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The Lock and Key of MedicineMonoclonal Antibodies and the Transformation of Healthcare$

Lara V Marks

Print publication date: 2015

Print ISBN-13: 9780300167733

Published to Yale Scholarship Online: January 2016

DOI: 10.12987/yale/9780300167733.001.0001

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The Challenge of Monoclonal Antibody Drugs

The Challenge of Monoclonal Antibody Drugs

(p.139) Chapter Seven The Challenge of Monoclonal Antibody Drugs
The Lock and Key of Medicine

Lara V. Marks

Yale University Press

Abstract and Keywords

This chapter discusses the efforts to develop monoclonal antibody (Mab) therapeutics. The quick commercialization of Mab diagnostics prompted many to assume that Mab therapeutics would soon reach the market. These high expectations were given a boost in June 1986 when the FDA approved Ortho Diagnostic Systems' Orthoclone (muromonab-CD3) in order to prevent kidney rejection in transplant patients. Orthoclone was the first Mab approved anywhere for use as a drug in humans. Yet Orthoclone was not without problems. Between 5 and 10 percent of patients on it experienced significant side effects, including fevers, thromboses, and anaphylactic shock. Other Mab therapies tested in this period also led to complications. Part of the problem was that the antibodies were derived from mice or rats, which the human immune system treated as foreign and attacked. Such antibodies also only survived for between fifteen and thirty hours in humans, so the drugs had to be infused in high and frequent doses. Moreover, their recognition of human receptors was poor.

Keywords:   Mab therapeutics, Mabs, monoclonal antibodies, Orthoclone, drug development, Mab drugs

GIVEN THE QUICK COMMERCIALIZATION of Mab diagnostics, many assumed that Mab therapeutics would soon reach the market. These high expectations were given a boost when in June 1986 the U.S. Food and Drug Administration (FDA) approved Orthoclone (muromonab-CD3), derived from the OKT Mab series, in order to prevent kidney rejection in transplant patients. Developed by Ortho Diagnostic Systems, a subsidiary of Johnson & Johnson, Orthoclone was the first Mab approved anywhere for use as a drug in humans. Hailed as a major improvement in transplant medicine, it was approved seven years after its discovery in 1979, a shorter development time than the average of eight to ten years for most drugs. Only two other biotechnology drugs, human insulin and human growth hormone, had been approved by this time, in 1982 and 1985, respectively.1

With Orthoclone’s approval, the future looked bright for Mab therapeutics. Yet Orthoclone was not without problems. Between 5 and 10 percent of patients on it experienced significant side effects, including fevers, thromboses, and anaphylactic shock, and these complications increased when the drug was given in multiple doses. Moreover, Orthoclone carried a risk of severe infections and cancer. Other Mab therapies tested in this period also led to complications. Part of the problem was that the antibodies were derived from mice or rats, which the human immune system (p.140) treated as foreign and attacked. Such antibodies also only survived for between fifteen and thirty hours in humans, so the drugs had to be infused in high and frequent doses. Moreover, their recognition of human receptors was poor.2

As was the case with diagnostics, biotechnology startups led the way with Mab therapeutic development. Focusing on Centocor, the second company after Ortho Diagnostics that attempted to gain approval for a Mab therapeutic, this chapter reveals the complexities accompanying the commercialization of such drugs. Commercialization entailed far more than just a quest to understand the dynamics between Mabs and the human body and finding a Mab suitable for therapeuticuse. What also mattered was the ability to negotiate both the intricacies of the stock market (to raise funds) and the regulatory hurdles (to achieve market approval).

Centocor faced much greater uncertainty in developing therapeutics than it had with diagnostics. Unlike diagnostics, therapeutics required direct absorption by humans so posed greater safety concerns. Drugs also necessitated the production of far greater quantities of Mabs than needed for diagnostics. Currently the doses of Mab drugs range from 0.5 mg to more than 5 mg/kg per treatment. This necessitates the production of between ten and hundreds of kilograms per year. Such quantities made the ten-liter fermenters used to produce Mabs for diagnostics inadequate. But scaling up fermenters to five-hundred-liter capacities posed significant challenges to manufacturing and quality control.3

Centocor decided it should first develop Mabs as contrast agents for diagnostic imaging procedures. While not therapies in themselves, these agents provided a way of testing the general safety of Mabs in humans and determining their therapeutic administration. The logic behind such tests was explained by the company to investors as follows: “In these tests, antibodies with radioisotopes or metals attached to them are injected into the blood stream and collected at disease sites. The location of the antibodies is then vizualised by equipment which detects the isotope or metal label. This diagnostic methodology allows a clinician to determine the extent and location of a disease area.”4

Imaging diagnostic products were forecast by analysts to generate between five and ten times more revenue for Centocor than it had received for its blood-based diagnostics. In 1985, for example, cancer-imaging diagnostics were globally predicted to earn $200 million by 1988. Cardiacimaging (p.141) products were also projected to increase earnings from $70 million to $130 million in this time. But Centocor was not the only company deciding to enter the imaging field.5

The first Mabs developed by Centocor were CA-19–9 for imaging gastrointestinal cancers and CA-125 for imaging ovarian cancer. By 1983 the company had tested CA-19–9 in more than 250 suspected gastrointestinal cancer patients in the United States and Europe. The tests had shown that Mabs could detect tumors of less than one centimeter in diameter, a size not easily detected by conventional x-ray techniques. Centocor also developed a number of cardiovascular tests. The first, trade-named Myoscint, was based on a Mab licensed from Massachusetts General Hospital and was designed to locate and measure dead heart tissue caused by a heart attack. It was intended for use in tandem with conventional nuclear imaging equipment. In addition to Myoscint, Centocor worked on a test called Fibriscint to detect blood clots in patients with deep vein thrombosis (DVT) and another, called Capriscint, to detect atherosclerotic plaque, which narrows and hardens arteries and can lead to heart attacks and strokes.6

By 1987 Centocor had established a number of alliances with other companies, including Ortho Biotech, a subsidiary of Johnson & Johnson. The company predicted that it would have marketable imaging diagnostics within a couple of years. Progress was hampered, however, because although Mabs were good imaging agents, they did not clear from the body immediately. Thus patients had to wait for Myoscint to clear before diagnostic images could be taken and read. This prevented its use for the routine diagnosis of a heart attack in its early phase as was intended originally. It proved better for use in late presenters of suspected heart attacks, and for the detection of heart transplant rejection and myocarditis (inflammation of the heart muscle).7

In August 1989, Myoscint was granted European approval after trials with more than six hundred patients. It was marketed in France, Germany, Italy, Spain, and the United Kingdom. Two years later an FDA Advisory Panel recommended its approval, but a number of problems delayed final approval until January 1996. By this time other less invasive and more accurate methods had appeared. Fibriscint also proved disappointing because it would bind only to a clot with blood circulating around it, yet most patients experiencing DVT have no such circulation. In addition, Fibriscint took six hours to clear from the body, which was necessary (p.142) before images could be taken. In the end, ultrasound proved less invasive, and provided more immediate results than Fibriscint for diagnosing DVT. As a result, Fibriscint was never commercialized.8

Like Centocor, many other companies struggled to market Mab imaging diagnostics, and profits were minimal. In 1987 one financial analyst predicted that Myoscint would earn $300 million annually and Fibriscint $400 million, but this was never achieved. Worldwide sales of diagnostic imaging Mab products also remained well below previous projections: they were calculated to be worth just $10 million in 1998. Income rose in the following years, but it remained negligible, totaling $15 million in 2005.9

While Centocor’s imaging diagnostics had limited clinical and marketing significance, they helped develop the company’s expertise in the clinical trials and manufacturing needed for drug development. Nothing, however, could fully prepare its executives for the risks that lay ahead: they were entering completely uncharted territory. In contrast to the nascent industry in biotechnology therapeutics, which was then focused on genetically engineered drugs for diseases with well-established treatment protocols and markets, the therapeutic conditions that Mabs could address and the commercial sector that they could penetrate were still totally unknown.

