Background A subcutaneous (SC) formulation of tocilizumab (TCZ) is available for treatment of adult patients (pts) with RA, based upon the positive efficacy and safety outcomes of the pivotal Phase III trials, BREVACTA and SUMMACTA, reporting a low immunogenicity risk overall. However, the effect of a temporary dosing break and reintroduction of TCZ treatment on immunogenicity, safety and efficacy has not been reported.
Objectives To analyze the immunogenicity, safety and efficacy of TCZ-SC in pts with RA who missed TCZ dose(s) and then restarted treatment.
Methods In BREVACTA, pts received either TCZ-SC 162 mg every 2 weeks (q2w) or placebo (PBO) q2w for 24 weeks. At week 24, pts in the PBO arm switched to TCZ-SC q2w and pts in the TCZ-SC arm continued TCZ-SC q2w to week 96. From week 12 onward, pts from both arms could escape to TCZ-SC weekly (qw) if they met the pre-set criteria. In SUMMACTA, pts received either TCZ-SC 162 mg qw or TCZ-IV every 4 weeks (q4w) for 24 weeks. Pts were then re-randomized to either switch or continue the same formulation to week 97. Blood samples were taken at baseline and regularly prior to TCZ dosing throughout the studies for anti-drug antibody (ADA) assessment using a standard 2-stage approach. In stage 1, all samples were subjected to screening enzyme-linked immunosorbant assay (ELISA) for ADAs and those that tested positive were analyzed by a confirmation assay for specificity. In stage 2, samples that were confirmation assay positive were further tested for neutralizing potential and immunoglobulin E (IgE) isotype. In addition, all samples from patients who withdrew due to hypersensitivity were tested with the IgE assay. Hypersensitivity and efficacy measures were also evaluated in association with ADA development.
Results In the 2-year BREVACTA and SUMMACTA studies, the proportions of pts who developed ADAs after TCZ treatment were low across treatment arms (Table). In BREVACTA, of the 366 pts who missed ≥1 dose(s), 5 (1.4%) developed ADAs after dosing was restarted (Table). In SUMMACTA, among the 219 pts who missed ≥3 consecutive TCZ-SC weekly doses and the 241 who missed ≥1 consecutive TCZ-IV doses, a total of 4 pts (0.9%) developed ADAs after restarting dosing. None of the patients who developed ADAs in either study after dosing interruptions experienced anaphylaxis, serious or clinically significant hypersensitivity reactions or injection site reactions. No pts from SUMMACTA or BREVACTA who missed doses and developed ADAs with neutralizing potential experienced loss of efficacy (defined as pts who withdrew due to insufficient therapeutic response and who experienced an American College of Rheumatology 50 percent response [ACR50] or disease activity score using the erythrocyte sedimentation rate [DAS–ESR]-based European League Against Rheumatism good response before withdrawal) or withdrew from the study due to lack of efficacy.
Conclusions TCZ-SC provides a low risk of immunogenicity potential overall and in pts who restarted treatment after dosing interruption, with no impact on safety or efficacy.
Disclosure of Interest G. Burmester Grant/research support from: Roche, Abbott, Pfizer, UCB, Merck Sharp & Dohme, and Bristol-Myers Squibb, Consultant for: Roche, Chugai, Pfizer, UCB, and Bristol-Myers Squibb, Speakers bureau: Roche, Pfizer, Merck Sharp & Dohme, Abbott, and Bristol-Myers Squibb, M. Bao Shareholder of: Roche, Employee of: Roche/Genentech, W. Reiss Shareholder of: Roche, Employee of: Roche/Genentech, T. Wallace Shareholder of: Roche, Employee of: Roche/Genentech, S. Lacey Employee of: Roche Products Ltd, A. Kivitz Grant/research support from: AbbVie, Amgen, AstraZeneca, BMS, Celgene, Genentech, Janssen, Pfizer, UCB, Consultant for: BMS, Genentech, UCB, Speakers bureau: BMS
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