Drug Truths

Dispelling the Myths About Pharma R & D

John L. LaMattina

• Publisher: Wiley
• Year: 2012
• Print ISBN: 9780470393185
• eBook ISBN: 9781118158968
• Edition: 1
• Topic: Medicine
• Subtopic: Pharmacology

This book answers the questions about the process and costs of pharmaceutical R & D in a compelling narrative focused on the discovery and development of important new medicines. It gives an insider's account of the pharmaceutical industry drug discovery process, the very real costs of misperceptions about the industry, the high stakes--both economic and scientific--of developing drugs, the triumphs that come when new compounds reach the market and save lives, and the despair that follows when new compounds fail. In the book, John LaMattina, former president of Pfizer Global Research and Development, weaves themes critical to a vital drug discovery environment in the context. This is a story that Dr. LaMattina is uniquely qualified to tell.

PART I: A MATTER OF THE HEART

IN THE 1990s, work from a number of academic laboratories suggested that infection with a certain pathogen, Chlamydia pneumoniae, might play a role in the development of coronary artery disease. The scientific evidence for this was intriguing. For one thing, blood analysis of patients with heart disease showed evidence of prior C. pneumoniae infection. In addition, multiple studies showed that this organism was actually present in atherosclerotic plaques. Finally, animal studies showed that infection with C. pneumoniae accelerated the development of atherosclerosis.

That a pathogen like C. pneumoniae could play a role in heart disease wasn’t far-fetched. The atherosclerotic process is initiated by inflammatory processes and bacteria are known to be a cause of such events. Furthermore, the role of bacteria in noninfectious diseases has precedence. Dr. Barry Marshall won the Nobel Prize for his work in showing that such a pathogen, Helicobacter pylori, was the cause of peptic and gastric ulcers, thereby leading to new methods of treating gastrointestinal disease.

Early clinical trials of preventative antibiotic treatment in patients with heart disease provided mixed results. These studies were deemed to be of too short duration or too small in terms of numbers of patients to see an effect on reducing heart attacks. Thus, in the late 1990s, three large-scale long-term studies were begun to get an answer to the relevance of C. pneumoniae in cardiovascular disease.

The first study was the “Weekly Intervention with Zithromax for Atherosclerosis and Its Related Disorders” (WIZARD).¹ In WIZARD, 7747 patients who had suffered a previous myocardial infarction were randomized to receive either azithromycin (Zithromax) on a weekly basis for 12 weeks or a placebo. These patients were then monitored for a year while looking for a reduction in cardiovascular events such as recurrent fatal or nonfatal heart attacks, hospitalization for bypass surgery, balloon angioplasty, or angina. The result: at the end of 12 months, there was no difference in cardiac outcomes between patients who took azithromycin as compared to placebo.

Perhaps to see the desired effect, azithromycin needed to be dosed for a longer period of time and patients needed to be followed for more than one year to see the potential overall benefit. This was the basis for the ACES trial,² “The Azithromycin and Coronary Events Study.” This trial, which involved 4012 patients, had a design that paralleled the WIZARD study except that patients were dosed for a year and then followed for 3.5 years. Unfortunately, the result for ACES was the same as in WIZARD: There was no significant risk reduction in heart attacks or strokes between azithromycin and placebo.

Finally the third study,³ “Antibiotic treatment of Chlamydia pneumoniae after Acute Coronary Syndrome,” was also conducted at this time using a different antibiotic, gatifloxacin. This trial enrolled 4162 patients who had recently been hospitalized with acute coronary syndrome. Patients were randomized to drug and placebo, but in this study the patients were given a monthly regimen of gatifloxacin for two years. After 30 months of follow-up at the end of the 2-year dosing period, again there was no difference between the antibiotic and placebo groups in terms of reducing cardiovascular events.

Why did these efforts to eradicate C. pneumoniae fail to provide a beneficial effect on heart disease? There is no clear answer. It is possible that the bacteria must be eradicated at the early stage of the process of atherogenesis before the disease fully sets in. However, these studies proved conclusively that antibiotics should not be recommended for treating coronary heart disease.

These studies involved hundreds of scientists and physicians from around the world and cost tens of millions of dollars, and they could only be accomplished with the novel antibiotics discovered by the pharmaceutical industry along with their resources of talent and funds. These clinical trials were designed jointly by industry scientists and clinicians along with their academic collaborators who performed these experiments at academic medical centers. However, the risk involved in terms of financing these studies rested solely in the lap of the pharmaceutical company sponsors. The C. pneumoniae story is a great example of the core contribution that the pharmaceutical industry makes to medicine: it proves or disproves medical hypotheses—in this case, that eradication of C. pneumoniae has no impact in preventing cardiovascular events.

Part one of this book focuses on these contributions with respect to cholesterol and heart disease. As you will see, when a medical hypothesis is proven, patients and pharmaceutical companies benefit. Likewise, when a medical hypothesis turns out to be incorrect, the disappointment can reverberate not just through companies but also through patients, physicians, and scientists.