To minimize its risk and increase its financial, scientific, and technical resources as well as credibility, Centocor decided to collaborate with other companies to develop its therapeutics. By 1983 it had established partnerships with the American chemicals company FMC Corporation and the Swiss pharmaceutical company F. Hoffmann–La Roche. Centocor and FMC’s alliance began in 1980, with FMC providing $12.4 million to the venture. Managed by a committee with a representative from both companies, the collaborators’ aim was to find a way of producing Mabs from cell lines more closely resembling human antibodies, which they believed would reduce the risk of immunoreactions and enhance their therapeutic efficiency. In 1986 Centocor gained exclusive rights to the resulting technology in return for 1.35 million shares. The technology not only facilitated the production of more human antibodies than had been possible previously, but also gave Centocor a competitive edge in securing funding.10

(p.143) Alongside its efforts to improve the safety of Mabs, Centocor began to build its own manufacturing plant for producing Mab therapeutics in Leiden, the Netherlands. Its location outside the United States was important, because until 1986 U.S. law prevented drugs made in the United States from being exported without FDA approval, even if they had European approval. Because more than 80 percent of Centocor’s diagnostic products was being sold abroad, it was also a logical extension of its business to establish a plant outside of the United States. Other American-based biotechnology companies were also building manufacturing capacity abroad. By placing its plant in Leiden, Centocor hoped to get a head start in the European market, which handled over half of global healthcare sales. Leiden had a number of advantages as a location: its workforce could speak English; the Dutch government offered tax incentives to build such facilities; it was a leading center for fermentation technology, which was vital to Mab production; and it could draw on the expertise of the RIVM, a government institute based in Utrecht, in developing cell cultures for vaccine production.11

Scaling up Mab production for therapeutics posed several challenges. The major issue was how to mass-produce drugs at a reasonable cost. Most cell lines in the 1980s yielded only half a gram of Mabs per liter, so production was time-consuming and expensive. The ideal was to develop a hybrid cell line that could produce between five and ten grams of Mabs per liter. This demanded several steps, however, each requiring skill and patience. First was the creation of a hybrid cell, after which a clone had to be selected that secreted Mabs in high concentrations. Then a culture medium had to be developed to encourage the optimal growth of the hybridoma. Scaling up such media was not easy in terms of quality control because they contained fifty or more ingredients, and it was important to determine how many nutrients to add. Hybridomas stop secreting Mabs, for example, if given too much glucose.12

Just as vital to production was having a good vessel, or bioreactor, in which to grow the hybridomas. This involved complex engineering. A bioreactor needs to have the right pH balance and amount of oxygen to promote cellular growth. Its stirring mechanism also needs to have the right speed because stirring too vigorously can damage cell membranes. Given that the end product is a drug, the bioreactor must also be free from (p.144) contamination. The high degree of sterility required is not easy to achieve given the many different biological ingredients it contains. In addition, many of a bioreactor’s components, such as its pH probes, can be destroyed by the high temperatures required for cleaning it.13

Every stage of scaling up the manufacturing was a process of trial and error, requiring that Centocor not only break new ground, but also educate contractors and regulatory authorities. The whole venture was also financially draining. Any infrastructure had to be constructed and validated years before any therapeuticuse was approved, and it cost money for it to function once in place. The risk was that Centocor could be burdened with expensive extra capacity should a drug not receive approval or market demand be less than anticipated. Like all startup biotechnology companies, Centocor had to tread a fine line between not having enough capacity and having too much.

Centocor’s manufacturing plant in Leiden became fully operational for producing commercial quantities of therapeutic Mabs in 1988. Completing the plant had cost 20 percent more than expected. In 1989 the facility had more than two hundred staff working in three shifts. The following year Centocor expanded its production base by opening a 48,000-square-foot facility for mammalian cell culture in Saint Louis, Missouri.14

This expansion in manufacturing capacity was part of the firm’s longterm objective to become a globally integrated pharmaceutical company. This strategy was pursued by many other biotechnology companies at the time, encouraged in part by Genentech’s launch in October 1985 of Protropin, which was designed to treat growth hormone deficiency and was the first recombinant pharmaceutical product manufactured and marketed independently by a biotechnology company. To become a global integrated company, Centocor needed not only to build its own manufacturing base, but also to recruit its own sales force, because until then it had relied on other companies to market its diagnostic products.15

Encouraged by Wall Street advisers and board members, Centocor’s executives decided to develop their therapeutics independently, financed by the high profits the company was gaining from its blood tests and the revenue collected from technology licensing and select product marketing. Centocor’s total assets had increased nearly fivefold, and its sales had more than tripled between 1986 and 1988. Capital had also been raised (p.145) through public stock offerings and research and development limited partnerships, a financial arrangement that allowed companies to raise funds from private investors for specific research projects off the balance sheet. In 1986 Centocor generated $91 million from research and development partnerships for the development and clinical testing of its drugs.16

By 1988 the firm had identified thirty new entities for drug development, including some for treating cancer. While many of its competitors were investing in the development of Mab therapeutics for cancer, Centocor’s preferred lead product targeted septic shock, one of the most intractable and frequently fatal conditions in critical care. At least a third of septic-shock cases are caused by Gram-negative bacteria, which are difficult to treat with antibiotics and other drugs. Before the 1940s, Gramnegative sepsis was uncommon, but by the 1970s it had become a major problem. In 1980 it was thought to contribute between ten and fifteen cases for every thousand hospital admissions in the United States, causing mortality in 21 to 31 percent of patients overall, and 40 and 70 percent in cases complicated by organ failure. The incidence of the disease had increased with the rise in the range and administration of antimicrobial agents, and the emergence of antibiotic-resistant bacteria. Greater use of radiography and chemotherapy also appears to have increased patients’ vulnerability to such sepsis.17

In the early 1970s William McCabe and co-workers at Boston University School of Medicine demonstrated that serum taken from patients suffering from Gram-negative sepsis contained antibodies against endotoxin (a toxin released by Gram-negative bacteria) that could help diminish the frequency of septic shock and death. Following this, in the early 1980s, Abraham Braude and Elizabeth Ziegler at the University of California, San Diego, successfully reduced the mortality of patients with Gram-negative sepsis by 37 percent using serum (labeled J5) collected from healthy male volunteers vaccinated with an inactivated strain of Gram-negative bacteria. Representing the first original line of treatment for many years, this work electrified the field. With sepsis accounting for up to $10 billion in health care expenditures annually, the market for such a treatment was predicted to exceed $300 million in 1990. Soon pharmaceutical companies and newly emerging biotechnology companies were investing millions of dollars in different serums for treating sepsis.18

