Elsevier

Clinical Therapeutics

Volume 34, Issue 4, April 2012, Pages 788-802.e3
Clinical Therapeutics

Pharmacotherapy
Review article
Systematic Review of Tocilizumab for Rheumatoid Arthritis: A New Biologic Agent Targeting the Interleukin-6 Receptor

https://doi.org/10.1016/j.clinthera.2012.02.014Get rights and content

Abstract

Background

Tocilizumab (TCZ), a humanized anti–interleukin-6 receptor monoclonal antibody, represents a new treatment strategy for patients with rheumatoid arthritis (RA) and is currently approved in the United States for RA patients who have failed to improve with at least one anti–tumor necrosis factor therapy.

Objective

The goal of this study was to summarize the efficacy and safety profile of TCZ.

Methods

A systematic literature review was conducted to identify English-language articles within PubMed and the Cochrane Library from January 1989 to August 2011 reporting results from Phase III TCZ double-blind, randomized controlled trials (RCTs), noncontrolled clinical trials, and open-label extensions with a duration ≥6 months. Study outcomes had to include at least one of the following: American College of Rheumatology (ACR) 20, 50, or 70 response rates; tender/swollen joint count; Health Assessment Questionnaire–Disability Index; radiographic outcomes and drug persistence. Phase II RCTs were included only if they contained relevant information not available in Phase III RCTs. Relevant studies were selected to evaluate TCZ's pharmacokinetics and pharmacodynamics.

Results

Ten published clinical trials (7 Phase III, 3 Phase II) for TCZ were retrieved (7833 articles initially identified) from PubMed and 31 from the Cochrane library. Compared with methotrexate (MTX) monotherapy, TCZ 8 mg/kg IV monotherapy had higher rates of ACR20 (P < 0.001), ACR50 (P = 0.002), and ACR70 (P < 0.001) scores at week 24. TCZ 8 mg/kg IV plus oral MTX had a higher ACR20 response rate than oral MTX plus placebo in patients with RA who failed to respond to MTX or anti–tumor necrosis factor therapy (P < 0.001). Patients receiving TCZ 8 mg/kg had less radiographic progression on the Genant-modified Sharp score (85% had no progression) than the control group (67% had no progression) (P < 0.001). The rate of serious infections was 4.7 events/100 patient-years of exposure in the TCZ groups. A greater frequency of neutropenia, thrombocytopenia, hyperlipidemia, and transaminitis was observed with TCZ compared with placebo.

Conclusion

The short-term efficacy and safety profile of TCZ is promising. Additional long-term safety data are needed to better characterize the risk–benefit profile of this agent.

Introduction

Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease characterized by persistent synovitis and progressive destruction of cartilage and bone.1 It is associated with progressive joint damage, pain, fatigue, and disability, as well as the elevation of acute-phase reactants such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR).2, 3, 4, 5 It is a common disease, affecting about 1% of adults aged >35 years and >2% of adults aged >60 years in the United States.6, 7 Similar prevalence figures have been reported worldwide.7, 8 Even though the cause of RA is not fully understood, pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6 play an important role in disease pathogenesis.3, 4 More than a decade of experience with anti-TNF therapy has shown these agents to be effective in a significant proportion of patients with RA. However, at least two thirds of patients with RA have a partial but incomplete response to anti-TNF therapy.9 Tocilizumab (TCZ) was introduced as a new approach for the treatment of RA because it targets the IL-6 pathway, which is important in the pathogenesis of RA.

