From a twinkle in the eye to a blockbuster drug: the story of Celebrex[R] holds lessons for R&D...

Modern drug discovery is a difficult, arduous process, filled

with enormous risk. Success, however, can provide relief of human suffering and increased longevity, worthy goals by any standard. Because the discovery and development of new pharmaceuticals is so difficult, application of the best management techniques to the process is essential. The story behind Celebrex[R] (celecoxib), a highly successful pain reliever and anti-inflammatory medicine used in the treatment of arthritis, illustrates many of these management tools and principles very well.

For more than 100 years, salicylates have been used to relieve pain and inflammation. Unfortunately, the naturally occurring compound, salicylic acid, has severe gastrointestinal and other side effects. Over 100 years ago, a Bayer chemist synthesized the acetylated derivative of salicylate, to obtain a compound, aspirin, with fewer side effects. Seventy-five years after the synthesis of aspirin, John Vane showed that the drug acted by decreasing the synthesis of inflammation-promoting prostaglandins, which are produced in the body through the action of an enzyme called cyclooxygenase. In time, a whole class of pharmaceuticals called non-steroidal anti-inflammatory drugs (NSAIDs) was developed, including ibuprofen and naproxen. These acted mechanistically like aspirin but had improved pharmacological profiles with fewer side effects. By the mid-1980s, there were at least 22 NSAIDs being sold on the global pharmaceutical market.

While traditional NSAIDs were certainly an improvement over high-dose aspirin therapy for the treatment of arthritis, they still retained some serious side-effects. Because prostaglandins are involved in the protection of the gastrointestinal tract from hydrochloric acid and are also involved in blood clotting, NSAID's tend to cause gastrointestinal bleeding as a severe side effect. In fact, in the United States alone in 1998, there were at least 120,000 hospitalizations per year resulting from NSAID-induced complications, and perhaps more than 16,000 deaths.

It was against this historical backdrop that in the mid-1970s my colleagues and I at Washington University in St. Louis became interested in the biology of inflammation. The experimental system that we chose to study was perfused rabbit kidney, which, as a model for inflammation, had the great advantage of having a built-in contralateral control (the kidney on the opposite side). It turned out that inflamed kidney produced large quantities of prostaglandin-like substance, which was reduced to zero by the concomitant application of aspirin. Follow-up work over the course of several years led to the hypothesis in 1988 that there were really two forms of cyclooxygenase in the body. One form, dubbed COX-1, was apparently a "house-keeping" or constitutive enzyme, found in many tissue types and responsible for the steady synthesis of those prostaglandins involved in the protection of the gastrointestinal tract and in blood clotting. The other form of the enzyme, imaginatively named COX-2, appeared to be inducible, that is, its level was dramatically increased at sites of inflammation.

In 1989, I joined the Monsanto Company to become chief scientist and later head of R&D of Monsanto's pharmaceutical subsidiary, Searle. (Monsanto and Searle merged in 2000 with Pharmacia & Upjohn to create a new company called Pharmacia.) Not surprisingly, I found industrial research and development to be different from science in academia. In academic science, the "product" is the discovery of new things about Nature. In industry, the product is something useful for unmet medical needs and with commercial value. This is a much riskier enterprise.

Target Selection Takes "Taste"

One of the greatest challenges facing a head of R&D in a drug company is the selection of targets. Today, the disciplines of molecular biology, analytical chemistry, synthetic organic chemistry, genomics, and computational biology provide unprecedented and powerful tools. But it is absolutely critical to choose a good target, most often an enzyme or receptor that seems to be at the crux of the disease process. Selection of this target involves something intangible that I call "taste." Scientific taste enables the experienced scientist to sift through all available information to find the most likely candidate. Taste has elements of intuition and analysis, as well as a bit of luck.

Taste also means killing non-productive projects early and often so that vital resources can be deployed to more promising therapeutic targets. Thus, moving rapidly to the so-called "killer" experiment that validates or invalidates a target is extremely important. It is often tempting to continue to apply resources to dead ends and even to delay the most critical, decision-making experiments because, perhaps unconsciously, we do not want to terminate a project in which so much has been invested already. It is my view that the winners in drug discovery are the scientists who move most rapidly to critical decision points and re-deploy resources without hesitation. This is also an important part of focusing on those areas where one has the greatest chance of success and not trying to do everything.