(p.146) Those in the commercial race included both Centocor and one of its competitors, Xoma, a California company founded in 1980 to exploit Mabs. Each decided to develop in-licensed Mabs. In the case of Xoma this was a murine Mab, Xomen E5, created by Lowell S. Young at the University of California, Los Angeles, who filed for a patent in April 1986. In contrast Centocor dedicated its efforts to a human Mab known as HA-1A, which was developed by the radiologist Henry Kaplan, a close friend of Braude, and Kaplan’s oncologist colleague Nelson Teng, both based at Stanford University.19

While HA-1A (trade named Centoxin) was a promising candidate, its development posed significant challenges. Not only did the Mab necessitate extensive purification and formulation; its effects remained unknown in humans and Centocor had little expertise in therapeutic development. Even so, Centocor’s executives, encouraged by Wall Street advisers and board members, decided that the company should finance Centoxin’s development on its own, based on their belief that the drug could be a major breakthrough for managing sepsis and could yield sales of $400 million in the first year. They were encouraged by the fact that Amgen, a Californian biotechnology company set up in 1980 to commercialize recombinant DNA, was forging ahead on its own with what many at the time forecast would be two blockbuster drugs.20

Centocor’s strategy was risky. Until then, most biotechnology companies that had succeeded in marketing drugs had done so by licensing their products to another company. Developing Centoxin alone required Centocor to oversee all the internal processes of development, clinical testing, and management of the regulatory reviews, as well as the recruitment and training of an internal marketing and sales force. Centocor executives estimated that to bring Centoxin to market would cost $150 million, and they launched a campaign to raise the money. Between 1986 and 1992, they secured $500 million based on Centoxin’s promise and its possible superiority to Xoma’s drug. This money was quickly swallowed up in clinical trials, the creation of a European and American sales force of 275 people, and the construction of its two new manufacturing plants. At the insistence of Wall Street advisers, Centocor also restructured its management team, bringing in staff from large pharmaceutical companies to help advance the company’s skills in drug development and marketing. The new recruits dramatically shifted the company’s culture, (p.147) bringing with them new management styles, more aggressive marketing, and much higher expenditures. Centocor’s research and development expenses, for example, increased by 76 percent between 1985 and 1986.21

In September 1988, Centocor filed a product license application for Centoxin with the FDA, the first step toward drug approval. Expectations were high. As Hubert Schoemaker and James Wavle, the company’s newly appointed chief operating officer, wrote, getting Centoxin to market put Centocor at the forefront of writing “the first chapter in the story of human monoclonal antibodies, powerful new tools which will undoubtedly lead to great advances in medicine well into the next century.”22

The drug was initially tested for its safety, pharmacokinetics, immunogenicity, and optimum dose in a pi lot study involving a small sample of cancer patients who did not have Gram-negative sepsis. Soon after that, an open-label trial was launched in six American hospitals with thirty-four patients diagnosed with Gram-negative sepsis. The results were encouraging: the patients experienced no immunogenicity. The trial’s results were published in January 1990, and thereafter a multicenter clinical trial, modeled on the J5 study and led by Ziegler, was initiated. Patients with sepsis or suspected Gram-negative sepsis were to be selected using strict diagnostic criteria, including a blood test, and randomly assigned either the drug or a placebo. All were to be followed after treatment for twenty-eight days or until death. Published in February 1991, the trial consisted of 543 patients, including 281 placebo recipients. Centoxin was found to reduce Gram-negative sepsis by 39 percent and the mortality of those who went into septic shock by 47 percent. Another trial, started in early 1991, demonstrated that Centoxin also helped decrease the mortality of children suffering from meningococcal septic shock (MSS), a rare but highly fatal form of meningococcal disease.23

The drug gained extra validation in early 1991 when the U.S. army placed an order for Centoxin, costing $2,500 a vial, for use by soldiers fighting in the first Gulf War. Following this, in March 1991, the drug received European regulatory approval for the treatment of Gram-negative sepsis and in September 1991 an FDA advisory committee recommended its approval in the United States.24

Based on all of these developments, expectations were running high—but it wasn’t all smooth sailing. Some members of the FDA committee had expressed reservations about the validity of some of its trial results (p.148) and ordered restrictive labeling for Centoxin. In late October 1991, too, a San Francisco federal court ruled that Centocor’s patent for Centoxin infringed Xoma’s patent for its drug E5, which Xoma was testing in partnership with the pharmaceutical company Pfizer. The decision, which came after months of bitter wrangling between the two companies, was a major blow. Patent disputes are common in the industry and can be devastating for the companies concerned. This patent dispute not only cost Centocor dearly in terms of time and finance, but also shined a spotlight on its Centoxin trial results. In late November 1991, a trial in specially bred beagles by the NIH Clinical Center’s Department of Critical Care Medicine indicated that Centoxin offered no protection against sepsis and was potentially lethal. This resulted in a tempestuous meeting among the NIH, the FDA, and Centocor.25

The furor was heightened because medical practitioners elsewhere were expressing concerns about the drug. The most damning criticism came from Jean-Daniel Baumgartner and his colleagues in Lausanne, Switzerland, who tested HA-1A for Merieux Laboratories, which had also licensed the compound. In March 1990 Baumgartner reported that he could not reproduce the laboratory and animal results that allegedly showed Centoxin’s usefulness against Gram-negative sepsis. While Centocor dismissed these findings, in July 1991 Baumgartner and his colleagues wrote a stinging attack, concluding, “Clearly, there is an urgent need for an adjunctive therapy for Gram-negative septic shock. However, it seems premature to rely entirely on a single clinical study before embarking on the large-scale use of such an expensive form of therapy, when there were possible imbalances between the study groups at entry and when the basic understanding of the specificity and the function of HA-1A is incomplete.”26

In addition to anxieties about safety, medical practitioners also voiced concerns about the drug’s high cost. Research published by Kevin Schulman in a leading American medical journal in December 1991 estimated that the average cost of Centoxin treatment for an individual patient in the United States would be $5,650. If given to all patients with sepsis it would amount to $24,100 per year of life saved. Schulman claimed that the total cost of treating septic patients would be $2.3 billion a year, of which the drug alone would account for $1.5 billion; acute hospital care would account for the rest of the costs.27

(p.149) Schulman indicated that the cost of Centoxin would be two-thirds lower if used to treat only those diagnosed specifically with Gram-negative bacteria. No appropriate diagnostic existed, however. It could take up to two days to identify the bacteria, and sepsis can kill within a matter of hours. Clinicians working in Royal Victoria Hospital, Belfast, highlighted the problem: “In our intensive care unit Gram-negative organisms were isolated only five times in the past year (September 1990–September 1991) in a population of 500 patients, of whom 40 had severe sepsis. From the data of Ziegler et al, if only 40% of septicaemic episodes prove to be due to Gram-negative organisms, then 60% of patients with septicaemia will derive no benefit from Centoxin. For 100 patients with septicaemia this represents a wastage of £120,000 out of a total of £200,000. This wastage will continue until an accurate reliable method of identifying those patients with endotoxaemia becomes available.”28 Such concerns were not confined to Britain where the National Health Service bud get constrained hospital expenditure. Duke University Hospital in North Carolina, for example, estimated that Centoxin would increase its pharmacy bud get by between 10 and 40 percent. The San Francisco General Hospital, which served large numbers of nonpaying patients, also questioned whether financing Centoxin was an appropriate use of resources given its high costs and the difficulty of predicting which patients would most benefit from it.29

