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COX-2 Update Page

Posted April 18, 2002 Last updated February 15, 2003

This page is provided as a service to my patients who want to know the latest about COX-2 inhibitors. This is very active area of research, so there is a lot of news. You may have read something about these topics, or heard about it from friends. I provide this information as a service to you, so that you are not unduly influenced by word-of-mouth information. Most of this information is preliminary (that is, there is not yet good enough research data to base decisions on), but it may give us some insight into the uses and limits of this class of drugs.

Study Questions COX-2 Inhibitor Cost for Arthritis

Monday, May 19, 2003 5:03 p.m. ET By David Morgan Reuters News Service

PHILADELPHIA (Reuters) - Expensive new anti-inflammatory drugs that are now widely used to combat arthritis may not be as cost-effective as older generic pain killers, according to a study released on Monday.

The study, by researchers at UCLA and the VA Greater Los Angeles Healthcare System, found that the drugs known as Cox-2 inhibitors were vastly more expensive than the nonsteroidal anti-inflammatory drug naproxen for many patients, considering costs that included potential cardiovascular side-effects.

In fact, researchers estimated that Cox-2 inhibitors could become the dominant treatment for arthritis pain only if their estimated $2.66 cost per tablet were reduced by 90 percent. Naproxen tablets cost 18 cents apiece.

Cox-2 inhibitors, which appeared in 1999 amid great fanfare, are designed to control pain and inflammation without potentially deadly side-effects including bleeding ulcers that are associated with generic painkillers such as naproxen, aspirin and ibuprofen. The patented drugs work by suppressing the Cox-2 enzyme that causes inflammation.

With 15 percent of the U.S. population believed to suffer from some form of arthritis, global sales have surpassed the $6 billion mark for four Cox-2 inhibitor products: Celebrex and Bextra from Pfizer Inc. ; and Vioxx and Arcoxia from Merck & Co .

But sales have slowed amid questions about safety vis-a-vis the older nonsteroidal anti-inflammatory drugs, including concerns about possible cardiovascular side-effects.

Monday's study, which appeared in the Annals of Internal Medicine, measured the cost-effectiveness of Cox-2 inhibitors in quality-adjusted life years, or QALYs, for a hypothetical 60-year-old patient with moderate to severe arthritis pain.

The study cited evidence that Cox-2 inhibitors reduce the absolute risk for ulcer complications by only 1-2 percent, and by less than 1 percent for significant ulcer-related problems.

What researchers found was that it cost Cox-2 inhibitors $275,809 more than naproxen to produce one additional QALY for an arthritis patient, even though their research was designed to give a "best case" scenario for the newer treatment.

Adding possible cardiovascular side-effects to the mix, the additional cost soared to $395,324 per QALY.

But the study did find a QALY cost of $55,803 for patients already at high risk for ulcer complications.

5-LOX and COX-2?

Reuters June 14, 2002 Licofelone, a new type of anti-inflammatory painkiller is showing promise in experiments on people with arthritis in their knees. Research presented at the European Congress of Rheumatology in Stockholm indicated the drug works just as well for arthritis as traditional nonsteroidal anti-inflammatory drugs such as aspirin and ibuprofen, but is gentler on the stomach. Experts say licofelone could offer an alternative to newer arthritis drugs, such as Vioxx and Celebrex. Licofelone, being developed by German pharmaceutical manufacturer Merckle, works in a slightly different way from other anti-inflammatory painkillers. Conventional nonsteroidal anti-inflammatories work by shutting off production of prostaglandins by blocking the action of the enzyme cox. In the late 1980s, scientists discovered there were two varieties of the cox enzyme. While cox-2 causes pain and inflammation as part of the body's repair process, cox-1 protects the lining of the stomach. Vioxx and Celebrex block only cox-2 rather than both cox enzymes. Licofelone blocks both cox-1 and cox-2, like the older painkillers, but also interferes with the action of another enzyme involved in pain and inflammation, called 5-lox. A study, involving 710 people with arthritic knees, followed for a year, found that licofelone worked as well as the older drugs, was gentle on the stomach and showed no trace of side effects that could cause heart problems. The lead investigator, Dr. Jean-Yves Reginster of the University of Liege, said those on the new drug were 80% less likely than the others to get a stomach ulcer. Dr. Reginster said the study did not directly address heart safety, but that swelling in the feet and ankles, and elevated blood pressure-both side effects suggested in studies of cox-2 blockers-did not affect patients taking the new drug. There is preliminary evidence that 5-lox may play a role in deterioration of the joints and licofelone is being investigated as a possible disease-slowing drug, he said.

