-methyl glutaryl coenzyme A reductase (HMG-CoA reductase) as the rate limiting enzyme in cholesterol biosynthesis, and one which could possibly be fruitfully inhibited.

It was Japanese biochemist Akiro Endo who painstakingly discovered the first statin in a broth of a Penicillum fungal strain (it's interesting that this humble mold has yielded two of the most important drugs in history, statins and peniciilin). However it was Merck who ran with the idea and brought the first statin to market (lovastatin, Mevacor). The 1980s were the golden age of Merck. During this decade Merck was led by one of the best CEOs in the industry, P. Roy Vagelos who was an accomplished researcher himself and a true visionary. Under his direction Merck was voted as the best company (and not just pharmaceutical company) in the country for three successive years. The reason why Merck thrived and indeed the reason why everyone today should emphatically remember Merck's success was because it followed a time-honored tradition of recruiting only the best scientists (frequently from academia) and more importantly, focusing intensely on basic academic-style research. In the 1950s Merck hired two brilliant academic scientists, Lewis Sarret (Princeton) and Max Tishler (Harvard) whose work catapulted the company into the front lines of drug discovery. This trend continued in the 70s and 80s. Vagelos himself had been the head of the biochemistry department at Washington University School of Medicine when he was hired and had done important work in elucidating the role of HMG-CoA reductase in cholesterol biosynthesis. During the 80s Merck regularly published papers in the best academic journals. In an age where an emphasis on profits and a relative lack of interest in basic research has slowed down drug discovery, it should be time for pharmaceutical companies to again look at the 1980s Merck model of basic research.

It was this model that brought the first statin (Mevacor) to market after intense development. Li engagingly tells us the story of both Merck and Mevacor. However the bulk of the book thereafter is the story of the best selling drug of all time, Lipitor (atorvastatin). Atorvastatin was discovered by Parke-Davis (which was subsequently bought by Pfizer). By the time the Parke-Davis group plunged into statin discovery they already had a tough act to follow since four statins were already on the market. However, as Li describes, statin research at Parke-Davis benefited from a combination of thorough assay development and highly talented scientists. Foremost among them were Bruce Roth, a synthetic chemist who first synthesized Lipitor, and Roger Newton, a biologist who developed the assays. The researchers started with some known statin structures and experimented with installing novel cores and side chains by overlapping the molecules on top of each other. One of the strategies to improve bioavailibility turned out to be to use the ring opened compound instead of the lactone which had been a mainstay of some other statins. The synthesized molecules were shuttled into animal testing which was no cakewalk. The choice of animal turned out to be important since rats are not good models for testing cholesterol lowering medicines; among other factors this is because rats have a dramatically different LDL/HDL ratio compared to humans. Other animals including dogs and monkeys yielded valuable results.

Clinical trials finally demonstrated that atorvastatin had much better pharmacokinetic and bioavailability characteristics compared to earlier statins. Atorvastatin also has a much more favorable profile with respect to the one serious side effect seen with statins- rhabdomylosis or muscle weakness and wasting. Indeed, statins have emerged as some of the most well-tolerated drugs of all time. Total sales are now more than 20 billion dollars. Any new drug developed for lowering cholesterol will have to meet the extremely high bar that statins have set. These drugs are the best examples of the kind of genuinely life-altering research that can come from the pharmacutical industry.

These days the pharmaceutical industry is often maligned as a notorious example of the money-milking, profit-making entities that apparently exemplify the worst in capitalism. But the story of statins reminds us of some valuable facts. Firstly, it is always worth looking at the other side of the coin, at how many lives and dollars would have been expended had such drugs not been discovered; the immense benefits accruing from the avoidance of heart attacks and stroke handsomely pay off in social and economic terms. Secondly, contrary to some public perception, scientists in the pharmaceutical company are as dedicated not just to improving the lives of people but to gaining basic scientific knowledge as are academic researchers; as a corollary to this fact, a lot of industrial research is as exciting as academic research. Thirdly, the story of statins also shows the close interplay between academic and industrial scientists and discoveries that drive innovative drug discovery. As in many other case, the choice is not binary, and it is only healthy public support of both industrial and academic research that can lead to a thriving scientific establishment. Finally and importantly, the story is ominous but also hopeful in a sense since it demonstrates that true scientific and commercial productivity can only come from focusing on basic and long-term scientific research and not just on short-term profits. This is a message that today's pharmaceutical companies should heed well.

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