Evaluation of abatacept administered subcutaneously in adults with active rheumatoid arthritis: impact of withdrawal and reintroduction on immunogenicity, efficacy and safety (phase Iiib ALLOW study)

Jeffrey Kaine, Geoffrey Gladstein, Ingrid Strusberg, Manuel Robles, Ingrid Louw, Sheila Gujrathi, Ramesh Pappu, Ingrid Delaet, Miranda Pans, Charles Ludivico, Jeffrey Kaine, Geoffrey Gladstein, Ingrid Strusberg, Manuel Robles, Ingrid Louw, Sheila Gujrathi, Ramesh Pappu, Ingrid Delaet, Miranda Pans, Charles Ludivico

Abstract

Objectives: To assess the effect of a temporary interruption in subcutaneous (SC) abatacept on immunogenicity, safety and efficacy in patients with active rheumatoid arthritis despite methotrexate in a phase III trial.

Methods: Following a 12-week open-label introduction (period I; intravenous abatacept loading dose and weekly fixed-dose SC abatacept 125 mg), patients were randomised 2:1 to double-blind SC placebo or SC abatacept for 12 weeks (period II). At the end of period II, patients receiving SC abatacept continued treatment and patients on placebo were reintroduced to SC abatacept (12-week open-label period III). The co-primary end points were ELISA-detected immunogenicity rate and safety at the end of period II. Efficacy was also monitored.

Results: Of 167 patients entering period I, 72% qualified for period II; during periods II and III, three patients discontinued treatment. Mean (SD) disease duration was 6.6 (6.5) years and Disease Activity Score 28 was 4.8 (0.8). The primary end point was met, with a non-significant increase in immunogenicity upon withdrawal (7/73 placebo vs 0/38 abatacept in period II; p=0.119) which was reversed upon reintroduction of SC abatacept (2/73 vs 1/38, end period III). Safety was comparable regardless of withdrawal, with no unexpected events upon reintroduction. Two patients experienced reactions at the SC injection site. On withdrawal, patients experienced slight worsening in efficacy which improved following reintroduction.

Conclusions: Overall immunogenicity to SC abatacept is low, consistent with intravenous abatacept, and is not significantly affected by a 3-month interruption and reintroduction. This stop-start schedule was well tolerated, with little impact on safety and efficacy. These are important considerations for the clinical use of SC abatacept.

Clinicaltrials: gov Identifier NCT00533897.

Conflict of interest statement

Competing interests JK has received research grants from Bristol-Myers Squibb, Pfizer, Abbott, Vertex, Astra Zeneca, Chelsea, Lilly, Roche, Centocor, Merck, Amgen, UCB, Aventis and has participated in speakers' bureaux for Amgen, Bristol-Myers Squibb, Novartis Pharmaceuticals Corporation and UCB. GG has received research grants from Pfizer, Genentech, Roche, Forest, Cephalon, Regeneron, Centocor, Bristol-Myers Squibb and New England Research Associates, has participated in a speakers' bureau for Bristol-Myers Squibb and has received consulting fees from Bristol-Myers Squibb. IS has received consulting fees and honoraria from, and has participated in a speakers' bureau for, Bristol-Myers Squibb. MR and IL have no competing interests to declare. CL has received clinical research grants from, and has participated in speakers' bureaux for, Bristol-Myers Squibb. SG, RP, ID and MP are full-time employees of, and stockholders in, Bristol-Myers Squibb.

Figures

Figure 1
Figure 1
Study design. *Most frequent reason for not being treated was no longer meeting entry criteria. †Patients who discontinued during period II (Withdrawal phase) due to lack of efficacy could enter period III (Reintroduction phase) prematurely. IV, intravenous; LTE, long-term extension; MTX, methotrexate; SC, subcutaneous.
Figure 2
Figure 2
Patient disposition. *Most frequent reason for not being treated was no longer meeting entry criteria. †Patients discontinued period II (Withdrawal phase) early due to disease flare and directly entered period III (Reintroduction phase). IV, intravenous; LTE, long-term extension; SC, subcutaneous.
Figure 3
Figure 3
Clinical efficacy. (A) Mean change in DAS28 (CRP) over time by period II (Withdrawal phase) treatment group. (B) Proportion of patients achieving LDAS and DAS28-defined remission by period II (Withdrawal phase) treatment group. (C) Mean change in HAQ-DI score over time by period II (Withdrawal phase) treatment group. Data are as-observed for all patients who received ≥1 dose of study drug during period II. Error bars represent 95% CI. CRP, C reactive protein; DAS28, Disease Activity Score 28; HAQ-DI, Health Assessment Questionnaire-Disability Index; LDAS, low disease activity state; SC, subcutaneous.

