Immunogenicity, Safety, and Efficacy of Abatacept Administered Subcutaneously With or Without Background Methotrexate in Patients With Rheumatoid Arthritis: Results From a Phase III, International, Multicenter, Parallel‐Arm, Open‐Label Study

Abstract

Objective. To evaluate the impact of concomitant methotrexate (MTX) on subcutaneous (SC) abatacept immunogenicity, and to assess safety and efficacy.Methods. This phase III, open-label study had a 4-month short-term (ST) period and an ongoing long-term extension (LTE) period. Rheumatoid arthritis patients were stratified to receive SC abatacept (125 mg/week) with (combination) or without MTX (monotherapy), with no intravenous loading dose; patients receiving monotherapy could add MTX in the LTE period. Immunogenicity (percentage of anti-abatacept antibody-positive patients) was assessed. ST and LTE period data are reported, including efficacy through LTE month 14 and safety through LTE month 20. Results. Ninety-six of 100 enrolled patients completed the ST period; 3.9% (combination) and 4.1% of patients (monotherapy) developed transient immunogenicity, and no patients were antibody positive at month 4. Serious adverse events (SAEs) were reported in 3.9% (combination) and 6.1% of patients (monotherapy); 5.9% (combination) and 8.2% of patients (monotherapy) experienced SC injection reactions, and all were mild in intensity. Mean 28-joint Disease Activity Score (DAS28) changes were ؊1.67 (95% confidence interval [95% CI] ؊2.06, ؊1.28; combination) and ؊1.94 (95% CI ؊2.46, ؊1.42; monotherapy) at month 4. Ninety patients entered and were treated in the LTE period; 83.3% (75 of 90) remained ongoing at month 24. One LTE-treated patient (1.1%) developed immunogenicity, 14.4% of patients experienced SAEs, and no SC injection reactions were reported. For patients entering the LTE period, mean DAS28 changes from baseline were ؊1.84 (95% CI ؊2.23, ؊1.34; combination) and ؊2.86 (95% CI ؊3.46, ؊2.27; monotherapy) at month 18. Conclusion. SC abatacept did not elicit immunogenicity associated with loss of safety or efficacy, either with or without MTX.

Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2012: Table 1

“…There was a tendency to an increase in autoantibodies if one to two doses of abatacept were missed. No relationship was found between the antibodies and clinical response or adverse events (category A evidence44). …”

No impact of concomitant methotrexate use on serious adverse event and serious infection risk in patients with rheumatoid arthritis treated with bDMARDs: a systematic literature review and meta-analysis

“…Finally, we retained 16 articles. [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] All of these trials included 4975 patients, representing a total of 6764 patient-years followed up and including 3866 patient-years in the 'bDMARD and methotrexate' group and 2898 patient-years in the 'bDMARD alone' group.…”

Formation, Clearance, Deposition, Pathogenicity, and Identification of Biopharmaceutical-related Immune Complexes

“…To the contrary, repeated-dose rat and monkey studies have shown that intramuscular dosing with interferon b-1a (Rebif 1 ) was associated with higher ADA titers compared with IV dosing (Ponce et al 2009). For a different rh therapeutic protein (abatacept), SC/IV immunogenicity differences were not observed in patients (Fathallah, Bankert, and Balu-Iyer 2013;Keystone et al 2012;Nash et al 2013), but SC administration elicted greater ADA titers compared with IV dosing in rat preclinical studies (Srinivas et al 1997). For adalimumab in monkeys, IV dosing was associated with higher ADA titers compared with SC dosing (Ponce et al 2009).…”

“…Immunogenicity can also be affected by the mechanism of action of the drug itself (Brennan et al 2010;Srinivas et al 1997). For example, abatacept, a human IgG constant region of immunoglobulin (Ig) molecule (Fc) fused with the extracellular domain of cytotoxic T-lymphocyte antigen 4 (CTLA-4), is highly immunosuppressive, and low doses are associated with ADA development, while higher doses do not elicit ADA, in rat preclinical studies (Fathallah, Bankert, and Balu-Iyer 2013;Keystone et al 2012;Nash et al 2013). When ADA neutralize or accelerate clearance of the rh therapeutic protein, they may be associated with altered PK and/or PD properties of the therapeutic protein; however, some ADA may have no discernible effect on PK/PD levels (Leach 2013;Ponce et al 2009;Rojas et al 2005).…”