Abatacept is a fusion protein, produced by recombinant DNA technology, consisting of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4, linked to a modified portion of human immunoglobulin G1 (IgG1).
Abatacept selectively modulates a key co-stimulatory signal required for full activation of T lymphocytes. It decreases antigen specific TNF alpha, interferon gamma and interleukin-2 production by T lymphocytes.
The safety and efficacy of abatacept has been assessed in several phase III trials in adult patients with active RA diagnosed according to American College of Rheumatology (ACR) criteria. In these trials, patients received intravenous abatacept (fixed-dose regimen based on bodyweight) or placebo, in addition to background DMARDs other than anti-TNF alpha therapies.
The six-month ATTAIN trial1 randomised and treated 391 patients with an inadequate response to anti-TNF alpha therapy. Patients stopped anti-TNFa therapy at least 28 days (etanercept) or 60 days (infliximab) prior to randomisation; at randomisation patients were required to have been taking an oral DMARD and/or anakinra for at least three months, and to have been on a stable dose for at least 28 days.
There were two primary efficacy endpoints: the proportion of patients achieving an ACR 20 response (indicating a decrease of at least 20 per cent in the number of both tender and swollen joints), and the proportion of patients achieving a clinically significant improvement in the Health Assessment Questionnaire disability index (HAQ-DI) at six months. Secondary objectives included a 50 per cent and 70 per cent improvement in the ACR response.
After six months, all primary and secondary outcomes were improved in the abatacept group compared with the placebo group. Clinical improvements in ACR 20 were 50.4 per cent in the abatacept group and 19.5 per cent in the placebo group (P<0.001). These improvements were seen at day 15 and the rates increased over the six-month study period.
In addition, significantly more patients in the abatacept group than in the placebo group had a clinically meaningful improvement in physical function, as reflected by an improvement from baseline of at least 0.3 in the HAQ-DI (47.3 per cent versus 23.3 per cent respectively).
The 12-month AIM trial2 randomised and treated 652 patients with RA with an inadequate response to methotrexate (MTX). For the first six months of the trial, MTX at a minimum dose of 10—15mg/week was permitted; the MTX dosage could be modified or another nonbiologic DMARD added during the second six months.
There were three co-primary endpoints: the proportion of patients achieving an ACR 20 response at six months, the proportion of patients achieving a clinically significant improvement in the HAQ-DI at 12 months, and an assessment of radiographic progression of structural damage using the Genant-modified Sharp score at 12 months.
A significantly higher percentage of abatacept- than placebo-treated patients showed clinically meaningful improvements in physical function (64 per cent versus 39 per cent at 12 months). Clinical improvements in ACR 20 were 68 per cent at six months and 73 per cent at 12 months versus placebo (40 per cent at six and 12 months).
Abatacept recipients had significantly slowed structural damage progression.
Note: the patient population in the AIM trial does not comply with the Orencia licence – this allows use of Orencia in patients non-responsive to DMARDs, including at least one TNF inhibitor.
1. Genovese M, Becker J, Schiff M et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor a inhibition. NEJM 2005: 353;1114–23.
2. Hervey P, Keam S. Abatacept. Biodrugs 2006: 20(1).
Further information: BMS 01895 523000