References

    1. Haggerty HG, Abbott MA, Reilly TP, et al. Evaluation of immunogenicity of the T cell costimulation modulator abatacept in patients treated for rheumatoid arthritis. J Rheumatol 2007;34:2365–73
    1. Schellekens H. Factors influencing the immunogenicity of therapeutic proteins. Nephrol Dial Transplant 2005;20Suppl 6:vi3–9
    1. Emi Aikawa N, de Carvalho JF, Artur Almeida Silva C, et al. Immunogenicity of anti-TNF-alpha agents in autoimmune diseases. Clin Rev Allergy Immunol 2010;38:82–9
    1. Janssen Biotech, Inc Remicade prescribing information. (accessed February 2011)
    1. Vultaggio A, Matucci A, Nencini F, et al. Anti-infliximab IgE and non-IgE antibodies and induction of infusion-related severe anaphylactic reactions. Allergy 2010;65:657–61
    1. Bendtzen K, Geborek P, Svenson M, et al. Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor infliximab. Arthritis Rheum 2006;54:3782–9
    1. Wolbink GJ, Vis M, Lems W, et al. Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis Rheum 2006;54:711–15
    1. Radstake TR, Svenson M, Eijsbouts AM, et al. Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis. Ann Rheum Dis 2009;68:1739–45
    1. Corbo M, Valencia X, Raymond R. Subcutaneous administration of abatacept in patients with rheumatoid arthritis: pharmacokinetics, safety and immunogenicity (abstract). Ann Rheum Dis 2008;68Suppl 3:574
    1. Nash P, Nayiager S, Genovese M, et al. Immunogenicity is not increased with subcutaneous administration of abatacept with and without methotrexate in patients with rheumatoid arthritis: results from a phase III study (abstract). Arthritis Rheum 2009;60Suppl 10:1692
    1. Bristol-Myers Squibb Orencia prescribing information. (accessed July 2010)
    1. Dixon JR., Jr The International Conference on Harmonization Good Clinical Practice guideline. Qual Assur 1998;6:65–74
    1. Bartelds GM, Wijbrandts CA, Nurmohamed MT, et al. Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann Rheum Dis 2007;66:921–6
    1. Bartelds GM, Wijbrandts CA, Nurmohamed MT, et al. Anti-infliximab and anti-adalimumab antibodies in relation to response to adalimumab in infliximab switchers and anti-tumour necrosis factor naive patients: a cohort study. Ann Rheum Dis 2010;69:817–21
    1. Dore RK, Mathews S, Schechtman J, et al. The immunogenicity, safety, and efficacy of etanercept liquid administered once weekly in patients with rheumatoid arthritis. Clin Exp Rheumatol 2007;25:40–6
    1. Schiff M, Keiserman M, Codding C, et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis 2008;67:1096–103
    1. Kremer JM, Genant HK, Moreland LW, et al. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. Ann Intern Med 2006;144:865–76
    1. Corbo M, Valencia X, Raymond R, et al. Subcutaneous administration of abatacept in patients with rheumatoid arthritis: pharmacokinetics, safety and immunogenicity (abstract). Ann Rheum Dis 2009;68Suppl 3:574
    1. Nash P, Nayiager S, Genovese MC, et al. Low immunogenicity, consistent safety and sustained clinical efficacy over 18 months of subcutaneous (SC) administration of abatacept (ABA) with and without methotrexate (MTX) in patients with rheumatoid arthritis (RA): results from a phase III study. Oral OP0132. Ann Rheum Dis 2010;69Suppl 3:97.
    1. Bender NK, Heilig CE, Dröll B, et al. Immunogenicity, efficacy and adverse events of adalimumab in RA patients. Rheumatol Int 2007;27:269–74
    1. Wells G, Becker JC, Teng J, et al. Validation of the 28-joint Disease Activity Score (DAS28) and European League Against Rheumatism response criteria based on C-reactive protein against disease progression in patients with rheumatoid arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate. Ann Rheum Dis 2009;68:954–60

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