Reinduction with Certolizumab Pegol in Patients with Crohnʼs Disease Experiencing Disease Exacerbation

Crohn's disease is a lifelong, incurable inflammatory disease of the gastrointestinal tract that often arises in the earlier decades of life and is characterized by periods of exacerbation and remission. Tumor necrosis factor (TNF) α has a central role in the pathogenesis of inflammatory bowel diseases, and specific inhibition of this pleotropic cytokine with biological anti-TNF agents has been a major advancement in the treatment of these diseases including Crohn's disease.1,2 Anti-TNF therapy is generally well tolerated.3–5 However, because these agents have immunosuppressive properties, long-term use may increase the risk of serious infections,6 and careful consideration is given to the initiation of therapy. Only 3 anti-TNF therapies, including infliximab, adalimumab, and certolizumab pegol, are currently approved for the treatment of moderate to severe Crohn's disease in the United States. In randomized controlled trials, approximately 40% to 60% of patients with Crohn's disease had an initial response to induction therapy with anti-TNF therapy during the first 2 to 6 weeks, and of those approximately 40% to 60% were in remission after 6 months of therapy.3–5,7 However, the duration of clinical response varies widely among patients. Results of PRECiSE 2, a randomized, placebo-controlled study of certolizumab pegol maintenance therapy in patients with moderate to severe Crohn's disease, showed that approximately 40% of initial responders lost response within 6 months after treatment initiation.5 In clinical practice, 30% to 40% of patients treated with adalimumab required dose escalation; however, approximately one-third of those who received increased doses failed to maintain responses longer than 6 months.8 These examples illustrate that both primary and secondary failure to anti-TNF therapy remain significant challenges in the treatment of patients with Crohn's disease. Given the need for long-term maintenance therapy and the small number of available anti-TNF therapies, identifying strategies to maximize the benefit that a patient can derive from each agent is important. Recent studies have shown that reinduction therapy with another9 or the same10 anti-TNF agent in patients with secondary treatment failure provides clinically important short-term benefits. However, the longer-term benefit of reintroducing the same therapy to patients with primary and secondary treatment failure, including patients who previously received as little as 1 dose of induction treatment, has not been explored. Certolizumab pegol is a recombinant, humanized, polyethylene glycol–conjugated antigen-binding antibody fragment (Fab') with specificity for human TNFα. Two randomized, double-blind, placebo-controlled phase 3 studies, PRECiSE 17 and PRECiSE 2,5 demonstrated that certolizumab pegol is effective in the induction and maintenance of clinical response and remission in patients with moderate to severe Crohn's disease. Unlike patients in PRECiSE 2, who were randomized to maintenance treatment with placebo or certolizumab pegol after responding to 6 weeks of induction therapy with certolizumab pegol, patients in PRECiSE 1 were randomized to consecutive induction and maintenance treatment with either placebo or certolizumab pegol at the start of the trial. Patients who completed PRECiSE 1 or PRECiSE 2 were eligible for inclusion in PRECiSE 3, an open-label, 7-year extension study.11 In contrast, PRECiSE 4 (NCT00160706) was an open-label extension study for patients who withdrew from either treatment arm of PRECiSE 1 or PRECiSE 2 owing to exacerbation of Crohn's disease and was designed to assess the safety and efficacy of chronic certolizumab pegol therapy for up to 7 years. Here, we report efficacy and safety outcomes from the PRECiSE 4 study, which included patients with no previous exposure to certolizumab pegol, as well as patients with primary or secondary certolizumab pegol treatment failure.