Abatacept (Orencia)
Dr Andrew J K Ostor, Consultant Rheumatologist & Associate Lecturer, School of Clinical Medicine, University of Cambridge
Original article: 03/08/2007
Reviewed: 15/12/2009
Next review due: 15/12/2012
Introduction
Unprecedented change has occurred in the management of moderate to severe rheumatoid arthritis (RA) over the last decade. This has chiefly been due to the introduction of very effective medications, namely the biologic disease modifying anti-rheumatic drugs(DMARDs), which target specific molecules causing inflammation in RA. Unfortunately however, not everyone responds to or tolerates the currently available anti-TNF biologic DMARDs such as infliximab (Remicade), etanercept (Enbrel) and adalimumab (Humira). It is possible that up to 50% of patients over 5 years will have stopped anti-TNF treatment for a variety of reasons including poor initial response, secondary failure (an unsustained benefit) or the development of side effects. In addition some patients may not be appropriate for anti-TNF treatment. Thankfully this void is being filled to an extent by the second wave of biologic DMARDs which include abatacept, rituximab and tocilizumab.
What is Abatacept?
Abatacept, also know as (Orencia), is a fully human antibody which inhibits co-stimulation of T cells. T cells are know to orchestrate the inflammation in RA and in order for them to work two events are required. The first is when a receptor on the T cell recognises a foreign particle presented to it by a specialised antigen presenting cell. Nothing happens however until the T cell receives a second message (co-stimulation) which again occurs by interaction with the antigen presenting cell. Following this co-stimulation the T cell is activated and it then promotes inflammation. Abatacept works by blocking this second message (co-stimulation) thus stopping inflammation at a very early stage. It is worth noting that the body normally produces a molecule to down regulate inflammation and abatacept was constructed to mimic this naturally occurring process.
Evidence of benefit.
Multiple studies have now been published showing the benefit of abatacept in patients with RA. In the AIM (abatacept in inadequate responders to MTX) study, 652 patients not doing well on methotrexate were studied for one year. Up to 73% of patients who received abatacept gained at least some benefit and improvement was also seen in physical function and in x-ray changes. In the ATTAIN study, (abatacept trial in treatment of anti-TNF inadequate responders) involving 391 patients, significant benefit again was seen in around 50% of those who received abatacept including improvement in quality of life measures. In a similar manner to anti-TNF agents, abatacept was found to work rapidly. The benefits in these and other studies have also been seen in the longer term, with some patients having been on treatment for greater than 8 years. Interestingly in many patients who responded to the drug the benefit increased over time such that patients felt even better after two years of treatment.
Investigation continues looking at the prolonged benefit of abatacept in symptom relief, quality of life improvement and in halting radiological damage. In particular the results of a trial looking at abatacept use in RA patients whp had not yet trialled methotrexate are promising (AGREE study).
Current licence for Abatacept
The Food & Drug Administration (FDA) in the USA has approved abatacept for the treatment of RA in patients who have failed DMARD therapy including methotrexate and/or anti-TNFa therapy. The European Medicines Agency (EMEA) has licenced abatacept for those patients who have ongoing active RA who have failed anti-TNF treatment but not in those who have only failed on methotrexate. Unfortunately in the UK, NICE (The National Institute for Health and Clinical Excellence) did not recommend the use of abatacept in RA on cost effectiveness grounds.
How is Abatacept given?
Abatacept is administered as an intravenous infusion of 500mg, 750mg or 1000mg (depending upon patient weight) at 2 then 4 weeks after the first infusion then monthly thereafter. The infusion lasts for 30-60 minutes and is usually given in special infusion centres in hospital. No concurrent medications are required around the time of the infusion and reactions to the drug are uncommon. No specific tests are required for monitoring abatacept, however as most patients will also be taking traditional DMARDs, regular blood tests will be necessary.
Potential side effects of Abatacept
It has been very reassuring to the rheumatology community and patients that despite the introduction of these immune system modulatory medications the side effect profile has been favourable. Abatacept has been found to be safe and well-tolerated. Common side effects (occurring in 5-13% of patients) included headache, upper respiratory tract infections, nasophanyngitis and nausea. In all studies of patients on abatacept serious infections such as pneumonia, bronchitis and urinary tract infections occurred in 3% of those on the drug compared with 1.9% of those on placebo. The frequency of cancer overall was similar between the group of patients who received abatacept and those who received placebo. Thankfully therefore we have not witnessed an increase in infections or cancers following prolonged abatacept treatment.
Abatacept is not recommended for those wishing to conceive or those breast feeding. As we have previously seen, combining biologic DMARDs is not wise as the infection risk increases without additional improvement in symptoms (ASSURE study).
Summary
Over time up to 50% of patients with RA do not respond adequately to the currently available biologic DMARDs (anti-TNF agents). This area of need is being bridged to a significant degree by the newer biologic DMARDs including abatacept. Abatacept is a welcome addition to the armory used to treat RA and studies continue as to how to optimise its use.
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