Genesis of Statins

As evidence grew that high blood cholesterol levels were linked to heart disease, scientists in both academia and industry began to look for drugs to lower cholesterol as early as the 1950s. Before Akira Endo discovered the first statin, mevastatin, in the 1970s, many things, including hormones, vitamins, and resins, were tried to lower cholesterol. Some worked, and some did not. Thyroid hormone was one of the fi st drugs used for that purpose. The cholesterol-lowering properties of dextro-thyroxine were discovered by serendipity. At one point, surgical removal of part of the thyroid gland had been used to relieve angina, the pain brought on by exercise in coronary artery disease. Doctors observed that thyroid removal also raised the blood cholesterol level, which in turn sped up arterial degeneration. By deduction, the doctors reasoned that taking thyroid hormone should then decrease blood cholesterol levels. Initial clinical trials proved this theory, and dextro-thyroxine was used to lower cholesterol beginning in the 1950s, when thyroid extract became a standard treatment for hypercholesterolemic (high cholesterol) patients. Unfortunately, too much thyroid hormone made patients tremble all the time. Later, a large-scale, long-term clinical trial named the “Coronary Drug Project” established the association of dextro-thyroxine with ischemic heart disease as a severe side eff ect in men. As a consequence, thyroid hormone treatment was discontinued. Women, in contrast to men, enjoy natural cardiac protection through the action of the female sex hormones, the estrogens. In 1930, a minute quantity of estrogen was isolated from the ovaries of 80,000 sows. In the 1950s, reports appeared that estrogen could lower blood cholesterol levels even more effectively than nicotinic acid, another anticholesterol drug used at the time. Unfortunately, men on estrogen for too long began to develop feminine traits, including breast enlargement and loss of libido, and other side effects, although they did acquire relative immunity from heart attacks until late in life. Due to the lack of safe and effiicacious drugs, some doctors seemed willing to take their chances with estrogens.

Reflections

The story of statins is a success story for science (both basic and applied) and scientists (in both academia and industry). It contains one of the classic scientific and marketing battles in the history of the pharmaceutical industry. More important, it has been a great boon for the millions of patients who have benefited from statins in preventing coronary heart disease. The story of the statins is a triumph of the heart. Statins, a class of cholesterol-lowering drugs, have revolutionized the landscape of coronary heart disease treatment. Since Merck’s marketing of Mevacor in 1987, the world has benefited from statins in numerous ways. As a class of drugs, statins have set standards on numerous fronts in helping manage LDL cholesterol, one of the major risk factors for coronary heart disease. Statins set a high standard in efficacy, a high standard in safety, and a high standard in financial success for the patients, payers, and the pharmaceutical industry. Not only do statins greatly reduce cholesterol and lower mortality in people at risk for heart attacks, but some studies also suggest that they might help prevent or treat a wide range of ailments, including Alzheimer’s disease, multiple sclerosis, bone fractures, some types of cancer, macular degeneration, and glaucoma. The world has already benefited from the statins in many ways. Low is good, but lower is even better. Fifty years ago, the connection between cholesterol and coronary heart disease was still in question. Twenty years ago, the merit of lowering LDL cholesterol was not even unanimously agreed upon. Cholesterol drugs before the statins, such as resins, niacin, and fibrates, worked to some extent but were also seriously limited by their side effects. Thanks to the emergence of the statins, with Mevacor as the first on the market in 1987, all these questions on the relationship between cholesterol and coronary heart disease are answered beyond any shadow of doubt. Today, the statins have annual sales of more than $20 billion. Hundreds of millions of patients have benefited from statins by delaying and even preventing coronary heart disease.

