STANFORD, Calif. -- A new drug appears to offer pain relief andincreased mobility to rheumatoid arthritis patients who have exhaustedtheir other medical treatment options. A researcher at the StanfordUniversity School of Medicine led a six-month, multicenter clinicaltrial that found patients were more than twice as likely to havesignificant improvement with the new drug than with standard therapy.The findings are reported in the Sept. 15 issue of the New EnglandJournal of Medicine.
The study was a phase-III trial, the final stage of human testingnormally required by the U.S. Food and Drug Administration before itwill consider approving a drug. Based on the results, an FDA advisorypanel met on Sept. 6 and recommended the drug's approval for thetreatment of rheumatoid arthritis in cases in which standard therapyhas failed.
Abatacept, marketed as Orencia, is made by Bristol-MyersSquibb, 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 isalso the associate chief of the medical school's Division of Immunologyand Rheumatology. "These patients had tried and failed the besttherapies to date, and they could still have a very good response tothis drug."
Autoimmune diseases such as rheumatoid arthritis arecharacterized by an overactive immune system that turns its attack tobody tissues instead of invading microbes. T cells are immune cellsthought to play a major role in the development of rheumatoidarthritis. Abatacept is the first of a class of drugs, calledco-stimulation blockers, that selectively impede one of the two signalsneeded to activate T cells.
"It's exciting to have a therapy with a new mechanism ofaction," said Genovese. "In the next few years we are going to get anincreasing sense of who the best patients are for this therapy and evenwhether 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 thedivision of rheumatology at Johns Hopkins University School ofMedicine, expressed optimism about the new drug. "This would likely bea useful addition to our armamentarium for patients who are failing orhave failed first-line therapy," said Levine, who has no financialconnections with Bristol-Myers Squibb and was not part of the study.
Rheumatoid arthritis is a disease of the joints that affectsmore than 2 million Americans. The disease is characterized by aninfiltration of the joints with immune cells aimed against the cellslining the joint. The immune system attack causes pain, stiffness andswelling 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 theirdisfigured joints.
Nonsteroidal anti-inflammatory drugs can provide pain relieffor rheumatoid arthritis but do not treat the underlying disease.Standard therapy currently includes other agents that suppress theimmune system and can actually modify the course of disease. Inaddition, new medications that block the immune system's response havebecome available in recent years. Still, many patients don't benefitfrom these medications.
Bristol-Myers Squibb conferred with Genovese and others todesign an international trial to test whether abatacept could benefitthese rheumatoid arthritis sufferers who hadn't responded to existingtherapy. At 89 sites around the world, 258 of these patients receivedabatacept as an intravenous injection seven times over the course ofthe study, and 133 patients received a placebo. Neither the patientsnor the physicians knew who received active drug.
After six months of treatment, half of the patients takingabatacept achieved at least 20 percent improvement compared with one ofevery five taking the placebo. The FDA requires that a majority ofpatients benefit by this degree before a drug can be approved fortreating rheumatoid arthritis.
A 20 percent improvement means a lot, Genovese said,particularly for the severely affected patients in this study, who hadan average of 30 tender joints each. "For many of these patients, itmeans 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 50percent improvement and one in 10 achieved the definition for remission-- a difficult hurdle to clear for a group that failed to seesignificant 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 experiencedserious infections. Mild to moderate infections such as bronchitis andupper respiratory tract infections were slightly higher in the grouptaking the drug -- 38 percent compared with 32 percent in the placebogroup.
"It"s a fine line between trying to modulate the immune systemand suppressing it to an extent that you are at an increased risk forinfections," said Genovese. The higher risk of less serious infectionsis something to keep in mind with abatacept.
"Any time you modulate the immune system you are at a potentialrisk," he said, "but you just have carefully weigh the risks and thebenefits."
Stanford University Medical Center integrates research, medicaleducation and patient care at its three institutions -- StanfordUniversity School of Medicine, Stanford Hospital & Clinics andLucile Packard Children's Hospital at Stanford. For more information,please visit the Web site of the medical center's Office ofCommunication & Public Affairs at http://mednews.stanford.edu.
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