Subset analysis of patients experiencing clinical events of a potentially immunogenic nature in the pivotal clinical trials of tocilizumab for rheumatoid arthritis: Evaluation of an antidrug antibody ELISA using clinical adverse event-driven immunogenicity testing

ObjectiveTo evaluate the efficacy and safety of switching from intravenous (IV) tocilizumab (TCZ) to subcutaneous (SC) TCZ monotherapy in rheumatoid arthritis patients.MethodsPatients who had completed 24 weeks of TCZ‐SC (162 mg/2 weeks) or TCZ‐IV (8 mg/kg/4 weeks) monotherapy in the double‐blind period of the MUSASHI study were enrolled in an 84‐week open‐label extension period. All received TCZ‐SC (162 mg/2 weeks) monotherapy. Effects of the IV to SC switch were evaluated at week 36 (12 weeks after switching).ResultsOverall, 319 patients received ≥1 dose of TCZ‐SC during the open‐label extension period; 160 switched from TCZ‐IV to TCZ‐SC (TCZ IV/SC) and 159 continued TCZ‐SC (TCZ SC/SC). Disease Activity Score in 28 joints using the erythrocyte sedimentation rate clinical remission rates were 62.5% (100 of 160) for TCZ IV/SC and 50.0% (79 of 158) for TCZ SC/SC at week 24, and were maintained at 62.5% (100 of 160) and 57.0% (90 of 158), respectively, at week 36. In the TCZ IV/SC group, 9% of patients (9 of 100) who had achieved remission at week 24 could not maintain remission at week 36. In TCZ IV/SC patients weighing ≥70 kg, the percentage with a sufficient serum TCZ concentration (≥1 μg/ml) decreased from 90.9% (10 of 11) at week 24 to 45.5% (5 of 11) at week 36. Overall safety profiles were similar in TCZ IV/SC and TCZ SC/SC except for mild injection site reactions in TCZ IV/SC.ConclusionEfficacy is adequately maintained in most patients switching from TCZ‐IV (8 mg/kg/4 weeks) to TCZ‐SC (162 mg/2 weeks) monotherapy. Patients receiving TCZ‐IV can switch to TCZ‐SC without serious safety concerns. Clinical efficacy may be reduced after switching in some patients with high body weight.

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“…Anti‐TCZ antibodies were measured using the enzyme‐linked immunosorbent assay method described previously 13.…”

Section: Methodsmentioning

confidence: 99%

Sustainable Efficacy of Switching From Intravenous to Subcutaneous Tocilizumab Monotherapy in Patients With Rheumatoid Arthritis

Ogata

Atsumi

Fukuda

et al. 2015

Arthritis Care & Research

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“…Radiographic progression from baseline to weeks 24 and 48 was assessed using the modified total Sharp score analysis (mTSS) 10 and performed by 2 primary readers, with an adjudicator involved for any discrepancies. Safety assessments included adverse events (AE), laboratory measurements, and immunogenicity 11 .…”

Section: Methodsmentioning

confidence: 99%

“…Three patients (3.3%) in the escape-PBO group and 1 patient (1.0%) in the escape-TCZ-SC q2w group developed anti-TCZ antibodies 11 . Two patients (2.2%) in the escape-PBO group and 1 patient (1.0%) in the escape-TCZ-SC q2w group had a positive neutralizing antibody assay after the initiation of escape therapy.…”

Section: Rheumatologymentioning

confidence: 98%

Two-year Efficacy and Safety of Subcutaneous Tocilizumab in Combination with Disease-modifying Antirheumatic Drugs Including Escalation to Weekly Dosing in Rheumatoid Arthritis

Kivitz

Olech²,

Borofsky³

et al. 2017

J Rheumatol

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Objective.To evaluate the longterm efficacy and safety of subcutaneous tocilizumab (TCZ-SC) every 2 weeks (q2w) over 2 years in patients with rheumatoid arthritis who have an inadequate response to disease-modifying antirheumatic drugs (DMARD).Methods.Patients (n = 656) were randomized 2:1 to TCZ-SC 162 mg q2w or placebo-SC q2w plus DMARD. After a 24-week double-blind period, patients (n = 457) were rerandomized to open-label TCZ-SC q2w by means of prefilled syringe or autoinjector. Escape therapy with weekly TCZ-SC was available for patients with inadequate efficacy from Week 12. Maintenance of response and safety to 2 years was assessed. Analyses used nonresponder imputation.Results.The American College of Rheumatology (ACR) 20 response after TCZ-SC was maintained beyond Week 24 and was > 70% at each timepoint. ACR50/70, 28-joint Disease Activity Score remission, and ≥ 0.30 decrease from baseline in the Health Assessment Questionnaire–Disability Index response rates were also maintained after Week 24 in the TCZ-SC arm (≥ 50%, > 25%,> 32% and > 56%, respectively). Following escape for inadequate efficacy, many patients achieved ACR20 at the end of the study, 35% after escape from TCZ-SC, and 63% from placebo. The rates of serious adverse events [(11.20/100 patient-years (PY)] including serious infections (3.25/100 PY) were stable through Week 96. No association between anti-TCZ antibody development and loss of efficacy or adverse events was observed.Conclusion.Efficacy and safety of TCZ-SC q2w was maintained up to 2 years and remained comparable with previously published data for intravenous TCZ. Dose escalation to weekly TCZ-SC was associated with ACR responses in prior nonresponders and was well tolerated.

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“…IL-6 upregulates B-cell activating factor (BAFF), which supports the survival of B cells and plasma cells [55]. As these IL-6 mediated mechanisms are directly involved in antibody production, tocilizumab may reduce the development of anti-drug antibodies and, consequently, loss of efficacy due to immunogenicity [56]. This may explain, in part, why tocilizumab could be efficacious in monotherapy.…”

Section: Different Efficacy In Monotherapymentioning

confidence: 99%

Analysis of the Mechanism of Action of Biological Therapies in Monotherapy in Patients with Rheumatoid Arthritis: Beyond the ADACTA Study

Sanmarti¹

2013

Adv Pharmacoepidem Drug Safety

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The ADACTA study ADACTA is the first head-to-head study comparing two biological agents, tocilizumab and adalimumab on monotherapy. ADACTA was AbstractThe recently-published first head-to-head study comparing the efficacy of two biological drugs on monotherapy, tocilizumab and adalimumab, found better results for tocilizumab. Both are cytokine-specific antagonists: adalimumab targets tumor necrosis factor and tocilizumab targets interleukin-6 receptor.The aim of our review was to determine differences in the mechanisms of action of adalimumab and tocilizumab, in order to explain the differing results found, and to describe the immunologic and clinical aspects of the two drugs.

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Subset analysis of patients experiencing clinical events of a potentially immunogenic nature in the pivotal clinical trials of tocilizumab for rheumatoid arthritis: Evaluation of an antidrug antibody ELISA using clinical adverse event-driven immunogenicity testing

Cited by 68 publications

References 24 publications

Sustainable Efficacy of Switching From Intravenous to Subcutaneous Tocilizumab Monotherapy in Patients With Rheumatoid Arthritis

Sustainable Efficacy of Switching From Intravenous to Subcutaneous Tocilizumab Monotherapy in Patients With Rheumatoid Arthritis

Two-year Efficacy and Safety of Subcutaneous Tocilizumab in Combination with Disease-modifying Antirheumatic Drugs Including Escalation to Weekly Dosing in Rheumatoid Arthritis

Analysis of the Mechanism of Action of Biological Therapies in Monotherapy in Patients with Rheumatoid Arthritis: Beyond the ADACTA Study

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