Abatacept

Summary

Abatacept is a recombinant, fully-human fusion protein consisting of the extracellular domain of CTLA-4  (cytotoxic T-lymphocyte antigen-4) linked to the Fc portion of human IgG1 modified to prevent complement fixation. This agent selectively modulates the co-stimulatory signal required for full activation of T cells, which are found in the synovium of patients with Rheumatoid Arthritis (RA) and is implicated in the pathogenesis of RA.

Abatacept is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active RA.  Per published prescribing information, abatacept may be used as monotherapy or concomitantly with disease-modifying anti-rheumatic drugs (DMARDs), but should not be given concomitantly with TNF antagonists. It is not recommended for use concomitantly with other biologic Rheumatoid Arthritis (RA) therapy, such as anakinra.

In the pediatric population, abatacept is indicated for treatment of moderately to severely active polyarticular Juvenile Idiopathic Arthritis (polyJIA) in patients 6 years of age and older, as monotherapy or concomitantly with methotrexate.

Abatacept is administered as an IV infusion 2 weeks apart for the first three doses and then every 4 weeks.

In clinical trials of abatacept, concomitant use with a TNF antagonist increased the risk of infections and serious infections without showing an enhancement in treatment efficacy of RA.  Subjects with Chronic Obstructive Pulmonary Disease (COPD) developed more frequent respiratory adverse events.  Additional product recommendations include screening for latent tuberculosis infection prior to initiating therapy, with those testing positive receiving appropriate therapy for TB prior to initiating abatacept. Acute infusion-related events were reportedly more common in the abatacept-treated patients than placebo patients.

Though the overall frequencies of malignancies were similar in the abatcept- and placebo-treated patients in the placebo-controlled portions of the clinical trials, more cases of lung cancer were observed in abatacept-treated patients than placebo-treated patients, and the rate observed for lymphoma was approximately 3.5-fold higher than expected in an age- and gender-matched general population. As the data to date is limited, the potential role of abatacept in the development of malignancies in humans remains unclear.

Based on its mechanism of action, abatacept may blunt the effectiveness of some immunizations. Manufacturer's recommendations therefore include that live vaccines should not be given concurrently or within 3 months of discontinuation of abatacept. Patients with Juvenile Idiopathic Arthritis are recommended to be brought up to date with all immunizations prior to receiving abatacept. 

Brand Name

Orencia

Other Names

CTLA4Ig, BMS-188667

Molecular Target

B7-1 (CD80) & B7-2 (CD86)

Molecular Structure

CTLA4-Human IgG1 Fusion protein

Licensed Indication, Major Target Diseases

Rheumatoid Arthritis, Juvenile Idiopathic Arthritis

Manufacturer/Distributor

Bristol-Myers Squibb

References

Source	Link	Revision Date	Access Date
Orencia Prescribing Information	http://www.orencia.com	2008-April	2008-May-28
Kremer, J. M., Genant, H. K., Moreland, L. W., Russell, A. S., Emery, P., Abud-Mendoza, C., Szechinski, J., Li, T., Ge, Z., Becker, J.-C., Westhovens, R. (2006). Effects of Abatacept in Patients with Methotrexate-Resistant Active Rheumatoid Arthritis: A Randomized Trial. ANN INTERN MED 144: 865-876	http://www.annals.org/cgi/content/full/144/12/865	2006	06/04/2008
Review: Isaacs, J. D. (2008). Therapeutic T-cell manipulation in rheumatoid arthritis: past, present and future. Rheumatology	http://rheumatology.oxfordjournals.o.../full/ken163v1	May 2008 (online)	06/04/2008