On February 20, 1992, the FDA ruled that it needed additional information about Centoxin before it could recommend approval. This shocked the financial community, and sent Centocor’s shares tumbling 19 percent, representing a $675 million drop in its market value. Initially Centocor’s team believed that they could resolve the problem, but three months later the FDA requested additional trials before it would consider Centoxin’s approval. The day the news was announced, everything seemed to fall apart. Centocor was nicknamed “Centocorpse” by Wall Street, and shareholders saw $1.5 billion of Centocor’s market capitalization disappear. Capturing the feeling, one cartoon illustrated the slope of Centocor’s stock price plunging into a toilet with the title “Septic Shock.” The following week, disgruntled investors filed six lawsuits against Centocor, alleging violation of federal securities laws and calling for compensation for damages.30

Sensitive to the calamities of one of its leading companies, the biotechnology industry suffered its own financial aftershock with the news, (p.150) and many major companies lost faith in developing Mabs for therapeutic purposes. Don Drakeman, who was then chief executive officer of Medarex, a Mab-based company set up in 1987, recalled, “The Centoxin blow-up was really hard on all the antibody companies. There had been a number of prior clinical failures, and, with the high-profile Centoxin failure, Mabs became a four letter word on Wall Street. Our bankers told us to stop calling our products ‘antibodies,’ and just call them ‘proteins.’ ” This disillusion was reinforced by the news that Xoma’s sepsis drug had also failed to get FDA approval.31

The FDA’s decision had not killed Centoxin, but Centocor desperately needed time and money to rescue it. To stop the company’s cash burn of $50 million a quarter, many of the recently recruited pharmaceutical executives and hundreds of the sales representatives hired for Centoxin’s launch were dismissed. The human cost was great. Sandra Faragalli, one of Centocor’s administrators, recalled, “It was devastating to some folks. There were a number of people that were up in the higher ranks of the organization and the world just came crashing in on them. I remember … this gentleman literally crying, ‘What am I going to say to my wife? What am I going to do? We cannot afford the home that we live in. My wife doesn’t work. I have children. I have all these expenses. How are we going survive?’ ” Even for those who remained with the firm it was a rollercoaster year. Harlan Weisman, who headed the development of another Centocor drug, recalled, “I joined [Centocor] in January 1990 and at the time the price of the stock was just under $20. Based on the high hopes placed on Centoxin, the stock went to $50 to $55 a share by January 1991. I remember it well because it was my one-year anniversary, and I was awarded stock, which counted as income by the IRS. But when my taxes were due in 1992, the stock had fallen to $5.50 and I had to pay taxes at $55. My taxes due were higher than the value of the shares I owned. I had to borrow money from the company to pay my taxes.”32

Unable to raise any more capital from the market, Centocor’s founders began hunting for support from a suitable partner. There were other promising products in its pipeline and many leading pharmaceutical companies were keen to obtain Centoxin. In July 1992, Eli Lilly agreed to pay $100 million up front to help develop Centoxin—an unprecedented sum—in exchange for a 5 percent stake in Centocor. It also agreed to pay a further (p.151) $25 million toward the development of ReoPro, a cardiovascular drug it was developing.33

Having rescued the company from the brink of collapse, Schoemaker resigned as chief executive officer in September 1992. Centoxin’s failure to get FDA approval had taken a heavy toll on him. As his first wife, Ann McKenzie, put it, “Doing hard things like having to lay off people ripped [his] heart out.” Having eroded the company’s reputation with the financial market, Schoemaker recognized that it was time for Centocor to find a new face to define the company and its mission. The attitude of the investor community was summed up by one letter sent in July 1992 by one of Schoemaker’s investor friends: “It is with very mixed emotions that I take up a pen to write to you now…. The events of the last 6 months have done irreparable damage to your own credibility with investors, who quite frankly don’t believe anything you tell them any more. This is not [my] opinion, but rather a uniform consensus from numerous conversations with analysts, portfolio managers, bankers, brokers, and individual investors. Centocor desperately needs to be given a second chance by Wall Street, and this will only happen with a new hand on the helm.”34 Schoemaker was replaced by David Holveck, whom investors considered a safe pair of hands, having led the company’s successful diagnostic division. Schoemaker stayed on as the company’s executive chairman.

In the months that followed, Lilly and Centocor worked closely together on a new trial for Centoxin, which was launched in June 1992. Six months later, however, the trial was abandoned and European sales of Centoxin were halted because interim trial data indicated unexpectedly high mortality among patients without Gram-negative bacteria. Once again Centocor’s shares fell sharply, and the disappointment was great. Long after the event Michael Melore, who headed the company’s human resources, commented, “I think Centoxin does work. I read the compassionate use letters not only here but in Europe. It was unheard of: people would go into shock and then weeks later, depending on what their malady was, once again they were normal. That was unheard of. Once you got sepsis shock it was typically irreversible. There are still communities in Europe that would love to see the drug commercialised because they saw it work.”35

Many theories were put forward for what had gone wrong with Centoxin. One explanation was that the pressure to transform Centocor into (p.152) an integrated pharmaceutical company drove its executives to adopt new and more aggressive management practices that were ultimately destructive, as well as spending patterns that were unsustainable. But Kathleen Schoemaker, who was a cousin of Hubert and a member of the investment community, points out, “Nowadays a lot of CEOs have the luxury of history where they’ve seen what’s working and what’s not…. Centocor was one of the first big biotech companies. They were the frontiersmen in this industry…. At that point of time, to a lot of people it would have made sense [to build a big sales force] because when you’re approved you want to get up and running…. Nowadays it’s easy for someone to say, ‘Well, that was a bad move.’ But they have the luxury of hindsight.”36

Another reason given for Centocor’s failure was its fierce competition with Xoma, which had completed clinical development and submitted an application with the FDA for its Mab drug several months before Centocor. This led Centocor’s executives to put undue pressure on the FDA. Michael Wall, Centocor’s co-founder, explained, “When you’re losing $50 million a quarter, every week [your drug is] not on the market is crucial. So you call the FDA every day.”37 The need to call the FDA was intensified by the patent lawsuit with Xoma. Centocor’s executives also had no real experience of litigation and the lawsuit was totally unexpected. Xoma had the advantage of support from Pfizer, a powerful pharmaceutical company with which it was partnering to develop its septic drug. Schoemaker’s initial instinct was to settle, but Wavle persuaded him to fight because a settlement could have resulted in a cross-licensing agreement between Centocor and Xoma and therefore in the loss in revenue. Their hope was to have a positive outcome like Amgen had when it was sued by Genetics Institute for a patent it held on its flagship drug, Epogen, for anemia. The dispute had started in 1988 and been a bitter and prolonged affair. Amgen had refused an out-of-court settlement because the company believed it was Epogen’s rightful discoverer and saw no reason why Genetics Institute should get royalties through clever patenting. The battle ended in May 1993 with Genetics Institute having to pay Amgen $15.9 million.38