CHAPTER 1

CHOLESTEROL DRUGS ARE UNNECESSARY

IT IS virtually impossible to go a day without being reminded of the relationship of heart disease and high cholesterol levels. While walking through grocery store aisles, you are hit with a variety of no-cholesterol, low-fat foods. Simply reading a magazine or watching television will expose you to advertisements warning of the dangers of high cholesterol resulting from diet or from poor genes. Drugs to treat high cholesterol, commonly known as statins, are the most highly prescribed drugs in history. Even the spokespeople for statin drugs, such as the inventor of the artificial heart, Dr. Robert Jarvik, have become highly scrutinized.

And yet, a little over 20 years ago, the relationship between heart disease and high cholesterol levels was unproven and largely ignored.¹ In fact, in 1989 The Atlantic Monthly featured an article entitled “The Cholesterol Myth,” which said: “Lowering your cholesterol is next to impossible with diet, and often dangerous with drugs—and it will not make you live any longer.”² Furthermore, if you had a total cholesterol level of 300 mg/deciliter (dL), you were considered to be on the upper end of normal. And no one had a clue as to their own relative ratios of high-density lipoproteins (HDL), the so-called “good” cholesterol, and low-density lipoproteins (LDL), the “bad” cholesterol. This began to change in the 1980s with the publication of a number of studies that began to provide concrete evidence that there was truly a causative role for cholesterol and particularly LDL cholesterol in heart attacks and strokes. One such study was the Framingham Heart Study.

This landmark study has been ongoing since 1948. It has been administered by the National Heart, Lung and Blood Institute of the NIH and was begun with over 5000 adults from Framingham, Massachusetts. Studying this population for 25 years enabled the identification of a number of risk factors for identifying potential victims of heart disease. These factors included smoking, excess weight, lack of exercise, stress, hypertension, and a high total cholesterol/HDL ratio.³ While some of these risk factors were already well-accepted, the Framingham Study provided strong evidence that abnormal lipids were also a major risk factor.

At the same time, the results of another major study appeared. The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) studied the effects of lowering cholesterol levels in reducing heart disease in 3800 middle-aged asymptomatic men with high cholesterol.⁴ These men were studied for seven years with half of the group on placebo and the other half on a compound called cholestyramine, a resin that acts as a bile acid sequestrant and thereby was known to lower cholesterol levels modestly. Both groups were on a moderate cholesterol-lowering diet. The results of this study proved convincing. The cholestyramine patients had their overall cholesterol lowered by 13% and their LDL cholesterol lowered by 20%, as compared to 5% and 8% for those on placebo. This lowering of cholesterol resulted in a 24% reduction in definite death due to heart disease, as well as reductions in heart attacks, angina, and coronary bypass surgeries. For the first time, proof was in hand that lowering total cholesterol and LDL cholesterol had a direct impact in reducing heart disease. These results were compelling enough that the NIH began to encourage physicians to teach patients about the importance of treating high cholesterol.⁵

While these data were encouraging, a major difficulty needed to be overcome. Cholestyramine was not a patient friendly medicine. Up to 20 grams of this drug needed to be taken in divided doses two to three times per day. These large doses tended to cause adverse gastrointestinal effects such as constipation, gas, and bloating. But the biggest hurdle for patients was taking the dose of medicine itself as it is an insoluble resin. It has been described as drinking liquid cement. Clearly, better-tolerated cholesterol-lowering medicines were needed.

At about this same time, a discovery was made that eventually revolutionized the treatment of heart disease. A Japanese microbiologist, Akira Endo at the Sankyo company in Tokyo, was searching fermentation broths of Penicillium citrinum for novel antimicrobial agents.⁶ During this work he found a compound now known as compactin. This agent proved to be an inhibitor of an enzyme called HMG-CoA reductase. This enzyme is involved in the critical step in the body’s synthesis of cholesterol. Ironically, compactin did not have useful antimicrobial activity. However, the potential for using this agent in controlling high cholesterol levels was recognized by Endo. Theoretically, if one could safely block the actions of HMG-CoA reductase, the biosynthesis of cholesterol would be reduced, thereby lowering total cholesterol.

Sankyo designed and managed a clinical trial to explore the effects of compactin in humans. This study showed that it did, in fact, effectively lower both total cholesterol and LDL cholesterol in patients who were genetically disposed to high plasma lipids.⁷ Unfortunately, Sankyo had to suspend clinical trials with compactin due to unspecified adverse findings in animal studies.

