Nonsteroidal Anti-Inflammatory Drugs – Celebrex
In the early 1970s, John Vane and his colleagues demonstrated that NSAIDs work by blocking the cyclooxygenase enzyme. By the mid-1980s, evidence began to emerge that two subtypes of cyclooxygenase exist. Slowly but surely, the two isoforms of cyclooxygenase were deciphered thanks to the elegant work of several groups of scientists, including Philip Needleman of Washington University at St. Louis and later G. D. Searle, Daniel L. Simmons of Brigham Young University, Harvey R. Herschman of UCLA, and Donald Young of the University of Rochester. Between the two subtypes of cyclooxygenases, one is inducible and the other is constitutive. The inducible enzyme associated with the inflammatory process was named cyclooxygenase II (COX-2), whereas the constitutive enzyme was called COX-i. COX-2 is localized mainly in inflammatory cells and tissues and becomes up-regulated during the acute inflammatory response; COX-i is mainly responsible for normal physiological processes such as protecting the gastric mucosa and maintaining dilation of blood vessels. In general terms, COX-i is the «good» enzyme and COX-2 is the «bad» one. Therefore, it was envisioned that a COX-2 selective inhibitor would be beneficial in both inhibiting prostaglandin production and reducing adverse gastrointestinal and hematological side effects.
Using this novel approach, under the leadership of Philip Needleman, the first COX-2 selective inhibitor, celecoxib, was synthesized on October 4, 1993, in the Skokie, Illinois, laboratories of G. D. Searle. Searle began comarketing it with Pfizer as Celebrex in June 1999. Six months later Merck received approval from the FDA to market their version of a COX-2 selective inhibitor, rofecoxib (Vioxx). Both Celebrex and Vioxx quickly became blockbuster drugs for treatment of osteoarthritis (OA) and rheumatoid arthritis (RA). In 2003, Bextra was comarketed with Pfizer by Pharmacia, the name of the newly formed company that arose from a merger between Pharmacia, Upjohn, and Monsanto (the parent company of Searle).
In 1992, the University of Rochester had filed a patent on Donald Young’s invention covering the gene in humans that is responsible for producing COX-2. The patent also had blanket coverage of all COX-2 selective inhibitors that were discovered through approaches that involved selective blockage of COX-2. The U.S. Patent and Trademark Office granted the patent in April 2000 with patent number U.S. 6,048,850. The University of Rochester sued G. D. Searle and its marketing partner, Pfizer, charging that Celebrex was an infringement of their patent. In 2003, U.S. District Judge David G. Larimer in Rochester ruled that the patent was invalid. In July 2004, a federal patent appeal court in Washington, D.C., upheld the 2003 district court ruling by Judge Larimer, ending the first case of high-profile legal wrangling around the COX-2 selective inhibitors. Judge Larimer’s argument was worth noting in appreciating patent laws: to qualify for a patent, inventions must be useful, nonobvious, and novel. The Rochester patent did not contain the requisite sufficient written requirement: U.S. 6,048,850 contained no description or claims of compounds that selectively block COX-2. The inventors did not have possession of a substance; therefore, the invention was merely theoretical. Judge Larimer finally concluded that «what the ‘850 does not do … is to provide the necessary link between these two steps: actually finding a compound that works.» Sadly, the Rochester v. Searle lawsuit has by now shrunk in significance compared with other lawsuits currently going on today involving Vioxx.
Indeed, the fate of Vioxx represents one of the most dramatic medical sagas of our time. Merck’s VIGOR (Vioxx Gastrointestinal Outcome Research) clinical trials, published in 2000, found a fivefold increase in myo-cardial infarction (heart attack) among patients treated with Vioxx over those treated with naproxen. There could be three possibilities, according to John Vane: (1) that it was a chance effect; (2) that naproxen protects the cardiovascular system; or (3) that Vioxx has a deleterious cardiovascular effect. In September 2004, APPROVe (Adenomatous Polyp Prevention On Vioxx) showed that Vioxx increased the risk of myocardial infarction and stroke. Merck voluntarily withdrew Vioxx from the market on September 30. The stock market reacted violently, wiping out $30 billion of Merck stock in a matter of a few months.
On February 18, 2005, a 32-member advisory panel for the FDA that evaluated the three COX-2 selective inhibitors on the market recommended keeping all of them on the market. The vote was 31-1 for Celebrex, 17-13 for Bextra, and 17-15 for Vioxx. In April 2005, acting against the vote of the advisory panel, the FDA asked Pfizer to voluntarily withdraw Bextra. Thus far, Celebrex is the only COX-2 selective inhibitor remaining on the market.
After all is said and done, COX-2 selective inhibitors are just like any other drug. One has to evaluate the risk versus the benefit of a particular drug when taking or prescribing it. For instance, a COX-2 selective inhibitor is a good choice for treating pain for a patient with gastrointestinal problems but is probably not a wise choice for another patient with cardiovascular problems. It is not surprising, then, that John Vane proposed a «Back to an Aspirin a day» after COX-2 selective inhibitors failed to meet their initial promises.