In retrospect, Schoemaker believed that Centocor’s failure to settle with Xoma had been a major strategic error, one made worse when Centocor agreed to fight the patent litigation in California, which was Xoma’s territory. Not only had Centocor lost the battle; waging it had cost the company time and money. The dispute also opened the design of the Centoxin (p.153) trials and their results to public scrutiny. Significantly, the FDA received a transcript of the patent hearing, which included a submission from Pfizer outlining the errors they thought Centocor had committed. This prompted the regulators to ask tougher questions than had been asked before. One concern was the possibility that bias could have been introduced into the trial results because some of Centocor’s executives had seen some unblinded interim results that had been handled by an indepen dent committee. It was alleged that these executives, together with Centocor statisticians, had helped to change the clinical endpoints of the trial while it was still running.39

Centocor was further handicapped as a new company competing with a well-established pharmaceutical company, like Pfizer, that had substantially more capital and greater experience in gathering the preliminary data necessary for designing appropriate clinical trials. As a new biotechnology product, Centoxin also presented different challenges than traditional pharmaceuticals. Moreover, it was aimed at treating a poorly understood disease. Medical practitioners had little consensus about how to define sepsis and little experience with it because its incidence had risen sharply only after the 1970s. Attempts had been made in 1989 to establish a simple definition of sepsis that included the source of the infection, but clinical signs of sepsis were frequently present in patients whose blood lacked measurable levels of bacteria. Moreover, the patients presenting were often gravely ill with other diseases. That sepsis is a complex entity that affects virtually every physiological regulatory mechanism within the body further complicates its diagnosis. Managing the disease is also difficult because a large spectrum of micro-organisms (such as Gram-negative and Gram-positive bacteria and fungi) can be responsible for sepsis. This makes it difficult to diagnose the specific micro-organism prior to the administration of a drug.40 Even so, in many ways the problems that Centocor executives faced were characteristic of the development of antibacterials in general—though at the time, Centocor had little experience with them.

The Centocor team was also entering uncharted territory in terms of trial design, which required the selection of appropriate endpoints and entry criteria, as well as the use of concomitant medications. Analysis was further complicated because the trial had multiple subpopulations, various definitions were used to determine the endpoint, and a number of (p.154) approaches were used to account for patients lost to followup. In addition, too few statistical adjustments were made for the different levels of other medications, such as antibiotics, given to patients in the trial. All these factors confounded the analysis and interpretation of the results. The inadequacies exposed in the Centoxin trial design were a lesson not only for the company, but also for FDA officials who were themselves new to the manufacture, clinical testing, and regulation of Mabs. The only other Mab therapeutic, OKT3, had been approved for a much narrower and well-defined purpose. Significantly, all subsequent agents developed for sepsis failed when tested in second confirmatory trials.41

Probably because they had so little expertise in the therapeutics market, Centocor also made grave mistakes in pricing Centoxin. Bruce Peacock, who was Centocor’s chief financing officer, recalled,

The finance team had prepared a price for Centoxin in the U.S. reflecting the cost of the infrastructure that was needed to be put in place and utilising the E.U. price of Centoxin. We had prepared an analysis projecting worldwide sales of the drug based on this price and I said to Hubert, “Look, I am not going to be the guy to tell you what the market penetration’s going to be, but even if it’s as high as this, you can’t make any money.” Hubert said, “That can’t be.” We walked him through it and in classic Hubert [optimistic] fashion, he said, “All right. We’ll just double the price.” That was the complete pricing analysis that was done, much to the dismay of the professional marketing people. So they had this really high price, which was getting picked up in the U.S. press as a big negative coming for the U.S. hospital industry. They were saying, “How are we possibly going to pay for this?”42

The high price also raised FDA regulators’ level of interest. As Holveck explained, “The FDA is a scientific regulatory governing body, but not without political peripheral vision. They thought it would be catastrophic to the health care system if they approved it because it would have to be on everyone’s shelves and it was something like sixteen hundred dollars a bottle. We kept raising the price and that made them want to have another study before ushering it in. It put out a caution light warning that we better know damn well what we were doing.”43

(p.155) While painful, the lessons learned from the development of Centoxin helped Centocor to advance. The first application of the lessons involved its ongoing trial of Centoxin in 269 children with MSS, or meningococcal septic shock. MSS was more easily diagnosed than sepsis owing to its characteristic skin hemorrhages. Unlike adults with sepsis, children with MSS were also less likely to have underlying diseases that could confound results, and they tended to have a higher incidence of Gram-negative bacteria in their blood than adults with sepsis. All of these factors yielded a much narrower and more defined population for testing than had been the case with sepsis. In the end, however, the trial showed that while Centoxin was well tolerated, it had no significant affect on MSS.44

Overall Centoxin’s failure marked the first of a number of commercial disappointments in the sepsis field. Significantly, the trial with MSS children indicated that the complex and multifactorial process involved in treating sepsis meant that no single treatment agent directed at only one stage of the disease would have an appreciable clinical benefit. Management of sepsis continued to be elusive into the twenty-first century.45

While Centocor did not win approval for Centoxin, the drug provided not only critical biological insights into sepsis as a disease, but also a stepping stone to the development of other Mab therapeutics. In December 1994, the FDA approved Centocor’s cardiovascular drug abciximab (ReoPro), the second Mab drug to gain the authority’s approval. ReoPro (also known as 7E3) was first developed by the cardiologist Barry Coller at the State University of New York at Stony Brook as a basic research tool for understanding the biochemistry of platelet physiology and pathology. Licensed by Centocor in 1986, much of ReoPro’s early development and testing was undertaken and sponsored by Centocor, with support from Lilly from 1992.46

When abciximab arrived at Centocor, scientists already knew that it could help prevent blood clots, but were uncertain about how it might be deployed clinically. Centocor’s team quickly set about transforming abciximab, which was rodent in origin, into a chimeric Mab, which was part mouse and part human, and therefore had less chance of causing immunoreactions.47 The chimeric Mab was seen as potentially useful for a number of different clinical situations, including the prevention of blood clotting in people undergoing or about to suffer a heart attack. Centocor therefore decided it should be developed as a drug to prevent acute (p.156) ischemic complications in patients undergoing coronary angioplasty, a common procedure to unblock coronary arteries. This would allow data on the drug’s effects to be easily and thoroughly measured.48

Leaning on Lilly’s long expertise of successful drug approvals, and learning from its mistakes with Centoxin, Centocor’s investigators were determined to apply the highest possible standards to the scientific planning of ReoPro’s clinical trials and for handling interim results. With the future of Centocor at stake, no chances were to be taken this time. Much to the relief of its team, results from the first trial in early 1993 indicated that ReoPro had achieved its primary endpoint. Denise McGinn, who was involved in the drug’s development, recalled the moment when the initial results were analyzed:

The data had all been entered, it had all been queried, cleaned and scrubbed…. The statisticians had run everything on sort of a test basis with other types of data just to make sure it would all work. The database was being held down at Duke University where the primary investigator site was. Everything was blinded which means that you didn’t know which patients got the treatment and which got the placebo. We had the data, but Duke had the code, and you needed to merge the two to know the results. That’s what was happening that night…. We all squeezed into Keaven [Anderson’s] office. It was thundering and lightning outside—a huge storm. Keaven pushed the button and we all sort of stood there looking at him as he was typing. He said “Okay, I’ve got the primary analysis done.”49

McGinn initially heard the wrong number and started questioning Anderson, at which point Schoemaker anxiously asked to see the bit of paper with the results. Quickly the team realized that the results were positive. The relief was enormous. As McGinn put it, “I get chills from telling this story. We had efficacy. We knew our trial had reached its primary endpoint. We had a drug that prevented heart attacks, death and recurrent angioplasty in patients who were at high risk to having these things happen. We had a drug and we knew it that night. We knew we had a company then too.”50

(p.157) The positive news, however, was only the beginning of the complex clinical development and regulatory review process, which was undergoing changes in the United States. ReoPro faced stiff scrutiny in the United States. At that time the FDA had split itself into two divisions: the biologics division, which was primarily focused on immune-response modifiers, and the traditional original drugs division. Although ReoPro was a biologic and an immune-response modifier, the FDA decided that because it was more of a cardiology drug it should go to the cardio-renal division within its traditional drugs division. The FDA cardio-renal advisory panel, however, had never previously handled or approved a biologic drug. Not wanting to repeat the same mistakes they had made with Centoxin, Centocor’s executives were especially careful to maintain a collaborative relationship with the regulatory authorities and followed the FDA’s advice to supply only relevant material. In the case of Centoxin, they had supplied too much paperwork, which in itself had complicated approval.51

Centocor submitted its application for ReoPro for review in 1993 after a team of its employees spent two and half months working seven days a week for between twelve and sixteen hours a day. ReoPro took just ten months to be approved by the European regulatory authorities and twelve months by the FDA. These approvals, which came through in December 1994, were particularly heartening given that many in the biotechnology industry had lost faith in Mab therapeutics, and few believed such a drug had merit or commercial application.52

ReoPro’s approval marked a critical milestone for Centocor and placed Mabs firmly on the therapeutic map. It also showed that Mabs could treat acute conditions. The first therapeutic product ever to be approved simultaneously in the United States and Europe, ReoPro passed through its development phase more quickly than any other cardiovascular drug then on the market. In December 1995 its marketing potential was further boosted when clinical trials showed it to be effective in patients with unstable angina undergoing percutaneous coronary intervention; this expanded its potential market to more than a million patients. More good news followed when research in 1996 showed the drug to be cost-effective, an issue that had plagued Centoxin.53

By the end of 1996 Centocor was reporting that its annual sales of ReoPro were $149 million.54 Centocor’s leaders had realized their dream (p.158) of creating a marketable Mab therapeutic. The company’s earlier challenges, however, are a powerful reminder that the path to the market was neither inevitable nor straightforward for Mab drugs. They presented major challenges both in terms of manufacturing and clinical testing and for raising funds. For the pioneers involved in the development and marketing of one of the first therapeutic Mabs, the journey had been characterized by substantial risks and personal sacrifices. Not only had they confronted major questions about the nature of disease pathology and the appropriate therapeutic options possible with Mabs, they had had to navigate the regulatory maze and wrestle with the volatility of the financial market. The process had been brutal, particularly when dealing with the investors, whose fickleness had threatened the very survival of the company.


(1.) Z. An, ed., Therapeutic Monoclonal Antibodies: From Bench to Clinic (Hoboken, N.J., 2009), ch. 1.

(2.) G. Goldstein et al., “OKT3: Monoclonal Antibody Plasma Levels during Therapy and the Subsequent Development of Host Antibodies to OKT3,” Transplantation 42 (Nov. 1986): 507–11; D. Abramowicz and M. Goldman, “Anaphylactic Shock after Retreatment with OKT3 Monoclonal Antibody,” NEJM 3 (Sept. 1992): 736; K. J. Palevliet and P. T. Schellekens, “Monoclonal Antibodies in Renal Transplantation: A Review,” Transplant International 5, no. 4 (Sept. 1992): 234–46; C. Sgro, “Side-Effects of a Monoclonal Antibody, Muromonab CD3/Orthoclone OKT3: Bibliographic Review,” Toxicology 105, no. 1 (Dec. 1995): 23–29; S. L. Smith, “Ten Years of Orthoclone OKT3 (muromonab-CD3): A Review,” Journal of Transplant Coordination 6, no. 3 (Sept 1996): 109–19; M. I. Wilde and K. L. Goa, “Muromonab CD3: A Reappraisal of Its Pharmacology and Use as Prophylaxis of Solid Organ Transplant Rejection,” Drugs 51, no. 5 (May 1996): 865–94; A. F. LoBuglio et al., “Mouse/Human Chimeric Monoclonal Antibody in Man: Kinetics and Immune Response,” PNAS 86 (June 1989): 4220–24.

(3.) G. Kretzmer, “Industrial Processes with Animal Cells,” Applied Microbiology and Biotechnology 59 (2002): 135–42; G. Bylinsky, “Coming: Star Wars Medicine,” Fortune (27 Apr. 1987); Interview with Renato Fuchs.

(5.) Centocor, Annual Report (1985): 11; Bylinsky, “Coming”; Interview with Stelios Papadopolous, 22.

(6.) Centocor, Annual Report (1983): 2, (1984): 16, (1990): 7; Centocor, Investment Prospectus, 14 Dec. 1982; PaineWebber, Centocor Common Stock, 13 Dec. 1985, 4, 6, 34; PaineWebber, Tocor II and Centocor Prospectus, 21 Jan. 1992; all in HS-PP; A. Pollack, “The Next Wave of Diagnostics,” New York Times (28 Aug. 1989).

(8.) Interview with Fuchs; Centocor, Annual Reports (1988): 4, (1990): 7; Anon., “Centocor’s Myoscint Imaging Agent Backed in USA,” Pharmaletter (5 Feb. 1996), available online at http://www.thepharmaletter.com/file/25880/centocors-myoscint-imaging-agent-backed-in-usa.html (accessed 19 Sept. 2014).

(9.) BCC Research, “Antibodies for Therapeutic and Diagnostic Imaging Applications,” Report BIO016D, Feb. 2000, available online at http://www.bccresearch.com/market-research/biotechnology/BIO016D.html, and (p.273) BCC Research, “Dynamic Antibody Industry,” Report BIO016F, Aug. 2005, available online at http://www.bccresearch.com/market-research/biotechnology/BIO016F.html (both accessed 2 Oct. 2014); R. Wolf, “Centocor Makes a Deal on Product Marketing,” Philadelphia Inquirer (7 Dec. 1987).

(10.) Cetus was the only other biotechnology company that had managed to develop more human antibodies at this stage. Centocor, Annual Reports (1983): 6 18, 28; (1985) 2; (1986); Rothschild, Centocor Inc (1983): 47; Interview with Stephen Evens-Freke; Bylinsky, “Coming.”

