Heart attack risk forces Merck to pull $2.5bn Vioxx
has been withdrawn from the market after comprehensive clinical
data confirmed long-established concerns that the treatment could
increase the risk of heart attacks and strokes.
Vioxx (rofecoxib), which is also used to combat acute pain, was voluntarily withdrawn worldwide by its maker Merck & Co, whose decision was based on new three-year data from the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial. The results could also have implications for other drugs in the same class.
The study, which assessed whether Vioxx may prevent the recurrence of benign polyps in patients who have a history of such tumours, also discovered an increased risk of cardiovascular events in those taking Vioxx in 25mg doses, which only became evident after 18 months.
Merck stressed that the difference related only to non-fatal attacks in the 2,600 people involved in the multicentre trials.
Long-standing safety concerns over Vioxx were reinforced after the results of a study, VIOXX GI Outcomes Research (VIGOR), were submitted to the FDA in June 2000. The research revealed that while patients taking Vioxx had fewer stomach ulcers and bleeding than patients taking naproxen, another non-steroidal anti-inflammatory drug (NSAID), however, the study also showed a greater number of heart attacks in patients taking Vioxx. As a result, Merck were forced to provide new safety information to the labelling for Vioxx in April 2002.
Since its launch in 1999, Vioxx has become a best selling drug, which is used by 84 million patients worldwide. Its annual sales figures for 2003 topped $2.55 billion (€2.05 billion) worldwide. While Vioxx is approved in more than 80 countries, its sales had begun to flatten because of fears of side effects.
The announcement is sure to hit profits hard and considering Merck's relatively small late-stage pipeline, all indications are it could struggle to fill the hole left by the blockbuster drug.
According to data from Pharmaprojects, Merck has no new active substances in development above Phase III, so is unlikely to be able to launch anything completely new for more than a year. Although Merck's near term pipeline prospects are less than glowing, it has a healthy early-stage pipeline that could prove fruitful in the future.
Indeed, speculation has mounted as to whether the shortfall may make Merck, a company that has previously 'gone it alone', a candidate for merger or takeover.
In a statement, Raymond Gilmartin, chairman of Merck said: "Although we believe it would have been possible to continue to market Vioxx with labelling that would incorporate this new data, given the availability of alternative therapies, and the questions raised by the data, we concluded that a voluntary withdrawal is the responsible course to take."
The withdrawal of Vioxx sends a powerful message regarding safety over similar drugs in the same class. Vioxx is a COX-2 selective nonsteroidal anti-inflammatory drug (NSAID) primarily used to relieve signs and symptoms of arthritis, acute pain in adults, and painful menstrual cycles. Conventional NSAIDs include ibuprofen and naproxen.
Acting FDA commissioner Dr. Lester Crawford said the FDA would closely monitor other drugs in this class for similar side effects. "All of the NSAID drugs have risks when taken chronically, especially of gastrointestinal bleeding, but also liver and kidney toxicity. They should only be used continuously under the supervision of a physician, " he said.
While none of the other NSAID's have been known to cause such serious side effects, the class of drug is far from perfect. In addition, to their anti-inflammatory effect these COX-2 inhibitors can cause stomach ulcers and gastrointestinal bleeding, albeit less often than traditional NSAIDs.
Despite this, worldwide sales of the class reached $6.4 billion in 2003 and had been expected to increase to $9.6 billion by 2009, according to consensus forecasts compiled by the independent consulting firm Evaluate.
Analysts believe Merck's hopes for its follow-up drug to Vioxx, Arcoxia (etoricoxib), also appear to have dimmed further following this latest news. The fear is that it will always be tainted by the Vioxx withdrawal because it belongs to the same class of drugs. In 2002 the UK became the first European country to approve the drug, which is now available in 47 countries, although it is not yet approved in the US.
Indeed, the U.S. Food and Drug Administration is expected to rule next month on whether to approve Arcoxia, which had been touted as a potential blockbuster. The FDA has already postponed reviewing the drug once because it required additional safety data.
The fallout from Vioxx's withdrawal could affect similar drugs from rival companies either way. It could potentially divide up the future market among fewer players, opening up the field of play. Pfizer's Celebrex (celecoxib) and its follow-up drug Bextra (valdecoxib) have not been associated with such risks in clinical trials. Pfizer issued a statement saying it was 'confident in the long-term cardiovascular safety of Celebrex'.
However Novartis of Switzerland could now have a harder task winning approval for its Prexige (lumiracoxib) product, which has already been delayed over concerns about side effects. Prospects remain uncertain for another early-stage drug from GlaxoSmithKline. The impact on GlaxoSmithKline is less significant because its experimental drug, 406381, is at an earlier stage of development.