In 1988, based on the hypothesis of two forms of cyclooxygenase, a twinkle in the eye appeared. What if a drug could be found that inhibited the pro-inflammatory form, COX-2, while sparing the constitutive form, COX-1? Might such a compound relieve pain and inflammation without a propensity to cause gastrointestinal bleeding? COX-2 could be just the right target for a major drug to meet a significant medical need.

Taking a leap of faith after I joined Monsanto, and with the help of a CEO who recognized the importance of having a critical mass of scientists focused on a problem, we mobilized 50 molecular and cell biologists to clone and express the human genes for both forms of the enzyme and to set up high-throughput assays looking for active compounds with differential activities against the two enzymes. We also mobilized one-third of all the medicinal chemists at Searle to synthesize candidate compounds, creating an intense, highly-focused effort. It turned out that COX-1 and COX-2 varied very little at the active site. Fortunately, the difference was sufficient. We found more than 2,500 active inhibitors and sifted through these based upon their relative toxicity, pharmacology, selectivity, probable cost of goods, etc. Celecoxib, the compound that would later move into commercial development, was synthesized in October 1993.

Time Really Is Money

At this point, speed became especially important. In drug development, time really is money. Consider an "average" pharmaceutical with peak sales of $365 million per year prior to patent expiration. This means that for each day that development is accelerated, there is $1 million added to the company's sales figure. For Celebrex[R], this figure could approach $10 million per day.

When development of celecoxib began, Searle's last drug had required 84 months from the first patient to regulatory submission. The most rapid drug development in the industry required 72 months. We made some innovations in the process that decreased the time for Celebrex[R] to an unprecedented 39.5 months. Key to this reduction in time was getting manufacturing on board very early. They helped in the selection of the three candidate COX-2 inhibitors that were forwarded simultaneously. We developed complete manufacturing processes for all three, knowing that effort might be wasted on two of them, but knowing also that having a back-up candidate ready to go was absolutely essential in this competitive arena.

Drug development occurs in predetermined stages. First, preclinical work in animals demonstrates efficacy in models of the disease, as well as the drug candidate's toxicological profile. Phase I studies represent trials in a small number of human volunteers to determine safety and dosing. Phase II studies are done in a relatively small number of patients who have the disease to determine efficacy of the drug. Finally, Phase III trials are performed in a much larger patient population (perhaps thousands) to show both safety and efficacy. Obviously, the more patients involved, the greater the cost. Phase I trials are in the single digit millions, Phase II are in the double digit millions, and Phase III trials may represent hundreds of millions of dollars of investment.

Two "Killer" Findings

There were two "killer" findings absolutely essential for decision-making. First, we had to show that celecoxib was effective against pain in humans. Animal models simply could not answer this question. The result was an unequivocal yes for dental pain (the standard model) and was obtained nine months after celecoxib was given to the first patient. The second "killer" finding was that celecoxib caused fewer gastrointestinal side-effects than traditional NSAID's. Indeed, this proved to be the case.

Early in 1997, I challenged the team to obtain regulatory filing of celecoxib by mid-1998 and commercial launch of the drug on my 60th birthday, February 10, 1999. At first glance, this may seem a bit silly and arbitrary. But it served to focus the team on achieving the seemingly impossible. Indeed, the launch occurred on February 22, 1999, though I did obtain the first prescription for Celebrex[R] through a drop shipment to a Skokie, Illinois pharmacy on my birthday.

Vital Laser Beam Focus

Product life cycle management is another important aspect of pharmaceutical R&D. One part of life cycle management is the creation of therapeutic platforms, where the goal is to develop improved or second-generation drugs, as well as drugs aimed at the treatment of diseases that are related to each other in some way. Because no company has an unlimited budget for research, laser beam-like focus is critical. It is impossible to work in every therapeutic area, and a good R&D leader chooses those areas where success is most probable and then continues to build on that platform. At Pharmacia, we have done exactly that. Two additional COX-2 inhibitors are in clinical trials. One is parecoxib, a pain reliever that can be given intravenously, and the other is valdecoxib, a second-generation oral drug with even greater efficacy than celecoxib.