(11.) Interviews with Pedro Tetteroo, Bruce Peacock, and Erik and Kathleen Schoemaker; PaineWebber, Centocor Common Stock, 13 Dec. 1985, 4, 6, 34. Centocor, Annual Report (1988): 8; P. Pfeiffer Chambers, “Two Area Firms Ready for Biotech Boom,” Focus (15 July 1987): 17–19.

(12.) Interviews with Tetteroo and James Christie.

(13.) Interview with Christie; Kretzmer, “Industrial.”

(15.) Interview with Tetteroo. Email from Jacques Fonteyne to Anne Faulkner Schoemaker, 8 Nov. 2005, HS-PP; Centocor, Annual Reports (1986): 17; (1988): 5; S. Dickinson, “Biotech’s Centocor Jockeys for Position in Drug Field,” Scientist 4 (14 May 1990): 1–5, 2.

(16.) Centocor, Annual Report (1986): 2. Genentech was one of the first biotechnology companies to use R&D partnerships, in 1982, using it to develop human growth hormone and gamma interferon drugs. R&D partnerships had tax benefits and potentially higher returns than equity investments. Interview with Evens-Freke.

(17.) Centocor, Annual Report (1985): 29, (1988): 2, 12; Interviews with Fuchs, Richard McCloskey, Denise McGinn, David Holveck (1), and Vincent Zurawski; B. E. Kreger, D. E. Craven, P. C. Carling, and W. R. McCabe, “Gram-Negative Bacteremia, III: Reassessment of Etiology, Epidemiology and Ecol ogy in 612 Patients,” American Journal of Medicine 68 (1980): 332–43; R. C. Bone, “Gram-Negative Sepsis: Background, Clinical Features and Intervention,” Chest 100 (1991): 802–808.

(18.) W. R. McCabe, B. E. Kreger, and M. Johns, “Type-Specific and Cross-Reactive Antibodies in Gram-Negative Bacteremia,” NEJM 287 (1972): 261–67; E. J. Ziegler et al., “Treatment of Gram-Negative Bacteremia and Shock with Human Anti-Serum to a Mutant Escherichia Coli,” NEJM 307 (1982): 1225–30; K. F. Bayston and J. Cohen, “Bacterial Endotoxin and Current Concepts in the Diagnosis and Treatment of Endotoxaemia,” Journal of Medical Microbiology 31 (1990): 73–83; E. J. Ziegler et al., “Treatment of Gram-Negative Bacteremia and Septic Shock with HA-1A Human Monoclonal Antibody against Endotoxin: A Randomized, Double-Blind, Placebo-Controlled Trial. The HA-1A Sepsis Study Group,” NEJM 324 (1991): 429–36; A. Cometta, J. D. Baumgartner, and M. P. Glauser, “Polyclonal Intravenous Immune Globulin for Prevention and Treatment of Infections in Critically Ill Patients,” Clinical and Experimental Immunology 97 (1994): 69–72.

(p.274) (19.) D. Shaw, “A Bruising Battle over Two Lifesaving Drugs,” Philadelphia Inquirer (5 Nov. 1991); N. N. Teng et al., “Protection against Gram-Negative Bacteremia and Endotoxemia with Human Monoclonal IgM Antibodies,” PNAS 82 (1985): 1790–94; I. R. Poxton, “Antibodies to Lipopolysaccharide,” J Immunol Methods 186 (1995): 1–15; P. J. Scannon, “Applying Lessons Learned from Anti-Endotoxin Therapy,” Journal of Endotoxin Research 2 (1995): 217–20; B. Momich, “Building Something Significant at Centocor,” Pennsylvania Technology (2nd quarter, 1990): 25–31.

(20.) Interview with Tony Evnin; R. Koenig, “Remembering Hubert,” American Enterprise Magazine (16 May 2006). Amgen’s blockbuster drugs were Epogen, approved in 1989 to treat anemia, and Neupogen, approved in 1991 to help cancer patients receiving chemotherapy avoid infections.

(21.) Centocor, Annual Reports (1986): 16, (1988); Dickinson, “Biotech’s”; R. Longman, “The Lessons of Centocor,” In Vivo: The Business and Medicine Report (May 1992); 23–27; R. Winslow, “Centocor’s New Drug Clears FDA Panel, Xoma’s Put on Hold: Both Stocks Go Wild,” Wall Street Journal 217 (5 Sept. 1991): 47; Interview with Peacock; Interview with Sandra Faragalli, Ray Heslip and Patty Durachko; Interviews with Paul Touhey and Pat D’Antonio.

(23.) C. J. Zimmerman et al., “Initial Evaluation of Human Monoclonal Anti-Lipid A Antibody (HA-1A) in Patients with Sepsis Syndrome,” Critical Care Medicine (1990): 18, 1311–15; Ziegler et al., “Treatment of Gram-Negative Bacteremia and Septic Shock”; S. A. Syed, “Successful Use of Monoclonal Anti-Lipid-A IgM in Infant with Meningococcal Sepsis,” Lancet (22 Feb. 1992): 339, 496.

(24.) Anon., “Centocor Inc,” Wall Street Transcript (27 May 1991): 111; J. M. Luce, “Introduction of New Technology into Critical Care Practice: A History of HA-1A Human Monoclonal Antibody against Endotoxin,” Critical Care Medicine 21, no. 8 (1993): 1233–40; Winslow, “Centocor’s New Drug Clears FDA Panel”; Anon., “Centocor’s Drug Is Ruled Safe,” New York Times (5 Sept. 1991); Anon., “Centocor, Inc.,” Times Magazine (25 Feb. 1991).

(25.) “Xoma Sues Centocor on Patent Infringement,” Biotechnology Law Report 90 (1990): 90, no. 2; Centocor, Annual Report (1991): 38–39; Shaw, “Bruising”; Longman, “Lessons,” 24; L. L. Valerino, “Centocor Stock Slides on News of Drug Snag,” Wall Street Journal (20 Feb. 1992); L. M. Fisher, “Centocor and Xoma Settle Patent Fight,” New York Times (30 July 1992); Winslow, “Centocor’s New Drug Clears FDA Panel”; Centocor, Annual Report (1991): 38–39; Interviews with Bernie Schaffer, Holveck (1), Faulkner Schoemaker and Papadopoulos; Quezado et al., “Controlled”; D. N. Leff, “Animal Study Showed Mortality with HA-1A,” BioWorld Today 1993 (1991): 5.

(26.) J. D. Baumgartner et al., “Association between Protective Efficacy of Anti-Lipopolysaccharide (LPS) Antibodies and Suppression of LPS-Induced Tumor Necrosis Factor Alpha and Interleukin 6: Comparison of Side Chain-Specific Antibodies with Core LPS Antibodies,” JEM 171 (1990): 889–96; (p.275) J. Baumgartner, “Letter to the Editor,” NEJM 325 (1991): 281–82; Anon., “At the Market’s Edge: How a $1 Billion Drug Fell Flat,” New York Times (Feb. 1993); F. Curie, M. D. Feher, and A. F. Lant, “How to Pay for Expensive Drugs,” BMJ 303 (1991): 1476–78.

