VIENNA, Austria-The experimental costimulation blocker abatacept (CTLA4Ig) blocks progression of joint damage in rheumatoid arthritis (RA) patients failing methotrexate (MTX), according to results from a Phase III trial presented here on Thursday at the Annual European Congress of Rheumatology of the European League Against Rheumatism (EULAR). The new agent works by shutting down a costimulatory signal that is required for optimum activation of T cells.
In the Abatacept in Inadequate Responders to Methotrexate (AIM) trial,1 abatacept users showed a 50% reduction in joint space narrowing scores, erosion scores, and total scores, compared with participants taking MTX plus placebo. Researchers looked at erosion at 14 sites on the hand and wrist and joint space narrowing at 13 sites and measured progression via the Genant-modified Sharp scoring system.
"Costimulation blockade is extremely important because it offers an entirely different alternative for patients failing MTX and tumor necrosis-alpha therapy," lead study author Harry K. Genant, MD, director of the Osteoporosis and Arthritis Research Group at the University of California at San Francisco, tells CIAOMed. "That's a substantial number of patients."
New agent may follow same path as TNF-blockers
Dr. Genant tells CIAOMed that his team is now reviewing data from a long-term extension of the AIM trial as well as looking at the role this agent may play in psoriatic arthritis, seronegative spondyloarthropathies, potentally lupus, and early RA.
No doubt, "[abatacept's] first indication will be in patients failing TNF-α inhibitors," forecasts Paul Emery, MD, professor of rheumatology at the University of Leeds in the UK. Dr. Emery believes costimulation blockage will play a major role in the future. "It will have use in other diseases with autoimmune dysregulation and that's one of the very exciting things about it," he observes.
In the one-year study, 433 patients received abatacept plus MTX and 219 received MTX plus placebo. Patients received 10 mg/kg of abatacept on days 1, 15, 29, and every 28 days thereafter. Overall, 88.9% of participants taking abatacept and 74.0% of those taking placebo completed the study.
Abatacept "showed robust efficacy versus MTX alone across the board-largely independent of baseline clinical, biochemical, or radiographic characteristics," Dr. Emery points out.
While all study participants showed improvements in ACR20, ACR50, and ACR70 at 6 months, only abatacept users continued to see marked improvement after one year.
Disconnect with ACR20 noted
Interestingly, there was a disconnect between clinical response as assessed by ACR responses and joint damage as has been seen with TNF-blockade.
"It's not entirely clear why we see that disconnect, but it's related to the manner of actions, and perhaps in later studies, we will get a better handle on it," Dr. Genant says. Overall, treatment was well-tolerated and safe and only a slightly greater percentage of adverse events (AEs) was reported among abatacept users, which included headache, nasopharyngitis, and nausea. Serious AEs were reported in 15% of abatacept users and 11.9% of the placebo arm. Of the initial cohort, 4.2% of abatacept users discontinued after 1 year due to AEs, as did 1.8% of those taking placebo. Participants were allowed to add a nonbiologic DMARD at 6 months, including hydroxychloroquine, sulfasalazine, and gold. In the placebo group, 14.0% added a DMARD as did 3.8% of abatacept users, the study found.
Dr. Emery tells CIAOMed that he sees the new drug mainly as a competitor of the TNF-α inhibitors. "It has the same efficacy and there are theoretical reasons why it may be safer," he says.
According to data from Abatacept Study of Safety in Use with other RA therapies (ASSURE),2 patients treated with abatacept in combination with anti-TNF drugs were more likely to develop a serious infection (5.8%) compared with counterparts taking abatacept plus a nonbiologic DMARD (2.6%), patients taking placebo plus a nonbiologic DMARD (1.7%), and patients taking placebo plus a biologic (1.6%). Overall in ASSURE, 90.3% of patients taking abatacept experienced an AE compared with 86.5% taking placebo.
"They are not as safe with anti-TNF drugs as with methotrexate," Dr. Emery tells CIAOMed.
References:
- 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.
- Weinblatt M, Combe B, White A, et al. Safety of abatacept in patients with active rheumatoid arthritis receiving background non-biologic and biologic DMARDS: 1-year results of the ASSURE trial. Presented at: Annual European Congress of Rheumatology of EULAR; June 8-11, 2005; Vienna, Austria. Abstract OP0012.