New COX-2 Inhibitor on the horizon

Merck Press Release June 11, 2002 Merck & Co. said it would refile an expanded New Drug Application (NDA) for Arocoxia (etoricoxib) with the FDA in the second half of 2003. Merck has been in ongoing discussions with the FDA since the withdrawal of the original NDA for the drug on March 15. In a meeting last week, Merck said the FDA requested additional data on the acute pain indications for Arocoxia and additional cardiovascular safety data for Arocoxia vs. comparators other then naproxen. Merck will provide data from several ongoing studies on Arocoxia in acute pain. As previously announced, Merck will be submitting additional efficacy data to support a new indication for ankylosing spondylitis and will seek indications for osteoarthritis, rheumatoid arthritis, chronic pain, acute pain, dysmenorrhea and acute gouty arthritis.

Vioxx and Celebrex Too Expensive?

Associate Press, June 4, 2002 A class of very popular -- and expensive -- pain relievers are often prescribed when cheaper medications would likely be just as effective, contributing to rising health care costs, according to a new survey by Express Scripts Inc.

The drugs -- Vioxx and Celebrex -- are heralded for their ability to relieve pain without the gastrointestinal upsets of older, cheaper drugs like ibuprofen or naproxen. However, the study found that 76 percent of prescriptions written are for patients who show no risk of such side effects, calling into question the cost effectiveness of the medicines.

"This therapeutic class of drugs is definitely a major driver of pharmaceutical costs," said Emily Cox, outcomes research manager at Express Scripts, a pharmacy benefits management firm.

The study is part of Express Scripts report scheduled for release Tuesday, which found that its prescription drug costs rose 16.9 percent last year to an average of $592.05 per person. Express Scripts is a pharmacy benefit manager that provides coverage for 50 million people in numerous health plans.

Meanwhile, over the weekend, an editorial in The British Medical Journal resurrected criticisms previously raised in The Washington Post about the design of a clinical trial which found Celebrex was safer than ibuprofen or diclofenac because it caused fewer ulcers and ulcer complications.

Celebrex's manufacturer Pharmacia Inc. stands by its trial design. In fact, Pharmacia submitted the study to the Food and Drug Administration to have its label reflect what is says is a superior safety profile.

The study and editorial just add to the blistering debate over the use of the drugs, which many believe is being driven more by advertising than medical need. Last year, Vioxx was the most heavily advertised drug to consumers, with its manufacturer Merck & Co. spending $135 million to promote the medicine in the United States, according to IMS Health, a research firm.

Vioxx is the world's 10th-biggest selling medicine, registering $2.6 billion in revenues in 2001

Celebrex was the second most advertised drug in the United States with Pharmacia spending $130 million. Its sales totaled $3.1 billion, making it the seventh-biggest selling drug in the world. Bextra is Pharmacia's recent addition to the class of drugs known as Cox-2s and was introduced earlier this year and isn't included in the study. Vioxx and
Celebrex were introduced in 1999.

"Any time there are new drugs on the market that are heavily advertised doctors and patients want to try them," said Raulo Frear, vice president of clinical services at Express Scripts.

But the study calls into question how much of the Cox-2 sales are medically necessary. For example, the study also found new users of the drug had consumed less than a 60 day supply of the medicine, a year after the initial prescription. That suggests the drugs are not being prescribed for conditions requiring long term therapy where the risk of gastrointestinal adverse events is of greatest concern. Side effects are most common in the elderly and people taking blood thinning medication or steroids.

