Steroids are highly effective for the induction of remission in patients with active Crohn's disease.1 However, the long-term prognosis of these patients is poor. More than 50% of patients become steroid-dependent or undergo a surgical resection within 1 year of commencing treatment with these agents.2 Although controlled trials have demonstrated that azathioprine and mercaptopurine are effective for maintenance of steroid-induced remission in patients with active Crohn's disease,3, 4 these agents have not been evaluated in steroid-dependent patients. Methotrexate is effective for the induction and maintenance of remission and for steroid-sparing in patients with steroid-treated Crohn's disease.5, 6 Nevertheless, for various reasons, acceptance of this drug by gastroenterologists has been modest.
Infliximab is an IgG1 chimeric monoclonal antibody to tumour necrosis factor-α (TNF-α) that is effective for the induction and maintenance of remission in patients with moderate to severe Crohn's disease.7, 8 Although a subgroup analysis within a maintenance study demonstrated that infliximab is effective for steroid sparing in patients,8 this indication has not been independently evaluated in steroid-dependent patients. Furthermore, infliximab is immunogenic and patients frequently develop human anti-chimeric antibodies (HACAs). These antibodies may cause infusion reactions and loss of efficacy.9–11
Consequently, humanized monoclonal antibodies were designed to reduce the immunogenicity associated with murine and chimeric antibodies. The process of humanization entails grafting a human antibody to the antigen binding complementarity determining regions (CDRs) of a murine antibody variable domain, resulting in a protein that is approximately 95% human.12 CDP571, a humanized monoclonal antibody specific to human TNF-α, was created by linking a human IgG4 antibody framework to the CDR of a murine TNF-α monoclonal antibody.13 Previous trials indicated that intravenous (i.v.) CDP571 might be effective for the short-term treatment of active Crohn's disease14, 15 and possibly for steroid sparing.16 A large-scale study subsequently demonstrated that i.v. CDP571 was effective for the short-term treatment of active Crohn's disease, but failed to demonstrate long-term efficacy over 28 weeks [(Sandborn, 2004 no. 1855)]. Post hoc analyses of the data from this study showed that CDP571 had both short- and long-term efficacy in a subgroup of patients with increased serum concentrations of C-reactive protein (CRP) [(Sandborn, 2004 no. 1855)]. Here we describe the results of a 36-week Phase-III trial in which patients with steroid-dependent Crohn's disease received i.v. CDP571 10 mg/kg or placebo 8-weekly through to week 32.