ALBANY, NY – The newly approved co-stimulation blocker abatacept (Orencia®) significantly reduces disease activity and retards radiographic progression in patients with active rheumatoid arthritis (RA) despite treatment with methotrexate (MTX), according to results from the phase III, 1-year Abatacept in Inadequate Responders to Methotrexate (AIM) trial, published in the June 20 issue of the Annals of Internal Medicine.¹ Abatacept was approved by the US Food and Drug Administration in January 2006 and works by shutting down a costimulatory signal that is required for T-cell activation.

"Observations of the slowing of radiographic progression by abatacept, which we believe that our study is the first to demonstrate, as well as the safety and clinical findings, are expected to be extended with longer-term observations on this and other patient populations," conclude the researchers, led by Joel M. Kremer, MD, a rheumatologist at the Center for Rheumatology in Albany. "Overall, abatacept seems to be a rational and effective treatment strategy for patients with RA who have an inadequate response to weekly MTX."

In the pivotal randomized double-blind placebo-controlled trial of 652 patients with active RA despite MTX treatment, patients who received a once-monthly infusion of approximately 10 mg/kg of body weight of abatacept showed greater improvements in the signs and symptoms of RA compared with patients taking placebo. All patients were taking MTX for 3 months or longer and on a stable dose for 28 days prior to enrollment. Joint damage among patients in the abatacept group progressed at half the rate of those in the placebo arm, the study showed.

Abatacept improved ACR 20, ACR 50, and ACR 70 at 6 months and 1 year

In the study, 433 patients received abatacept and 219 received placebo. At 1 year, 385 patients taking abatacept and 162 patients taking placebo were still taking part in the study. Kremer et al performed a modified intent-to-treat analysis and found that at 6 months,  67.9% of abatacept users achieved ACR 20 compared with 39.7% of participants taking placebo; close to 40% of abatacept users achieved ACR 50 compared with 16.8% of patients taking placebo; and 19.8% of abatacept users hit ACR 70  compared with 6.5% of those receiving placebo.

At 1 year, 73.1% of abatacept users achieved ACR 20 compared with 39.7% of those receiving placebo; 48.3% of abatacept users achieved ACR 50 compared with 18.2% of those taking placebo; and 28.8% of abatacept users achieved ACR 70 compared with 6.1% of those taking placebo. At 1 year, patients taking abatacept also had less radiographic progression compared with their counterparts taking placebo, and 63.7% of abatacept users showed improvements in physical function, compared with 39.3% of those receiving placebo, the study showed.

Improvements in DAS28

Patients taking abatacept also showed reductions in disease activity score 28 (DAS28). At 6 months and 1 year, 30.1% and 42.5% of abatacept users, respectively, had a DAS28 of 3.2 or less, compared with 10.0% and 9.9% of participants taking placebo, respectively. Abatacept induced a DAS28 of <2.6 in 14.8% of abatacept recipients at 6 months compared to 2.8% of placebo recipients. At 1 year, 24.8% of abatacept users had a DAS28 of <2.6, compared with 1.9% of those in the placebo arm. Improvements in pain and self-assessment of disease activity with abatacept occurred in as early as 15 days, the study showed.

Adverse events similar among groups

Risk of infection is a concern with many of the biologic agents, and abatacept is no exception. Prespecified serious infections occurred in 2.5% of abatacept users and 0.9% of those taking placebo. Overall, however, participants in both groups experienced a similar rate of adverse events including headache, nasopharyngitis, or nausea. More participants in the abatacept group dropped out of the study due to adverse events and more infusion reactions occurred with abatacept than placebo, the study showed.

Clinicians carving out a role for abatacept

"We are currently using abatacept in patients who have not responded to tumor necrosis factor (TNF) inhibitors, and that continues to be the primary situation in which abatacept and rituximab, for that matter, are being used," said Philip J. Mease, MD, of the department of internal medicine at the Swedish Medical Center and Rheumatology Associates in Seattle, Washington. "This new data shows that it is also effective in patients early in disease."

The finding that this agent retards joint damage is critical, according to Dr. Mease. "One of the criticisms that we have of MTX is that although it can effectively reduce symptoms in a number of patients, it does not slow x-ray progression," Dr. Mease said. "These data show that x-ray progression is inhibited by abatacept, and for us, that is critically important, because we know that in the long run, disease morbidity and mortality are linked to x-ray progression."

Abatacept infusions are not associated with any meaningful infusion reactions, Dr. Mease told CIAOMed. "It is a rapid-infusion, once-a-month treatment that makes it a fairly easy drug to recommend to patients," he said. "There are typical cautions about infection, but there's not a laundry list of other side-effect issues that we have to be concerned about."

Calling the new research "an important study that will improve clinical practice," John Klippel, MD, president and chief executive officer of the Arthritis Foundation in Atlanta, Georgia, said that "the data just reinforce the value of this agent in the management of RA."

He added that they were "able to show improvement [in] the signs and symptoms of RA, improvement of function, and slowing of the signs of joint damage, and all three are very important."

Mixed message for clinicians

In an editorial accompanying the new report,² Maarten Boers, MD, PhD, of the VU University Medical Center in Amsterdam, the Netherlands, writes that the new study "marks the coming of age of a new therapeutic pathway based on the inhibition of full T-cell activation."

However, he writes, the study does not contain all the data that clinicians need to incorporate this new agent into practice. In particular, clinicians want to see trials that compare the new drug with an active comparator, but the nature of registration trials precludes this.

"Abatacept had intrinsic activity in patients with RA whose methotrexate and TNF inhibitor therapies have failed," he writes. "However, we don't know how well abatacept will do in practice compared with other alternatives, such as combinations of traditional disease-modifying anti-rheumatic drugs (DMARDs) that include glucocorticoids."

References

1. Kremer JM, Genant HK, Moreland LW, et al. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis. Ann Intern Med. 2006;144:865-876. 
2. Boers M. Abatacept in rheumatoid arthritis: A new branch on the "biologics" tree.  Ann Intern Med. 2006:144:933-935.