Abatacept

Compound Name:AbataceptMolecular Target:B7-1 (CD80), B7-2 (CD86)Molecular Structure:CTLA4-Human IgG1 Fusion proteinLicensed Indication:Rheumatoid Arthritis, Juvenile Rheumatoid ArthritisManufacturer and/or Distributor:Bristol-Myers SquibbInitial FDA Approval:2005Summary:

Abatacept (Orencia) is a recombinant, fully human fusion protein consisting of the extracellular domain of CTLA-4 (cytotoxic T-lymphocyte antigen-4) and the Fc portion of human IgG1 that is engineered to prevent complement fixation. By binding to CD80 and CD86, the CTLA-4 (CD152) moiety prevents the “second signal” and thereby provides potent inhibition of co-stimulation required for full activation and production of T cells. Activated T cells are implicated in the pathogenesis of rheumatoid arthritis via stimulation of the inflammatory cascade, and therefore, joint inflammation and damage. Trials in adults with rheumatoid arthritis have demonstrated that abatacept treatment resulted in improvement in disease control, health-related quality of life and reduction in joint damage in patients who did not respond to other disease-modifying anti-rheumatic drugs (DMARDs). It also decreased serum levels of several cytokines and acute-phase reactants, particularly C-reactive protein, TNF-α, IL-6, and metalloproteinase-3. Studies in children, including long-term follow up studies, have suggested that Abatacept is effective, safe and on occasion, may be combined with methotrexate. Whether Abatcept is more effective than TNF inhibitors in children has not been established, but it seems to be as effective. Data from a European registry suggest that obesity does not impair response to abatacept in contrast to some studies indicating decreased response to TNF inhibitors.

 

Until recently, abatacept was only available as a monthly intravenous infusion. The intravenous dose for adults is: <60kg = 500mg; 60-100kg = 750mg; >100kg = 1000mg every 4 weeks. Children 6 – 17 years of age weighing less than 75kg are given a dose of 10mg/kg; those over 75kg are given doses based on adult weights. On July 29, 2011, the FDA approved the use of subcutaneous abatacept for the treatment of moderate to severe rheumatoid arthritis. The subcutaneous dose for adults is 125mg every week. However, efficacy and safety with the subcutaneous route in children 6 - 17 year old have not yet been established as of 2015.

 

Abatacept may be used as monotherapy or concomitantly with DMARDs. Abatacept is indicated for adult patients with moderately to severely active rheumatoid arthritis and for pediatric patients 6 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis (polyJIA). Studies are underway evaluating the use of abatacept in giant cell arteritis, Sjogrens syndrome and systemic and cutaneous sclerosis.

 

Abatacept should not be combined with TNF antagonists, as this use has been shown to increase the risk of serious infections without showing an enhancement in treatment efficacy of RA. Patients treated with abatacept are at increased risk for infections. This is particularly true of patients with other predisposing factors. Before initiating therapy, all patients should be screened for latent tuberculosis infection, and if positive, they should receive appropriate therapy for TB prior to initiating abatacept. Similarly, screening for viral hepatitis should be performed. Live vaccines should be avoided in patients on abatacept. Pediatric patients should have their immunizations updated before initiating therapy. Subjects with chronic obstructive pulmonary disease (COPD) may develop more frequent respiratory complications. Hypersensitivity reactions, including anaphylactic shock (usually early in the initiation of therapy) have also been reported.

 

As with all biotherapeutics, the cost of therapy is substantial and is reviewed in a Dutch study comparing Abatacept, rituximab and TNF inhibitors.

References

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1. Genovese MC, Becker JC, Schiff M, Luggen M, Sherrer Y, Kremer J, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med. 2005 Sep 15;353(11):1114-1123.



2. Schiff M, Bessette L. Evaluation of abatacept in biologic-naive patients with active rheumatoid arthritis. Clin Rheumatol. 2010 Jun;29(6):583-591.