To Market, to Market

Parke-Davis submitted Lipitor’s New Drug Application to the FDA in June 1996 and received approval in December 1996, a relatively short turnaround due to its priority review status. At the time, four statins were already on the market: Merck’s lovastatin (Mevacor, 1987) and simvastatin (Zocor, 1991), Bristol-Myers Squibb’s pravastatin (Pravachol, 1991), and Sandoz’s fluvastatin (Lescol, 1994). Th e sixth statin, Bayer’s cerivastatin (trade names Baycol and Lipobay), another optically pure synthetic statin like Lipitor, was soon to be on the market. The success of the four existing statins had already educated physicians about the benefits of lowering cholesterol levels. More important, Merck’s “4S” clinical trials (the Scandinavian Simvastatin Survival Study; see chapter 3) decisively demonstrated the positive impact of lower cholesterol levels in decreasing coronary heart disease. As a consequence, not only did the FDA approve Lipitor in only six months, but it was also widely and warmly accepted by general practitioners and patients immediately after it was available. When the drug was launched at the beginning of 1997, Warner-Lambert chose Pfizer as its comarketing partner because Pfizer had the strongest sales muscle in the drug industry. Today it is hard to imagine that when Pfizer was founded in 1849, it was a modest laboratory in Brooklyn, New York. By 2008, more than 150 years later, it had grown to become the largest pharmaceutical company in the world. In the revolutionary year of 1848, thousands of Europeans immigrated to America to seek new opportunities. Among them were a chemist (the equivalent of today’s pharmacist), 20-year-old Charles Pfizer, and his brother-in-law, 22-year-old confectioner Charles Erhart, from the small town of Ludwigsburg in Wuerttemberg, Germany. Unlike many German immigrants at the time who immediately joined the Gold Rush, Pfizer and Erhart decided to stay in New York City and make a living by taking advantage of the crafts that they learned in Germany. With $2,500 borrowed from Pfizer’s father and a $1,000 mortgage, they bought a small brick factory in the Williamsburg section of Brooklyn, largely a German neighborhood. Thus, Chas. Pfizer Co., Inc., Specialists in Fine Chemicals was founded.

Discovery of Lipitor

Parke-Davis was not the first drug company to put a statin on the market (Merck was), but it was the one to do it the best, with Lipitor (atorva statin). When Parke-Davis Pharmaceuticals in Ann Arbor, Michigan, began to look for its own statin in 1982, it was late in the game. Parke-Davis’s Lipitor was discovered in the mid- to late 1980s and brought to market in 1997. Already ahead of it were four statins: Merck’s Mevacor was released in September 1987 and Zocor in December 1991, Bristol-Myers Squibb’s Pravachol in October 1991, and Sandoz’s Lescol in March 1994. Despite the competition, by 2006 Lipitor had become the best-selling drug in history, with one-year sales totaling $12.9 billion, more than the net worth of the 10th biggest drug company in the world. Although the drug firm Parke-Davis had in recent times been relegated to history books, half a century ago, Parke, Davis and Company once enjoyed the status of the largest pharmaceutical manufacturer in the world. In 1866, 38-year-old Hervey C. Parke, a businessman, and Samuel P. Duffield, a chemist and physician, founded Duffield, Parke & Company— Manufacturing Chemists in Detroit, Michigan. Duffield originally studied under the father of organic chemistry, Justus von Liebig, at the University of Giessen in Germany. He continued to pursue his academic interests even after the founding of the company and published several articles in the American Journal of Pharmacy. In 1867, 22-year-old George S. Davis joined the company as the firm’s first salesman. Four years later, Parke and Davis bought out Duffield’s shares of the company. In November 1871, Parke, Davis & Company was born, with Parke as the president and Davis as the general manager. The company’s inventory was typical of the time: aconite, belladonna, ergot, spirit of ammonia, arsenic, and ether. Davis, a Napoleonic, small-statured man, was clearly responsible for building the company’s sales and its enterprise in many directions. He pioneered product promotion by publishing books and magazines, a practice later followed by many other companies. When vaccines were first invented in Europe, Parke-Davis was one of the first pharmaceutical companies to move into this new field.

