The first head-to-head superiority study of two treatments in the anti-tumor necrosis factor (TNF) class has failed to meet its primary endpoints for superiority. The phase 4 study compared certolizumab pegol (Cimzia, UCB) plus methotrexate (MTX) with adalimumab (Humira, AbbVie) plus MTX in adults with moderate-to-severe rheumatoid arthritis (RA) who were inadequate responders to MTX.
The percentages of patients achieving a 20% improvement in the symptoms of RA, as defined by the American College of Rheumatology (ACR20), at three months were 69% for certolizumab and 71% for adalimumab, and the percentages of patients achieving a state of low disease activity at two years were 36% and 34%, respectively.
The EXXELERATE trial was a 24-month (104-week), randomized, single-blind, parallel-group, head-to-head superiority study. It was designed to evaluate the short- and long-term efficacy of certolizumab pegol compared with that of adalimumab, both administered in combination with methotrexate (MTX), in patients with moderate-to-severe RA who had not responded adequately to MTX.
The study’s primary endpoints were the percentage of patients with an ACR20 response at week 12 and the percentage of patients who achieved low disease activity (Disease Activity Score 28––Erythrocyte Sedimentation Rate [DAS28–ESR] of less than or equal to 3.2) at week 104.
A total of 915 biologic-naïve patients with moderate-to-severe RA and an inadequate response to MTX were randomly assigned at baseline to receive either a standard loading-dose regimen of certolizumab 400 mg plus MTX at weeks 0, 2, and 4, followed by certolizumab 200 mg plus MTX every two weeks, or adalimumab 40 mg plus MTX every two weeks, with placebo also given at weeks 0, 2, and 4 to maintain blinding.
MTX dosing was maintained at 15 to 25 mg per week orally or subcutaneously, with one dose adjustment permitted between week 12 and week 52, and a one-dose adjustment permitted between week 52 and week 104. For patients who were unable to tolerate MTX at these doses, the dose could be reduced to 10 mg per week after week 12.
At week 12, patients were categorized as responders if they achieved low disease activity, defined as a DAS28–ESR score of less than or equal to 3.2 or had a DAS28–ESR change-from-baseline reduction greater than or equal to 1.2.
A preliminary safety analysis across two years showed that overall safety, including serious adverse events and serious infections, was comparable between the two agents. Patients not responding to initial treatment at three months were switched to immediate treatment with the other agent without a wash-out period between the two treatments. (Patients switching from adalimumab to certolizumab received the loading dose of certolizumab.) No serious infectious events occurred in patients changing therapy during the period after the change when a patient was exposed, because of drug half-lives, to both agents (70 days).
Certolizumab is the only Fc-free, PEGylated anti-TNF agent. It has a high affinity for human TNF-alpha, selectively neutralizing the pathophysiologic effects of TNF-alpha.
Certolizumab is approved in the U.S. for the treatment of adults with moderately to severely active RA. It is also indicated for reducing the signs and symptoms of Crohn’s disease; for maintaining the clinical response in adults with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy; for the treatment of adults with active psoriatic arthritis; and for the treatment of adults with active ankylosing spondylitis.
Source: PipelineReview; March 24, 2016.