A second part of life cycle management is to find new uses for drugs that already exist. Here, the story for celecoxib is particularly intriguing. Epidemiological evidence has accumulated that patients taking NSAIDs have lower rates ofcolorectal cancer. This reduction may be as much as 40 to 50 percent in heavy users but there is, of course, a concomitant increase in gastrointestinal ulcerations. Other data continue to accumulate indicating that the COX-2 enzyme is involved in epithelial cell tumorigenesis and metastasis.

The data were sufficiently compelling for us to test celecoxib in patients with familial adenomatous polyposis. These patients, who are relatively few in number (perhaps 10,000 worldwide), have a genetic predisposition for the development of colonic polyps. Such polyps are the precursor for tumors and therefore these patients inevitably develop colorectal cancer. Celecoxib significantly reduced the number of polyps in these patients and has been approved by FDA for this indication. Pharmacia and others are now conducting clinical trials to determine whether celecoxib might reduce the incidence of sporadic adenomatous polyposis, which is the usual precursor of colorectal cancer in the general population (a disease causing 50,000 deaths per year in the U.S. alone). These trials, of course, have to be quite large. Given the safety profile of Celebrex[R], a positive result could be of enormous benefit.

So, the story of Celebrex[R] continues. Starting with science more than 100 years old, we have come to a class of drugs that not only relieves pain and inflammation with a highly favorable side-effect profile, but one that may even be among the first routinely prescribed chemopreventatives for cancer. The discovery and rapid development of Celebrex[R] required the work of hundreds of dedicated professionals who were committed to excellence. I am most grateful to have had the pleasure of working with all of them in this exciting adventure.

Acknowledgment

I thank Michael J. Montague, Pharmacia's director of research operations, for his assistance in preparing this article.

Annual Award of the Industrial Research Institute Medal

To PHILIP NEEDLEMAN

For his significant contributions to basic science in the field of pharmacology; for his leadership in redesigning and accelerating the process for pharmaceutical discovery and development, resulting in one of the most enviable pipelines in the pharmaceutical industry; and for the discovery, development, and commercialization of Celebrex[R] (celecoxib), an arthritis drug that has dramatically improved the quality of life for many people.

Head of the Pharmacology Department at Washington University Medical School from 1976-1989, Philip Needleman joined the Monsanto Company in 1989, rising to the position of Senior Vice President and Chief Scientist, while simultaneously holding the office of President of Searle Research and Development, a unit of Monsanto. In his capacity as Chief Scientist, Dr. Needleman influenced virtually every aspect of Monsanto's businesses, including its transition to a life-sciences based company. His vision was essential in providing senior management with the assurance that investments in mechanism-based drug discovery and design, as well as genomics and allied technologies, were worthwhile and would pay off.

With the merger of Monsanto with Pharmacia & Upjohn, a new company named Pharmacia Corporation was formed and Philip Needleman was named its Chief Scientific Officer. In this position he is responsible to the Board of Directors for the success or failure of Pharmacia's total R&D spending.

Philip Needleman was selected as Basic Science Teacher of the Year in 1971, 1972, 1977, and 1988 at Washington University Medical School. He has a long record of government and civic service in the interest of science and technology. He was elected to the National Academy of Sciences in 1987 and to the Academy's Institute of Medicine in 1993. He was also the recipient of the John Jacob Abel Award of the American Pharmacology Society in 1974.

Dr. Needleman earned his Bachelor of Science in Pharmacy from the Philadelphia College of Pharmacy in 1960, his Masters of Science in Pharmacology from the Philadelphia College of Pharmacy in 1962, and his Ph.D. in Pharmacology from the University of Maryland Medical School in 1964.

Philip Needleman, chief scientific officer for the Pharmacia Corporation, St. Louis, Missouri, is the Industrial Research Institute Medalist for 2001. His article is based upon the address he delivered upon accepting the Medal at the IRI Annual Meeting in Boca Raton, Florida, May 2001.