(27.) Curie et al., “How”; K. A. Schulman, H. A. Glick, and J. M. Rubin, “Cost-Effectiveness of HA-1A Monoclonal Antibody for Gram-Negative Sepsis: Economic Assessment of a New Therapeutic Agent,” Journal of the American Medical Association 266 (1991): 3466–71; R. C. Bone, “Monoclonal Antibodies to Endotoxin: New Allies against Sepsis?” Journal of the American Medical Association 266 (1991): 1125–26; C. J. Hinds, “Monoclonal Antibodies in Sepsis and Septic Shock,” BMJ 304 (1992): 132–33; G. D. Magi, “Letter to Editor,” BMJ 303 (1991): 1477.

(30.) Interview with Faragalli, Heslip and Durachko; Interviews with Holveck (1), and Anne Faulkner Schoemaker; D. Shaw, “FDA, Wall Street Brings Bad Tidings to Centocor,” Philadelphia Inquirer 20 (1992): 11; Centocor, Annual Report (1986): 16; L. L. Valeriano, “Centocor Stock Slides on News of Snag,” Wall Street Journal (1992); S. Usdin, “Wall St. Vents Frustration at Centocor,” BioWorld Today (1992); Koenig, “Remembering”; D. Shaw, “Centocor Absorbs New Blows,” Philadelphia Inquirer (1992); Anon., “FDA: Centoxin Data Insufficient,” BioWorld Today 3 (1992): 1.

(31.) A. Newman and D. Pettit, “Biotech Stock Lead Index 0.64% Lower; Centocor Plunges on Worry over Drug,” Wall Street Journal (20 Feb. 1992); Email from Don Drakeman to Marks, 4 May 2012; Longman, “Lessons.”

(32.) Interview with Faragalli, Heslip and Durachko; Interviews with Papadopolous and Michael Melore. For the Weisman quotation, see R. L. Shook, Miracle Medicines (New York, 2007), 206.

(33.) Centocor, Annual Report (1992): 7; Interviews with Touhey, Papadopoulos, and J. P. Garnier; L. Marks, “Collaboration—A Competitor’s Tool: The Story of Centocor, an Entrepreneurial Biotechnology Company,” Business History 51, no. 4 (2009): 529–46; Anon., “Lilly to Acquire Marketing Rights to Centocor Drug”; Centocor, Centroids; N. Garcia, “Centocor Resumes Trials in Children,” BioWorld Today (20 Jan. 1993); D. Shaw, “A New Round of Bad News: Unexplained Test Deaths,” Philadelphia Inquirer (19 Jan. 1993); R. M. Enigma, “Centocor to Terminate HA-1A,” Centocor press release, 15 Mar. 1993, HS-PP; N. Garcia, “But Company Kills HA-1A Trials,” BioWorld Today 4, no. 52 (17 Mar. 1993): 1.

(34.) Hubert Schoemaker to David Kessler, Sept. 1992, HS-PP; Interview with Ann McKenzie.

(35.) Garcia, “Centocor”; Garcia, “But”; R. M. Enigma, “Centocor to Terminate HA-1A: Centocor Press Release” (1993), HS-PP; G. Kolata, “Halted at the Market’s Door: How a $1 Billion Drug Failed,” New York Times (12 Feb. 1993); Interview with Melore.

(p.276) (36.) Interviews with Garnier and with Erik and Kathleen Schoemaker.

(38.) Interviews with George Hobbs and Papadopoulous; Amgen SEC filing: Form:10-Q, 8/10/1994, available online from Amgen and at https://www.sec.gov. B. Stavro, “George B. Rathmann Dies at 84; Co-Founder of Biotech Giant Amgen,” Los Angeles Times (24 Apr. 2012).

(39.) Interviews with Bernie Schaffer, Jay Siegel, Holveck (1), Papadopolous, and Faulkner Schoemaker; Usdin, “Wall”; Shaw, “FDA, Wall Street Bring Bad Tidings to Centocor”; Anon., “FDA Snag and Loss Hurt Centocor Stock,” New York Times (20 Feb. 1992); Valeriano, “Centocor”; Newman and Pettit, “Biotech”; Longman, “Lessons”; J. P. Siegel, “Biotechnology and Clinical Trials,” J Infect Dis 185 (2002) 52–57.

(40.) Interview with Siegel; H. J. P. Schoemaker and A. F. Schoemaker, “The Three Pillars of Bioentrepreneurship,” Nat Biotechnol 16 (1998): 13–15; R. C. Bone et al., “Severe Sepsis Study Group: Sepsis Syndrome; a Valid Clinical Entity,” Critical Care Medicine 17 (1989): 389–93; K. C. Fang, “Monoclonal Antibodies to Endotoxin in the Management of Sepsis,” Western Journal of Medicine 158 (1993): 393–99; E. F. Mammen, “Perspectives for the Future,” Intensive Care Medicine 19 (1993): 29–34; R. P. Wenzel et al., “Current Understanding of Sepsis,” Clin Infect Dis 22 (1996): 407–12; N. C. Riedemann, R. F. Guo, and P. A. Ward, “The Enigma of Sepsis,” J Clin Invest 112 (2003): 460–67.

(41.) Interviews with Siegel and Thomas Schaible; Siegel, “Biotechnology”; D. A. Sweeney, et al., “Once is Not Enough: Clinical Trials in Sepsis,” Intensive Care Medicine 34 (2008): 1955–60.

(42.) Interview with Peacock.

(43.) Interview with Holveck (1).

(44.) Garcia, “But”; B. Derkx, J. Wittes, R. McCloskey, and European Pediatric Meningococcal Septic Shock Trial Study Group, “Randomized, Placebo-Controlled Trial of HA-1A, a Human Monoclonal Antibody to Endotoxin, in Children with Meningococcal Septic Shock,” Clin Infect Dis 28 (1999): 770–77.

(45.) Interview with Harlan Weisman; J. C. Marshall, “Sepsis: Rethinking the Approach to Clinical Research,” Journal of Leukocyte Biology 83 (2008): 471–78.

(46.) Anon., “Lilly to Acquire.”

(47.) For more on chimeric Mabs, see Chapter 9.

(48.) Interviews with Weisman and McGinn; B. S. Coller, “Blockade of Platelet GPIIb/IIIa Receptors as an Antithrombotic Strategy,” Circulation 92 (1995): 2373–80; D. M. Knight et al., “The Immunogenicity of the 7E3 Murine Monoclonal Fab Antibody Fragment Variable Region Is Dramatically Reduced in Humans by Substitution of Human for Murine Constant Regions,” Molecular Immunology 32 (1995): 1271–81.

(49.) Interview with McGinn.

(50.) Ibid. Keaven Anderson was senior director at Centocor from 1991 to 2003.

(p.277) (51.) Interviews with McGinn, Melore, and Schaible.

(52.) Interview with McGinn.

(53.) D. B. Mark et al., “Economic Assessment of Platelet Glycoprotein IIb/IIIa Inhibition for Prevention of Ischemic Complications of High-Risk Coronary Angioplasty,” Circulation 94 (1996): 629–35; C. F. Farrell, S. Elliot Barnathan, and H. F. Weisman, “The Evolution of ReoPro Clinical Development,” in K. Disembowel and P. Staler, eds., Novel Therapeutic Proteins: Selected Case Studies (Hoboken, N.J., 2001).

(54.) Centocor, Annual Report (1996): 5.