Treatment of rheumatoid arthritis (RA) has improved in the past decade, owing in part to the more aggressive use of disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, and the introduction of TNF-α inhibitors. Despite these advances, unmet needs remain, especially in patients who have failed TNF-α inhibition. According to data from a randomized, double-blind phase III study that appears in the September 15 issue of the New England Journal of Medicine, patients with inadequate or unsustained response to TNF-α inhibitors show significant clinical and functional benefit when switched to the costimulation blocker abatacept (Orencia®).¹  

"There are currently no clinically proven treatment options for patients with inadequate response to anti-TNF-α therapy," write the authors, led by Mark C. Genovese, MD, of Stanford University Medical Center in California. "Abatacept is the first in a new class of agents for the treatment of RA that selectively modulate the CD80 or CD86-CD28 costimulatory signal required for full T-cell activation." Bristol-Myers Squibb is seeking approval to market the drug to patients with moderate-to-severe RA who have failed other treatments.

Study findings

Patients with active RA and an inadequate response to anti-TNF-α therapy were randomized 2:1 to received abatacept (n = 258) or placebo (n = 133) on days 1, 15, and 29, and every 28 days thereafter for 6 months in addition to at least one DMARD including methotrexate, gold, leflunomide, and azathioprine. Patients discontinued anti-TNF-α therapy before randomization.

After 6 months, the rates of American College of Rheumatology (ACR) 20 responses, indicating a clinical improvement of 20% or higher, were 50.4% in the abatacept group and 19.5% in the placebo group (P <0.001). The respective rates of ACR 50 and ACR 70 responses were also significantly higher in the abatacept group than in the placebo group, the study showed.

At 6 months, close to 50% of patients in the abatacept group had a significant improvement in physical function, as reflected by an improvement from baseline of at least 0.3 in the Health Assessment Questionnaire (HAQ) disability index, compared with about 25% in the placebo group.

Positive safety profile

Patients were monitored for adverse events, serious adverse events, and clinically significant changes in vital signs and laborator tests. The incidence of adverse events and peri-infusional adverse events was 79.5% and 5%  respectively in the abatacept group and 71.4% and 3% respectively in the placebo group. The incidence of serious infections was 2.3% in each group. The low incidence of serious infusion reactions among abatacept users did not appear to increase the incidence of autoimmunity.

While some experts have suggested that the safety profile of abatacept is comparable to anti-TNF drugs, Dr. Genovese is more cautious. "I think it's difficult to compare across classes because there have not been any head-to-head trials, but the safety profile with abatacept appears to be good.

"We were excited to see it worked even in 50% of patients who tried TNF-α inhibitors and failed," Dr. Genovese says. "It's nice to see something work where other drugs haven't." Dr. Genovese predicts that "most doctors will use [abatacept] for the TNF-α inhibitor nonresponder population and then get their own flavor for how it works and expand it possibly toward traditional DMARD failures. I'd like to think in the future that we will have some markers that will suggest which patients are more likely to respond to any therapy or experience safety problems," he says.

New results support recent FDA Advisory Panel action

Originally presented at the 2004 American College of Rheumatology meeting in San Antonio, Texas, the formal publication of the study results come just a week after the FDA Arthritis Advisory Committee unanimously (7–0) recommended approval of abatacept, stating that the benefits of the costimulation blocker for RA outweighed the risks of serious infections like pneumonia and some cancers. The FDA is expected to make a decision on whether to approve abatacept by December 31, 2005.

References

1.       Genovese MC, Becker J-C, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor-alpha inhibition. N Engl J Med. 2005;353:1114-1123.