Sep. 15, 2005 STANFORD, Calif. -- A new drug appears to offer pain relief and increased mobility to rheumatoid arthritis patients who have exhausted their other medical treatment options. A researcher at the Stanford University School of Medicine led a six-month, multicenter clinical trial that found patients were more than twice as likely to have significant improvement with the new drug than with standard therapy. The findings are reported in the Sept. 15 issue of the New England Journal of Medicine.
The study was a phase-III trial, the final stage of human testing normally required by the U.S. Food and Drug Administration before it will consider approving a drug. Based on the results, an FDA advisory panel met on Sept. 6 and recommended the drug's approval for the treatment of rheumatoid arthritis in cases in which standard therapy has failed.
Abatacept, marketed as Orencia, is made by Bristol-Myers Squibb, which sponsored the study. The lead author, Mark Genovese, MD, Stanford associate professor of medicine (immunology and rheumatology), is a paid consultant for the company.
"This drug works where others haven't," said Genovese, who is also the associate chief of the medical school's Division of Immunology and Rheumatology. "These patients had tried and failed the best therapies to date, and they could still have a very good response to this drug."
Autoimmune diseases such as rheumatoid arthritis are characterized by an overactive immune system that turns its attack to body tissues instead of invading microbes. T cells are immune cells thought to play a major role in the development of rheumatoid arthritis. Abatacept is the first of a class of drugs, called co-stimulation blockers, that selectively impede one of the two signals needed to activate T cells.
"It's exciting to have a therapy with a new mechanism of action," said Genovese. "In the next few years we are going to get an increasing sense of who the best patients are for this therapy and even whether patients with other autoimmune diseases might benefit." Bristol-Myers Squibb is also testing the drug for use in lupus.
Stuart Levine, MD, assistant professor of medicine in the division of rheumatology at Johns Hopkins University School of Medicine, expressed optimism about the new drug. "This would likely be a useful addition to our armamentarium for patients who are failing or have failed first-line therapy," said Levine, who has no financial connections with Bristol-Myers Squibb and was not part of the study.
Rheumatoid arthritis is a disease of the joints that affects more than 2 million Americans. The disease is characterized by an infiltration of the joints with immune cells aimed against the cells lining the joint. The immune system attack causes pain, stiffness and swelling of the joints and can eventually lead to cartilage breakdown, bone loss and weakness of the joints. Without effective therapy, approximately 15 percent of patients will be crippled by their disfigured joints.
Nonsteroidal anti-inflammatory drugs can provide pain relief for rheumatoid arthritis but do not treat the underlying disease. Standard therapy currently includes other agents that suppress the immune system and can actually modify the course of disease. In addition, new medications that block the immune system's response have become available in recent years. Still, many patients don't benefit from these medications.
Bristol-Myers Squibb conferred with Genovese and others to design an international trial to test whether abatacept could benefit these rheumatoid arthritis sufferers who hadn't responded to existing therapy. At 89 sites around the world, 258 of these patients received abatacept as an intravenous injection seven times over the course of the study, and 133 patients received a placebo. Neither the patients nor the physicians knew who received active drug.
After six months of treatment, half of the patients taking abatacept achieved at least 20 percent improvement compared with one of every five taking the placebo. The FDA requires that a majority of patients benefit by this degree before a drug can be approved for treating rheumatoid arthritis.
A 20 percent improvement means a lot, Genovese said, particularly for the severely affected patients in this study, who had an average of 30 tender joints each. "For many of these patients, it means a significant increase in their ability to function," he said. "That means turning on the shower, opening a car door, using the toilet -- little actions that make a huge change in their quality of life."
One in five patients taking abatacept achieved at least 50 percent improvement and one in 10 achieved the definition for remission -- a difficult hurdle to clear for a group that failed to see significant improvement from all other therapies.
According to the trial results, abatacept appears to be safe, with few side effects. About 2 percent of both groups experienced serious infections. Mild to moderate infections such as bronchitis and upper respiratory tract infections were slightly higher in the group taking the drug -- 38 percent compared with 32 percent in the placebo group.
"It"s a fine line between trying to modulate the immune system and suppressing it to an extent that you are at an increased risk for infections," said Genovese. The higher risk of less serious infections is something to keep in mind with abatacept.
"Any time you modulate the immune system you are at a potential risk," he said, "but you just have carefully weigh the risks and the benefits."
Stanford University Medical Center integrates research, medical education and patient care at its three institutions -- Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at http://mednews.stanford.edu.
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