Vioxx, Once Vilified Like Thalidomide, May Also Return To The Market

Thalidomide holds a special place in drug discovery lore. Initially marketed in Europe in the 1950s to help pregnant women overcome morning sickness and to help them sleep, thalidomide was found to be a teratogen – a compound that interferes with the growth of a fetus thus leading to birth defects. Thousands of babies were born with severe deformities as a result of this drug. Fortunately, the FDA never approved thalidomide thanks to the diligence of FDA reviewer Dr. Frances Kelsey. Despite being approved in Europe, Kelsey demanded additional test data, delaying FDA approval and thereby sparing Americans the misfortunes experienced in Europe. As a result of her actions, Kelsey was awarded the President’s Award for Distinguished Civilian Service by President John Kennedy. In addition, due to the public alarm that arose from this horror, Congress passed the Kefauver-Harris Drug Act in 1962 that revamped and toughened the U.S. drug approval process.

Theoretically, this episode should have ended the thalidomide story. However, a decade later Dr. Jacob Sheskin, while working at Hadassah Hospital at Hebrew University in Jerusalem, was trying to help one of his leprosy patients sleep. Remembering that thalidomide had helped patients with psychological problems get to sleep, he tried it. He soon found that, within days, the leprosy symptoms of his patients had dramatically disappeared. Thalidomide had soon became the drug of choice to treat leprosy, albeit under conditions carefully controlled by physicians.

But, the story gets even better. Investigations into the mode of action for thalidomide in leprosy patients uncovered that this drug stimulated the immune system and also had antiangiogenic effects that impacted the ability of tumor cells to grow blood vessels. This led scientists at Celgene to explore the use of thalidomide in treating multiple myeloma and it proved effective. Celgene got FDA approval for treating this disease with thalidomide in 2006 and sold it under the brand name, Thalomid. Amazingly, fifty years after it was condemned, thalidomide was being used to treat a form of cancer.

Merck’s Vioxx, a member of a class of anti-inflammatory drugs called COX-2 inhibitors, was flying high when it was launched in 1999. It boasted remarkable arthritis pain relief, yet didn’t cause the gastrointestinal distress that accompanied other non-steroidal anti-inflammatory drugs like ibuprofen and naproxen. These attractive properties drove Vioxx to billion dollar annual sales.

Besides being a valued pain drug, Vioxx was also being studied by Merck in long term trials to see if COX-2 inhibition could be used to prevent the formation of polyps that lead to colon cancer. In 2003, this study, known as APPROVe, was halted by the data safety monitoring board that was overseeing this trial because patients on Vioxx had an excess of cardiovascular events, including heart attacks and strokes, compared to patients on placebo. Merck immediately removed Vioxx from the market.

Again, that should have been the end of the story – until now. STAT’s Damian Garde has reported that a Vioxx resurrection could be imminent. A private Massachusetts biotech, Tremeau Pharmaceuticals, is trying to develop rofecoxib (generic Vioxx) to treat severe joint pain in people with hemophilia – a side effect called hemophilic arthropathy. In fact, as Garde reports, twenty years ago Vioxx was successfully used off-label to treat this condition. Dr. Ellis Neufeld, clinical director of hematology at St. Jude’s Children’s Research Hospital, feels that when Vioxx was pulled it robbed patients with hemophilia of an important treatment. Unfortunately, NSAIDS like ibuprofen can’t be used for this condition as they can often lead to internal bleeding, so the current alternatives include steroids and opioids.

But what about the risk of heart attacks and strokes that led to Vioxx’s discontinuation? Well, in the intervening years, it has been learned that ALL NSAID’s increase cardiovascular risk. In a landmark study called PRECISION, it was found that another COX-2 inhibitor, Pfizer’s Celebrex, was no different from ibuprofen and naproxen with respect to this risk. In fact, it appears that Vioxx poses the same heart attack risk as another generic NSAID, diclofenac, that is still marketed worldwide. Obviously, the FDA would want to be certain that the benefit for using Vioxx in hemophilic arthropathy outweighed the attendant risk before allowing Vioxx (rofecoxib) to be reintroduced to the marketplace. But, given the already known benefits in the hematology community, developing protocols to determine which patients are eligible for this therapy should be quite feasible.

What about the potential commercial opportunity for Vioxx in hemophilic arthropathy? It is possible that, in the next year, new hemophilia treatments will be available that could significantly reduce the number of patients with this condition. Even so, hemophilic arthropathy would be viewed as a rare disease and, as such, could command a price high enough to more than justify the expense of the clinical and regulatory expenses needed to bring it to market. Can Vioxx rise from the ashes as did thalidomide? History may indeed repeat.

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I was the president of Pfizer Global Research and Development in 2007 where I managed more than 13,000 scientists and professionals in the United States, Europe, and Asi...