Merck’s Triumph

Merck was not the first to discover a statin (Akira Endo at Sankyo was), but it was the first company to bring one successfully to market. In September 1987, the FDA approved Merck’s Mevacor (lovastatin) for marketing in the United States while Sankyo’s mevastatin was resting in peace in the big graveyard of drugs that failed to reach the market. In 2007, Merck & Co. was ranked the third largest pharmaceutical company in the world, both by capital and by revenue, behind only Pfizer and GlaxoSmithKline. The drug juggernaut traces its origin to a humble apothecary shop in Darmstadt, a central German city 20 miles south of Frankfurt. In 1668, 47-year-old apothecary Friedrich Jacob Merck purchased the Engelapotheke (Angel Pharmacy) in the Hessian town and began trading fine chemicals. Most popular was laudanum, an alcoholic solution of opium, which was in every physician’s medicine chest and used as a “panacea” for many illnesses. In 1827, Heinrich E. Merck inherited the family business and established a chemical laboratory named “E. Merck & Co.” beside the Angel Pharmacy. There, he pioneered the commercial large-scale production of various medicinal alkaloids, including veratrine, codeine, atropine, quinine, coniine, and morphine. In 1860, Albert Niemann, working in Friedrich Wöhler’s laboratory in Göttingen, Germany, isolated the active principle of coca leaves as a white crystalline alkaloid and christened it “cocaine.” Since new compounds were routinely tasted, Wöhler recorded that “cocaine was a substance which had a somewhat bitter taste and exerted a numbing influence upon the gustatory nerve, so that they became almost completely insensitive.” Capitalizing on its financial success with alkaloids, E. Merck began to isolate cocaine from coca leaves in the early 1880s and aggressively marketed it as a pain killer. Interestingly, Sigmund Freud, the father of psychoanalysis, enthusiastically took part in exploring cocaine’s medical utilities. After procuring some cocaine from E. Merck, the young neurologist swallowed a small quantity of the drug, which calmed his stomach and boosted his libido. Freud also applied some cocaine locally to himself and found that it temporarily paralyzed the sensitivity of a certain area without any marked effect on the central nervous system.

Baycol, Crestor, and Cholesterol Drugs beyond Statins

In 2001, the National Heart, Lung, and Blood Institute, a division of the National Institutes of Health, released new guidelines for the treatment of hypercholesterolemia. These guidelines called for patients with an average risk of coronary heart disease to reduce their LDL-cholesterol levels to less than 130 mg/dL; for those at high risk, the target is less than 100 mg/dL; and for the highest risk patients, the target is less than 70 mg/dL. The new guidelines nearly tripled the number of Americans who stood to benefit from drug therapy to get their lower cholesterol levels—to 36 million from 13 million. Statins had already become the drug of choice for cholesterol control. Statin awareness was further raised in the wake of former President Bill Clinton’s well-publicized heart attack in September 2004 after he stopped taking Zocor. Increasingly, new data demonstrated the benefits of reducing cholesterol levels even further than physicians had been advocating. The sales of statins therefore skyrocketed, reaching $21 billion in 2004 and $22 billion in 2005. Just like everything else, not all statins are created equal, a point clearly demonstrated by the story of Baycol. No medication, not even a nonprescription drug like aspirin or acetaminophen that you buy over-the-counter, is 100% safe. Whether or not you realize it, whenever you take a drug, you are weighing the potential benefits against the possibility that the medicine can hurt you. This analysis is what the experts call the risk–benefit profile of a drug. Four months after Lipitor was launched for sale, the FDA approved cerivastatin, the sixth statin, for use in lowering cholesterol in 1997. Germany’s Bayer A. G. sold it under the trade name Baycol and Lipobay (for the free acid form) until it was forced to withdraw it from the market in August 2001. Baycol was discovered by a group of Bayer scientists led by medicinal chemist Rolf Angerbauer and biologist Hilmar Bischoff in Wuppertal, Germany, in the late 1980s. It was only the second optically pure synthetic statin on the market (Lipitor was the first).

