HONOLULU — Certolizumab pegol, a novel anti-tumor necrosis factor-α agent, proved effective for both induction and maintenance of clinical remission in patients with Crohn's disease in a pivotal phase III, 26-week randomized trial, Dr. William J. Sandborn reported at the annual meeting of the American College of Gastroenterology.
Certolizumab (Cimzia) is a humanized monoclonal Fab fragment conjugated to polyethylene glycol, giving it a lengthy plasma half-life of nearly 2 weeks. It is considered far less likely to engender an immune response than infliximab (Remicade), at present the sole anti-TNF agent approved for Crohn's disease.
Also, unlike the intravenously administered infliximab, certolizumab is given by subcutaneous injection, a route that offers the potential for more convenient self-treatment, explained Dr. Sandborn, professor of medicine at the Mayo Medical School, Rochester, Minn.
He reported on 668 patients with moderate to severe Crohn's disease who participated in the PRECiSE 2 trial, sponsored by UCB Pharmaceuticals Inc., manufacturer of certolizumab.
All patients received an open-label induction regimen of 400-mg certolizumab at weeks 0, 2, and 4. The 64% who showed a significant clinical response by week 6 were then randomized to double-blind maintenance therapy with 400-mg certolizumab or placebo once a month.
The primary end point in PRECiSE 2 was maintenance of a clinical response, defined as at least a 100-point drop in the Crohn's Disease Activity Index at week 26, compared with baseline. The clinical response rate in the certolizumab group was 63%, significantly better than the 36% rate in controls.
In addition, the remission rate, defined by a Crohn's Disease Activity Index of 150 or less at 26 weeks, was 48% with certolizumab and 29% with placebo.
Certolizumab's efficacy was equally robust in patients with or without an elevated baseline C-reactive protein level, unlike the findings of an earlier trial in which only patients with a baseline CRP of at least 10 mg/L showed significant improvement.
The efficacy of certolizumab in PRECiSE 2 was similar in patients who were on immunosuppressive therapy and those who weren't. Certolizumab was significantly more effective than placebo, both in patients who had previously been on infliximab and those who hadn't. However, the 69% clinical response rate in anti-TNF-naive patients was markedly greater than the 44% rate among those previously on infliximab, Dr. Sandborn continued.
A single case of tuberculosis occurred in the certolizumab-treated group during the 26 weeks. The overall rate of significant infections was 1.8% during the 4-week induction phase and 2.8% during maintenance therapy. Antibodies to certolizumab developed in 8% of patients.
PRECiSE 3 and 4 are ongoing, 24-month, open-label trials designed to provide additional safety and tolerability data. UCB plans to file for marketing approval for certolizumab early next year.
Certolizumab is one of three new biologic agents that clinicians will likely be able to offer their Crohn's disease patients in 2007, according to Dr. Sandborn. The other two are adalimumab (Humira), a fully human monoclonal antibody directed against TNF-α with very low immunogenicity, and natalizumab (Tysabri), a humanized monoclonal antibody directed against α4 integrins.
Dr. Sandborn was principal investigator in the positive phase III Clinical Assessment of Adalimumab Safety and Efficacy Studied as an Induction Therapy in Crohn's Disease (CLASSIC-II) trial of adalimumab, as well as in the Efficacy of Natalizumab as Active Crohn's Therapy-1 and −2 (ENACT-1 and −2) trials.
Natalizumab was developed initially for the treatment of multiple sclerosis but was quickly taken off the market after three cases of progressive multifocal leukoencephalopathy occurred.
In September, the drug's manufacturer filed an application to resume marketing, since no more cases of leukoencephalopathy were ascertained.
Dr. Sandborn is a consultant to Centocor Inc., UCB, Abbott Laboratories, and Biogen Idec, the manufacturers of infliximab, certolizumab, adalimumab, and natalizumab, respectively.
Although all of the biologics are expensive to manufacture, the subcutaneous route of administration for certolizumab and adalimumab could spell substantial savings because prescribers won't need to set up an office infusion center, Dr. Sandborn said.