Certolizumab pegol in rheumatoid arthritis: a review of Phase III clinical trials and its role in real-life clinical practice

TNF inhibitors (TNFi) have been in use in clinical practice for the treatment of rheumatoid arthritis (RA) since 1998. The first to be licensed was etanercept, a fusion protein consisting of two soluble p75-TNF-receptor domains and the constant fragment of immunoglobulin. Next was the chimeric mouse human antibody infliximab (the first TNFi to be trialed in man) and later the fully human antibody adalimumab. In patients with RA failing conventional disease-modifying antirheumatic drugs (DMARDs), randomized controlled trials demonstrated all three were effective, especially when used in combination with methotrexate (MTX) [1–3]. Significantly higher proportions of patients achieved clinical responses (as defined by the American College of Rheumatology [ACR] criteria) in comparison to placebo. For example, in the ATTRACT study (patients with active RA despite receiving MTX for at least 3 months) the proportion of patients responding to infliximab with MTX at 30 weeks was significant at ACR20 and ACR50 levels (50 and 27% achieved these levels of response, respectively) in comparison to placebo with MTX (20 and 5% achieving these levels) [2]. This illustrates that although infliximab is effective, response is far from universal in this patient group, with subsequent trials of infliximab and alternative TNFi agents consistently reporting at least 30% of patients fail to meet even the lowest threshold of a definition of response, a 20% improvement (ACR20). With the present ideal being to meet higher targets of treatment, with the ultimate goal being remission, there is a need for alternative treatment options. Furthermore, over time, patients may also lose their initial response to therapy. An observational study of initial responders to infliximab demonstrated that up to half of patients may develop secondary nonresponse within the first year of treatment [4]. The frequency of primary and secondary nonresponse has contributed to the perceived need for new agents. Thus there has been the development of a number of other biologic agents for use in RA including the new TNFi agents: certolizumab pegol (CZP) and golimumab. Experience [5] and randomized controlled trial data [6] have revealed that despite nonresponse to one TNFi agent, patients may respond to a second drug in this class, with TNFi agents possessing different pharmacokinetic properties and potentially different mechanisms of action. For example, the ability of etanercept to inhibit the action of lymphotoxin has been implicated as a mechanism for response to etanercept in a patient with resistance to inf liximab [7]. Moreover, intolerance to TNFi therapy warranting cessation of treatment may be idiosyncratic (rather than a TNFi class effect) permitting use of an alternative TNFi. CZP has a unique structure, being a fragment of humanized monoclonal antibody and lacking the constant fragment of immunoglobulin (Fc). Thus, addition of CZP to the existing options for TNFi agents may therefore offer a significant alternative in clinical practice. In this article differences between CZP and other TNFi agents will be discussed. Over the last decade, evidence has accumulated demonstrating the effectiveness of early suppression of inflammation in patients with rheumatoid arthritis. This is reflected in evidence-based guidelines recommending treatment according to a target of disease activity or patient function, the ultimate target being clinical remission. In the same period, an increasing number of biologic therapies have become available, providing multiple treatment options for patients failing conventional disease-modifying antirheumatic drugs. Recently two new TNF inhibitor agents have been licensed: certolizumab pegol and golimumab. This article will examine evidence of the efficacy and safety of certolizumab pegol in rheumatoid arthritis, its potential utility in the context of a market comprising multiple TNF inhibitor agents and where its use may be positioned in the future.