COX-2 inhibitor debate rumbles on as Merck accused of delay

The US drug major recently withdrew its blockbuster Vioxx, after an increase in cardiovascular events was observed following 18 months of continuous use of the drug, and this prompted considerable debate about the safety of the overall COX-2 inhibitor class. The new study, published in Atherosclerosis, says Vioxx is not typical of other COX-2 inhibitor drugs.

The company with the most to lose if the 'class effect' theory is sustained is Pfizer, which sells Celebrex (celecoxib), the first COX-2 inhibitor to reach the market, and follow-up Bextra (valdecoxib). Pfizer was forced to defend its drug last week when a Canadian newspaper published an article linking 14 deaths to Celebrex.

Sales of Celebrex and Bextra were $779 million (€601m) and $324 million, respectively, in the third quarter of this year.

Over the course of their two-year investigation, the authors of the Atherosclerosis study discovered that Vioxx made certain lipid components of the blood, particularly low-density lipoprotein or "bad" cholesterol, more susceptible to free radical damage - changes that contribute to heart disease.

"Vioxx interacts at the molecular level in a way that Celebrex and other non-steroidal anti-inflammatories do not,"​ said lead author Preston Mason, president and founder of Elucida Research, which conducted the study. The group received no drug company funding for the research, but counts Pfizer as a sponsor.

In addition to Vioxx and Celebrex the researchers examined two other COX-2 inhibitors, Bextra and Merck's Arcoxia (etoricoxib), which is approved for sale in Europe but had its application withdrawn in the US. They also included a non-selective nonsteroidal anti-inflammatory drugs (NSAIDs - naproxen, diclofenac and ibuprofen) and Boehringer Ingelheim/Abbott Laboratories' Mobic (meloxicam), which also claims COX-2 selectivity.

Crucially, they concluded that the effects were independent of Vioxx' COX-2 function, and were not seen with the other drugs.

"Lipids are important molecular building blocks in cells of the artery. Abnormal changes in the structure or shape of lipids caused by Vioxx, especially in LDL, may explain why they are more susceptible to oxidative damage and, therefore, contribute to cardiovascular damage, "​ said Mason.

Merck is being tight-lipped about the class effect issue, but a spokesman did say that the company as investigating whether the effect occurred in other COX-2 inhibitors and less selective anti-inflammatories.

The latter group includes widely-use drugs such as naproxen and ibuprofen, and at the time that fingers were first pointed at Vioxx and Celebrex back in 2001 it had been suggested that the COX-2 inhibitors' cardiovascular safety profile suffered because they were being compared to NSAIDs with cardioprotective properties. However, subsequent studies did not support this view.

AHA study claims class effect​

Meanwhile, a study supporting the class effect theory was reported at the annual meeting of the American Heart Association in New Orleans last week, and concluded that Bextra may pose an even greater cardiovascular risk than Vioxx.

This meta-analysis of several studies looked at cardiovascular risk data from 2,000 heart bypass patients and nearly 5,700 arthritis patients. Pfizer has dismissed the findings, saying that the researchers' choice of studies was incomplete and flawed.

Merck is currently reeling from allegations that it was aware of the safety problems with Vioxx long before the company pulled the $2.5 billion drug from the market. The company is planning to make public a series of documents that, it claims, will prove that it acted responsibly in the five years since suspicions of safety issues with Vioxx surfaced.

But legal teams are already scouring the US for patients who suffered cardiovascular events while taking the drug, and Merck can expect some hefty claims for damages. The financial impact of such a case can be dramatic: Bayer has had to foot a bill of $1.1 billion - without admitting liability - as a result of its withdrawal of the cholesterol-lowering drug Lipobay/Baycol (cerivastatin) in 2001.

And three years later, the lawsuits still rage on. In September, Bayer said it had reached 2,861 settlements, but some 7,577 suits are still pending.

Raymond Gilmartin, Merck's chief executive, has been called to appear before the senate finance committee in the US on Thursday to answer questions about the company's actions in the case.

Meantime, regulatory authorities in both the US and Europe are set to review the safety of the entire COX-2 inhibitor class.