The experimental costimulation blocker abatacept (CTLA4Ig), designed to block a costimulatory pathway required for optimum activation of T cells, has been found to reduce disease activity and improve physical function over the course of 12 months in patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) treatment, according to a Phase IIb study published in the August issue of Arthritis & Rheumatism.1
"Despite recent advances in RA therapy, some patients do not respond to existing agents or may not be candidates for them, while others are unable to tolerate them. Therefore, there is still significant room for novel therapies with mechanisms of action that are different from those of existing agents," conclude the researchers, led by Joel M. Kremer, MD, a rheumatologist at the Center for Rheumatology in Albany, New York. "As the first in a novel class of agents—the selective costimulation modulators—abatacept has the potential to play an important role in the future treatment of patients with RA."
The new study did not look at X-ray progression, but CIAOMed recently reported promising Phase III data showing that abatacept users who failed MTX showed a 50% reduction in joint space narrowing scores, erosion scores, and total scores compared with participants taking MTX plus placebo.2
Higher dose more efficaceous
In the new double-blind, placebo-controlled study, 339 RA patients with active RA despite MTX therapy were randomly assigned to receive 10 mg/kg abatacept, 2 mg/kg abatacept, or placebo. According to 1-year data, 62.6% of patients treated with 10 mg/kg abatacept achieved an ACR20 response, compared with 36.1% of patients who received placebo (P <.001). Greater percentages of patients also achieved ACR50 and ACR70 responses, the study showed. Specifically, 41.7% of patients treated with 10 mg/kg abatacept achieved ACR50 responses versus 20.2% of patients in the placebo arm (P <.001), and 20.9% of patients given 10 mg/kg abatacept achieved ACR70 responses compared with 7.6% of patients given placebo (P <.003).
Nearly 50% of patients treated with 10 mg/kg abatacept showed statistically significant and clinically important improvements in modified Health Assessment Questionnaire (M-HAQ) scores, compared with 27.7% of patients who received placebo, the study showed.
Overall, the mean improvement in physical function was over two times greater in the 10 mg/kg abatacept group than in the placebo group, and a higher number of patients experienced zero disability in the 10 mg/kg abatacept group than in the placebo group, according to Kremer and colleagues.
Almost 35% of RA patients receiving 10 mg/kg of abatacept showed an increase in their rates of remission, according to the Disease Activity Score of <2.6 in 28 joints, compared with 10.1% of patients receiving placebo at 1 year, the study showed.
"Because the clinical responses at 12 months were clearly superior for the 10 mg/kg dose, this study supports the use of the higher dose regimen in the treatment of RA," the researchers conclude.
Placebo response higher than that reported for anti-TNF drugs
"The ACR20, 50, and 70 responses are very good with abatacept," says Philip J. Mease, MD, of the department of internal medicine at the Swedish Medical Center and Rheumatology Associates in Seattle, Washington. "But the delta from placebo is not as large as that seen in anti-tumor necrosis factor-alpha [TNF-α] inhibitors," he says. "There is a fairly large placebo response, and that takes away a bit from the robustness of the effect compared with anti-TNF drugs," he tells CIAOMed.
Although this study did not examine abatacept's role among patients who have failed anti-TNF drugs, "in all likelihood that will be the most likely scenario for abatacept," Dr. Mease says. "Patients will have tried one or two anti-TNF drugs before they go onto abatacept."
Abatacept is infused intravenously over a 30-minute period on days 1, 15, and 30, and every 30 days thereafter. "It's a quick infusion, and it has some of the same bugaboos of TNF inhibitors," Dr. Mease says. "There hasn't been an issue with infusion reactions, and the safety profile has been especially good, so a few patients may use it first if they have a higher risk of infections, especially tuberculosis."
The incidence of adverse events was comparable between the groups, and no significant formation of neutralizing antibodies was noted.
References
- Kremer JM, Dougados M, Emery P, et al. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase IIb, double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 2005;52:2263-2271.
- Genant H, Jiang Y, Wu C, et al. Abatacept significantly inhibits structural damage progression as assessed by the Genant-modified Sharp scoring system in rheumatoid arthritis patients with inadequate methotrexate response. Presented at: Annual European Congress of Rheumatology of EULAR; June 8–11, 2005; Vienna, Austria. Abstract OP0001.