3. Schiff M. Abatacept treatment for rheumatoid arthritis. Rheumatology (Oxford). 2011 Mar;50(3):437-449.



4. Isaacs JD. Therapeutic T-cell manipulation in rheumatoid arthritis: past, present and future. Rheumatology (Oxford). 2008 Oct;47(10):1461-1468.


5. Ruperto N, Lovell DJ, Quartier P, Paz E, Rubio-Perez N, Silva CA, et al. Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis. Arthritis Rheum. 2010 Jun;62(6):1792-1802.


6. Kremer JM, Genant HK, Moreland LW, Russell AS, Emery P, Abud-Mendoza C, et al. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. Ann Intern Med. 2006 Jun 20;144(12):865-876.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16785475

7. Keating G. Abatacept: a review of its use in the management of rheumatoid arthritis. Drugs. 2013;73(10):1095-1119.
http://dx.doi.org/10.1007/s40265-013-0080-9

8. Wells AF, Jodat N, Schiff M.  A critical evaluation of the role of subcutaneous abatacept in the treatment of rheumatoid arthritis: patient considerations.  Biologics. 2014; 8: 41 - 55.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933241/

9. Alten R, Kaine J, Keystone E, Nash P, Delaet I, Genovese MC. Long-term safety of subcutaneous abatacept in rheumatoid arthritis: integrated analysis of clinical trial data representing more than four years of treatment. Arthritis Rheumatol. 2014 Aug;66(8):1987-97.
http://www.ncbi.nlm.nih.gov/pubmed/24782324

10.  Golzweig O, Haskes PT. Abatacept in the treatment of polyarticular JIA: development, clinical utility, and place in therapy. Drug Des Devel Therapy 2011; 5:61-70. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038996/

11.  Manders S, Kievit W, Adang E et. al. Cost-effectiveness of Abatacept, Rituximab and TNF inhibitor therapy in Rheumatoid Arthritis; a pragmatic multicenter randomized trial.  Arthritis Research and Therapy 2015; 17: 134. http://www.arthritis-research.com/content/17/1/13

12.  Iannone F, Courvoisier DS, Gottenberg JE, Hernandez MV, Lie E, Canhão H, Pavelka K, Hetland ML, Turesson C, Mariette X, Choquette D, Finckh A. Body mass does not impact the clinical response to intravenous abatacept in patients with rheumatoid arthritis. Analysis from the "pan-European registry collaboration for abatacept (PANABA).Clin Rheumatol. 2016 Dec 14. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27966068

13. Tarp S, Eric Furst D, Boers M, Luta G, Bliddal H, Tarp U, Heller Asmussen K, Brock B, Dossing A, Schjødt Jørgensen T, Thirstrup S, Christensen R. Risk of serious adverse effects of biological and targeted drugs in patients with rheumatoid arthritis: a systematic review meta-analysis. Rheumatology (Oxford). 2016 Dec 24. pii: kew442. doi: 10.1093/rheumatology/kew442. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/28013201

14.  Meiners PM1, Vissink A1, Kroese FG2, Spijkervet FK1, Smitt-Kamminga NS3, Abdulahad WH2, Bulthuis-Kuiper J2, Brouwer E2, Arends S2, Bootsma Abatacept treatment reduces disease activity in early primary Sjögren's syndrome (open-label proof of concept ASAP study). Ann Rheum Dis. 2014 Jul;73(7):1393-6H2.http://ard.bmj.com/content/early/2014/01/28/annrheumdis-2013-204653.abstract

15.  Koster MJ1, Matteson EL, Warrington KJ. Recent advances in the clinical management of giant cell arteritis and Takayasu arteritishttp://journals.lww.com/co-rheumatology/Abstract/2016/05000/Recent_advances_in_the_clinical_management_of.4.aspx

16. A Study of Subcutaneous Abatacept to Treat Diffuse Cutaneous Systemic Sclerosis (ASSET) https://clinicaltrials.gov/ct2/show/NCT02161406 December 2016

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