IL-6 is a pleiotropic cytokine with a wide range of biologic activities in immune regulation, hematopoiesis, inflammation, and oncogenesis. Its activities are shared by IL-6–related cytokines such as leukemia inhibitory factor, ciliary neutrophic factor, and oncostatin M. There are 2 different IL-6–driven signaling pathways. One is mediated by membrane-bound IL-6 receptor (mIL-6R [CD 126])10, 11 via activation of glycoprotein 130; the second is mediated via proteolytic cleavage of the mIL-6R that leads to the generation of a soluble receptor for IL-6 (sIL-6R). sIL-6R is able to bind to IL-6 and can stimulate cells that lack endogenous mIL-6R.12, 13, 14 IL-6 is produced by various cell types, including T cells, B cells, monocytes, fibroblasts, endothelial cells, and synovial cells.10, 15 Higher levels of IL-6 have been found in the synovium of patients with RA.16 IL-6 can stimulate pannus formation through increased vascular endothelial growth factor (VEGF) expression and increase bone resorption as a result of osteoclastogenesis.5, 17 Systemic effects of IL-6 include regulation of acute-phase protein synthesis, as well as hepcidin production and stimulation of the hypothalamic-pituitary-adrenal axis, the latter 2 actions leading to anemia and fatigue, respectively.5

TCZ, a humanized anti–IL-6 receptor monoclonal antibody, represents a promising new treatment strategy for patients with RA and is currently approved in the United States for patients with RA who have failed to improve with at least one anti-TNF therapy. TCZ prevents IL-6 from binding to both mIL-6R and sIL-6R, thereby blocking the proinflammatory effects of IL-6.15, 18 The objective of this article was to review the pharmacology of TCZ and present results from pivotal trials regarding the efficacy, safety, and tolerability of TCZ in patients with RA.

Section snippets

Methods

To review the pharmacology of TCZ, relevant studies were selected as part of a narrative review to determine the agent's pharmacokinetic and pharmacodynamic properties. Relevant information was extracted from the identified articles and their references to identify pertinent publications, including meta-analyses, review articles, and pharmacologic studies.

To establish the evidence base for the remainder of the review, a systematic literature review using PubMed and the Cochrane Library was

Pharmacology of TCZ

TCZ is a recombinant humanized monoclonal antibody of the immunoglobulin G1 subclass against the IL-6 receptor. Its molecular weight is ∼150 Kd,21 and it binds to sIL-6R in a dose-dependent manner and saturates the receptor at ∼0.1 μg/mL. It also competitively inhibits IL-6 binding to sIL-6R; complete inhibition is seen at ∼4 μg/mL.22

The pharmacokinetics of intravenous TCZ have been determined using a population pharmacokinetic analysis on a database composed of 1793 patients with RA treated

Discussion

TCZ is a humanized monoclonal antibody against the IL-6 receptor that provides a promising treatment for the management of RA. Clinical trials results show that TCZ 8 mg/kg IV monotherapy has superior efficacy to oral MTX monotherapy. In combination with MTX, TCZ is comparable to the clinical efficacy seen with MTX + anti-TNF therapy.52, 53, 54 TCZ is currently indicated as monotherapy or combination therapy with MTX or DMARD for patients with RA with refractory disease who have failed to

Conclusions

TCZ is a new therapeutic option for patients with RA with refractory disease who have failed to improve with at least one anti-TNF therapy. TCZ seems to have a safety profile similar to other biologic agents on the basis of current data available from published trials. Although the short-term efficacy and safety profiles are promising, additional long-term safety data are needed to better characterize the risk–benefit profile of this agent.

Conflicts of Interest

The authors have indicated that they have no conflicts of interest regarding the content of this article.

Supplemental Material

Supplemental appendices accompanying this article can be found in the online version at doi:10.1016/j.clinthera.2012.02.014.

Acknowledgements

Dr. Navarro-Millán has nothing to disclose. Dr. Singh is supported by research grants from National Institute of Aging, National Cancer Institute, Agency for Health Quality and Research Center for Education and Research on Therapeutics (CERTs), and the resources and the use of facilities at the Birmingham VA Medical Center, Alabama, USA. Dr. Singh has received investigator-initiated research grants from Takeda and Savient; consultant fees from URL pharmaceuticals, Takeda, Ardea, Savient,

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