Merck scientists were also actively pursuing this field of research, and their chemists discovered the HMG-CoA reductase inhibitor, lovastatin.⁷ Lovastatin was shown to be safe in healthy volunteers and proved to be very effective in lowering total cholesterol and LDL cholesterol in patients with heart disease. The efficacy of lovastatin was elucidated by the Nobel Prize-winning work of Michael S. Brown and Joseph L. Goldstein, who showed that statins, by virtue of blockading cholesterol biosynthesis, improve the ability of the liver to remove LDL from the blood, thus making it less likely for LDL to deliver cholesterol to the artery wall.⁸

Lovastatin was launched by Merck under the trade name of Mevacor in 1987. They then followed this breakthrough with a superior statin, Zocor (generic name: simvastatin) in 1991. Despite the availability of these two compounds, statins were still not universally prescribed in the early 1990s. The reason for this was twofold: First, physicians were reluctant to prescribe a drug that patients were to take for the rest of their lives without some assurances that long-term use of such drugs were indeed safe; second, while lowering cholesterol had beneficial effects in reducing the risk of heart disease, there was no evidence that long-term survival was enhanced. This all changed in 1994 with the publication of the results of the landmark Scandinavian Simvastatin Survival Study (4S).⁹ In this study, 4444 patients who had a previous myocardial infarction and serum cholesterol of 215–310 mg/dL on a lipid-lowering diet were treated with either simvastatin or placebo for 5 years. Over this time period, simvastatin produced mean decreases of 25% in total cholesterol and 35% of LDL cholesterol. But more importantly, only 182 patients on simvastatin (out of 2221) had died as compared to 256 (out of 2223) on placebo—a statistically significant risk reduction of 30%. The controversy was over as was evidenced in an editorial in the British Medical Journal entitled “Lower Patients’ Cholesterol Now.”¹⁰ Based on the 4S study and other examples, the authors concluded the following for patients with angina or with a previous myocardial infarction: “There is no longer any controversy about what to do for these patients and no justification for inertia.”

Thus, by the mid-1990s the principle of lowering LDL cholesterol was established. Statins were by far the agents of choice to control high cholesterol. The safety and ease of administration of statins was such that these compounds became the biggest selling drugs of all time. But suddenly all of this was again challenged in 2008 with the announcement of the results of a clinical study known as ENHANCE.

ZETIA^®: AN INHIBITOR OF DIETARY CHOLESTEROL ABSORPTION

Statins clearly are efficacious in lowering plasma cholesterol. However, one’s cholesterol level is impacted not only by the body’s synthesis of cholesterol but also by the amount of cholesterol and fat taken in through one’s daily diet. Theoretically, a compound that could block the absorption of cholesterol in the digestive tract would lower plasma cholesterol.

Given that statins are so effective, why would one care about lowering cholesterol absorption in the gut? First of all, despite the tens of millions of people who are successfully treated with statins, not everyone can tolerate these drugs. A small minority of patients do experience side effects that prevent statin usage. This is not unusual. As will be discussed in subsequent chapters, no medication can be successfully used universally, not even aspirin. Thus, having an alternative to statins is important to those with high LDL cholesterol who cannot tolerate them. Second, in theory a cholesterol absorption inhibitor should be able to be used in combination with a statin because their mechanisms would be anticipated to be complementary. For those people with established heart disease and very high LDL cholesterol, the combination of a statin with a cholesterol absorption inhibitor could theoretically provide better control than a statin alone.

Scientists at Schering-Plough were successful in discovering and developing such a compound, namely, Zetia¹¹ (genetic name: ezetimibe). While not as potent as statins, Zetia lowers LDL cholesterol by 18% as a stand-alone agent. It was on the basis of this activity that the FDA approved Zetia.

It is important to note that, unlike the situation with cholestyramine, niacin, or statins, studies have not yet been published on the reduction of heart attacks or strokes with Zetia. The FDA approved Zetia on the basis of its ability to lower LDL cholesterol by more than 15%. Essentially, the FDA approved this drug on its effect on a surrogate marker. The FDA will give approval of new drugs on the basis of the drug’s beneficial effect on well-established markers of disease. In the case of heart disease, given that the lowering of LDL cholesterol by three distinct mechanisms was shown to have great benefits for this sick population, the FDA established that novel lipid-lowering agents with unique mechanisms can also be approved provided that these agents lower LDL cholesterol by at least 15%. The FDA also requires that the manufacturer of such an agent conduct long-term studies post-approval to show the impact of this new compound on long-term outcomes such as heart attacks and strokes. However, given the strong scientific precedence in an area like this, it is felt that patients should have access to a compound that lowers LDL cholesterol in advance of the long-term outcome study results. Zetia certainly fit this paradigm.

The use of surrogate markers is not unique to the lipid-...

Table of contents

• Cover
• Title page
• Copyright page
• Dedication
• ACKNOWLEDGMENTS
• INTRODUCTION
• PART I: A MATTER OF THE HEART
• PART II: THE ROLE OF PHARMACEUTICAL R&D IN HEALTH CARE
• PART III: THE PROFIT MOTIVE
• PART IV: THE FUTURE
• REFERENCES
• Index
• Color Plates