The cost differential is substantial: A month's supply of Celebrex or Vioxx costs about $80 a month while a month's supply of ibuprofen is about $15.

Express Scripts couldn't say how much is spent on the drugs unnecessarily, but Fred Teitelbaum, the company's vice president for research and planning, said stricter use of the drugs could reduce costs by 75 percent.

Representatives from Merck and Pharmacia said it's better than to be safe than sorry when it comes to prescribing the Cox-2 because annually 100,000 people are hospitalized from adverse reactions to drugs like naproxen.

Merck spokesman Greg Reeves said that adverse effects occur in those not considered high risk.

"We believe Vioxx is fairly priced," said Reeves.

Earlier this year, the FDA allowed Merck to change Vioxx's label to say it is less likely to cause gastrointestinal side effects than naproxen. However, Vioxx's label also had to say that patients taking Vioxx had a higher incidence of heart attacks than those taking naproxen. There has been a debate over whether Vioxx can cause heat attacks or whether naproxen actually protects the heart.

Pharmacia's label can't claim the same stomach benefit as Vioxx although the FDA is considering allowing a change.

Regardless of the labels, health insurers are limiting use of Vioxx and Celebrex because of the cost.

For example, WellPoint Health Networks requires doctors to get prior approval for the prescriptions. Humana Inc. requires patients who want Vioxx or Celebrex to shell out a copay of $40 to $50 a month to discourage unnecessary use.

Celebrex: A Treatment for Cancer?

Wall Street Journal May 22, 2002 Research is underway to determine if Celebrex, a COX-2 inhibitor, is a useful drug in the treatment of cancer. Studies have shown that COX-2 is over-expressed in 90% of lung cancer tumors and is in other cancers as well. Based on animal studies, researchers think COX-2 inhibitors used with other medications may not get rid of tumors, but may control their growth. The drug has already been FDA-approved as a preventative treatment to keep familial adenomatous polyposis from developing into cancer. In a small study, reported at a meeting of the American Society of Clinical Oncology, Celebrex was used in combination with chemotherapy as a treatment for cancer that was already diagnosed. Researchers gave 26 lung cancer patients Celebrex pills and chemotherapy daily for several weeks before the patients underwent surgery to remove the tumors. The scientists found that of 16 patients who completed the therapy, tumors in 12 patients (75%) had shrunk. There was no control group, but in other trials using chemotherapy alone typically only half of patients respond. In 37% of the patients in the Celebrex-chemotherapy group, researchers found 95% of the tumor cells were dead when they analyzed the malignancies that were removed. In other studies, chemotherapy alone is usually that effective in only 6% of patients. Pharmacia, the maker of Celebrex, plans a larger study with a control group to determine the effectiveness of the Celebrex-chemotherapy approach. Nasser Altorki, MD, professor of surgery at New York Presbyterian Hospital's Weill Medical College-Cornell, and principal investigator on the study, cautions that research with Celebrex is in the early stages and proof of its effectiveness beyond preventing familial adenomatous polyposis is not established.

COX-2 Decrease Bone Healing?