Development of Lipitor

From Sankyo’s experience, Roger Newton and his pharmacology colleagues at Parke-Davis learned that the rat is not a good animal model for cholesterol-lowering drugs because the rat’s liver is able to rapidly compensate for the drop of cholesterol. So, for initial in vivo efficacy studies, Newton’s team chose guinea pigs and divided them into two sets: one normal group and the other a chow-fed group. The pharmacologists then gave different groups of guinea pigs Merck’s Mevacor (lovastatin) as a reference or CI-981 in one of three different doses. When the results were tabulated, Parke-Davis scientists were underwhelmed: not only was CI-981 no better than lovastatin in lowering cholesterol, but it seemed even a little inferior. However, they continued with the animal studies with a higher species—the dog. They used cholestyramine-primed dogs since the plasma cholesterol-lowering effects became more pronounced after the dogs had been fed with the cholesterol-lowering resin. Unfortunately, again in dogs, CI-981 showed LDL-cholesterol–lowering efficacy about the same as that of lovastatin at the doses tested. Upon further scrutiny of the data, the only advantage that the pharmacologists could fi nd was that CI-981 lowered triglyceride levels slightly better (20–40%) than lovastatin in those animal models. In 1988, Mevacor had already been on the market for an entire year. Merck’s Zocor and Bristol-Myers Squibb’s Pravachol were poised to be launched in 1991, and Sandoz’s Lescol would be ready to launch in 1994. In addition, Rhône- Poulenc Rorer’s dalvastatin was at a similar stage as CI-981 in development. Either dalvastatin or CI-981 would have become the fifth of its kind on the market. Parke-Davis believed that they would need differentiation in order to successfully sell its drug. After all, CI-981 had to be different from, hopefully better than, existing drugs, for them to make a good profit. Parke-Davis’s belief that they needed to differentiate CI-981 from existing statins had its root in another Parke-Davis drug, Accupril (quinapril), an ACE inhibitor poised to launch in 1991.

Cholesterol

The story of statins starts with cholesterol because statins are a class of drugs that reduce low-density lipoprotein (LDL) cholesterol, the “bad” cholesterol. LDL cholesterol, in turn, is a major risk factor for coronary heart disease, the leading cause of death worldwide and projected to remain so through 2025. About 1.5 million Americans suffer heart attacks each year, and heart disease has emerged as the biggest cause of death in the United States, killing 911,000 people in 2003. Before the 1940s, the average lifespan in America was 47 years, and heart disease did not contribute to mortality to a large extent because people often died of infections. Currently, an average American lives to celebrate her 77th birthday. As a consequence, heart-related disease has risen to be the number one killer. Coronary heart disease manifests in many forms: angina, arrhythmia, atrial fibrillation, congestive heart failure, hypertension, atherosclerosis, myocardial infarction (heart attack), and sudden cardiac death. Atherosclerosis, or blockage in arteries, results when a buildup of cholesterol, inflammatory cells, and fibrous tissue called plaques forms on an artery wall. If these plaques rupture, they can block blood flow to critical organs such as the heart or brain and can lead to heart attack or stroke. Despite the many different forms of cardiovascular disease, the molecule cholesterol is a common denominator for most of them. Therefore, in order to understand coronary heart disease, we first need to take a look at the cholesterol molecule. According to Roman mythology, Janus is the guardian of portals and patron of beginnings and endings. Just like the two-faced Roman god, cholesterol is a double-edged sword for the human body. On the one hand, it is an essential building block for many crucial ingredients the body needs. On the other hand, it can be lethal when it forms plaques on the surface of the arteries and subsequently causes coronary heart disease. Make no mistake, cholesterol is vital to our existence. It is most abundant in our brains—23% of total body cholesterol resides there, making up 1/10th of the solid substance of the brain.