Journal of Bone and Mineral Research May 21, 2002 Celebrex (celecoxib) and Vioxx (rofecoxib), commonly prescribed to reduce pain and inflammation caused by arthritis, may also impair healing of bone fractures, suggests an animal study and an accompanying editorial in the June 2002 issue of the Journal of Bone and Mineral Research (JBMR). These anti-inflammatory drugs, known as COX-2 (cyclo-oxygenase 2) inhibitors or coxibs, are often prescribed to individuals who suffer fractures or are, already taken by these individuals for other ailments. The study, conducted by J. Patrick O'Connor, PhD, assistant professor in the Departments of Orthopaedics and Microbiology and Molecular Genetics at the University of Medicine and Dentistry of New Jersey-New Jersey Medical School-explored the role of prostaglandins in fracture healing. Prostaglandins are naturally occurring compounds, which under varying conditions may stimulate both bone formation and breakdown. They are synthesized with the involvement of COX-2. The researchers divided 253 six- to nine-month-old male rats into four groups. After hind leg bone fracture, two groups of rats were treated with one of two COX-2 inhibitors (celecoxib or rofecoxib). A third group was administered a traditional NSAID (indomethacin); and the fourth group served as a control, receiving no treatment or water "treatment." The animals were euthanized at two to eight weeks post-fracture; the researchers assessed the fracture healing with mechanical, radiographic and microscopic tests. The researchers found that the control group demonstrated regular progress in bone healing through an entire eight-week period. In the group of rats that received traditional NSAID treatment, the bridging of the fracture site with new bone tissue was delayed by one week. In addition, mechanical testing revealed that the bones in indomethacin-treated rats withstood physical stress less well than controls at the six-week mark, but exhibited a normal stress response eight weeks post-fracture. Treatment with the COX-2 inhibitors exhibited a more dramatic effect: Bone healing appeared normal at two and four weeks, but the fracture was still plainly evident at eight weeks, indicating that the rate of normal healing was incomplete. In addition, mechanical testing revealed that COX-2 inhibitors may also reduce bone strength. To confirm their findings, the researchers also examined mice that lacked a functional COX-2 gene and thereby expressed no COX-2 activity (a condition similar to the effects of the Celebrex and Vioxx). These mice failed to heal normally or completely after bone fracture, demonstrating that the expression of COX-2 is critical for bone healing. Thus, COX-2 is the first gene to be identified as essential for fracture healing but not for the development of a healthy skeleton during fetal growth. In an accompanying editorial, Thomas A. Einhorn, MD, Professor and Chair of the Department of Orthopaedic Surgery at the Boston University School of Medicine, describes the data as "compelling." While the dosage of the drugs employed in the animal studies may not exactly compare to those used in humans, Dr. Einhorn suggests "we may have to make clinical decisions based on our knowledge of basic mechanisms and the data derived from animal studies." Dr. Einhorn concludes that "based on our current understanding, it would seem that a prudent approach toward the management of patients is to temporarily avoid or discontinue the use of both NSAIDs and coxibs during a period of bone healing." Dr. Einhorn said these concerns may also extend to patients receiving dental implants or who undergo joint replacement while using an NSAID or coxib to manage arthritis in another joint.

COX-2 Increase Risk of Heart Attack?

AP April 18, 2002 A new study in mice adds to the concern that cox-2 inhibitors may increase the risk of heart attacks in people with heart disease. Merck & Co., maker of Vioxx, dismisses the study by University of Pennsylvania researchers, because it is in mice and presumes an effect in the human body far larger than the drug actually causes. However, Dr. Eric Topol of the Cleveland Clinic, a heart expert, called the new research an important step in explaining an earlier study that found certain Vioxx users suffered increased risk of heart attacks. "Now the only thing we're really missing is quantifying the magnitude of the risk," said Dr. Topol, who wants more research quickly to settle the issue. Meanwhile, he said, "If you have heart disease, it ought to be with particular care and concern that you take these medications, ... because there could be some risk." The study is in the April 19 issue of Science. One of the enzymes in people, Cox-1, makes thromboxane, which causes blood vessels to constrict and platelets to become sticky, steps important in a heart attack or stroke. The Cox-2 enzyme is a major source of prostacyclin, which dilates blood vessels and prevents platelets from clumping together. In a healthy person, the two coxes are thought to balance each other so blood doesn't excessively clot. Vioxx and Celebrex block only cox-2. In genetically engineered mice, researchers irritated an artery to increase release of both clotting chemicals. Mice resistant to prostacyclin's effects, experienced more thromboxane-caused clotting activity. That's not proof people would be endangered, stressed lead scientist Dr. Garret Fitzgerald, a University of Pennsylvania pharmacologist. He plans to begin studies in people to try to settle the issue. Dr. Alise Reicin, a Merck scientist, said the study looked at mice that had completely inhibited prostacyclin, while cox-2 drugs inhibit the chemical only half as much. She said the study contributed no new information to the debate, but Merck plans further safety studies to deal with the issue.