The first randomized controlled trial to complete a head-to-head comparison of two biologic disease-modifying antirheumatic drugs (DMARDs) in the anti-tumor necrosis factor (TNF) class failed to demonstrate the long-term and short-term superiority of certolizumab pegol plus methotrexate (MTX) vs adalimumab plus MTX in patients with rheumatoid arthritis (RA) with insufficient primary response to first TNF inhibitor at 12 weeks.1 No statistically significant differences in safety or efficacy were found between the regimens at 12-weeks or 2 years.
Despite not demonstrating the superiority of certolizumab pegol plus MTX to adalimumab plus MTX, missing that primary endpoint, the study was the first to demonstrate the clinical benefit of switching to a second anti-TNF agent without a washout period following an inadequate response to the first. That strategy is endorsed in American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) guidelines, which state that patients who have not responded satisfactorily to anti-TNF therapy at 12 weeks can be switched to another anti-TNF agent or to a different class of biological therapies.2,3
Results of the EXXELERATE study were presented at the 2016 annual meeting of the American College of Rheumatology in Washington, DC, and subsequently published in The Lancet.
The study population consisted of 915 patients with RA and serological factors prognosticating severe disease progression, including positivity for rheumatoid factor (RF) or anti-cyclic citrullinated peptide antibody (ACPA), who had inadequately responded to MTX and who were naïve to anti-TNF treatment.
High Yield Data Summary
- No efficacy difference was found between certolizumab pegol and adalimumab in combination with MTX at both 12-weeks and 2-years in MTX-inadequate responders with RA
Patients were randomized to receive either certolizumab pegol plus MTX (n=457) or adalimumab plus MTX (n=458). After 12 weeks, patients with an adequate response to treatment stayed on the same agent, while non-responders were switched to the other treatment for the duration of the study, which totaled 104 weeks. The switch was undertaken without a drug washout period.
At 12 weeks, 69% of patients who received certolizumab pegol plus methotrexate achieved a 20% improvement response as defined by American College of Rheumatology criteria (ACR20), compared to 71% of those who received adalimumab plus methotrexate.
At two years, 35% of patients in the certolizumab pegol arm achieved a state of low disease activity vs. 33% of those in the adilumumab arm.
Of patients classified as non-responders at week 12, 14% were in the certolizumab pegol arm and 13% were in the adalimumab arm. Fifty-eight percent of non-responders switched to certolizumab pegol and 62% of switched to adalimumab achieved low disease activity or reduction in Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR) ≥1.2 12 weeks following the treatment change.
These study results suggest that switching to a second TNF inhibitor after primary TNF inhibitor failure in methotrexate inadequate responders is safe and effective, even without a drug washout period.
More research is needed to support decision-making among rheumatologists in their selection of therapies. “We need biomarkers that inform us on differential responses to the different biological DMARDs,” said lead investigator Josef S. Smolen, M.D. in an email interview with Rheumatology Advisor. “Currently the only marker for a good response is an early clinical improvement.”
Summary and Clinical Applicability
“Prior to EXXELERATE, the body of evidence supporting the use of anti-TNFs after initial anti-TNF treatment failure was limited, as no trials have evaluated the efficacy of an immediate switch from one anti-TNF to another. EXXELERATE, among other important information, provides evidence supporting the treat-to-target approach, emphasizing the importance of clinical decision making three months after initiating therapy,” commented Dr. Smolen in a press release.4
“By following this approach, and using a second anti-TNF at Week 12 in the event of inadequate response, clinicians maximize the potential benefit of anti-TNF therapy. This also allows early identification of patients within six months who may not have an adequate response to anti-TNF therapy and who may benefit from a different mode of action.”
Limitations and Disclosures
The study was limited to two particular anti-TNF agents. Extrapolating these results to other anti-TNF agents might not be appropriate.
Patients were not blind to treatment after week 12 of the study, potentially biasing patient-reported outcomes.
The study sample size was calculated based on analyses of findings from studies which supported a superiority hypothesis of certolizumab pegol over adalimumab.
Drs Cioffi, Ecoffet, Gervitz, Ionescu and Peterson are company employees of UCB Pharma and contributed to the study design, data analysis, data interpretation, and writing of the report, but had no involvement in data collection. The authors had full access to all of the study data and had final responsibility for the decision to submit for publication. All monitoring was done by Parexel (an external contract research organization) and 100% of the study was source verified.
The study was funded by UCB Pharma, the manufacturer of certolizumab pegol.
Smolen JS, Burmester G-R, Combe B, et al. Head-to-head comparison of certolizumab pegol versus adalimumab in rheumatoid arthritis: 2-year efficacy and safety results from the randomised EXXELERATE study. Lancet Lond Engl. 2016;388(10061):2763-2774. doi:10.1016/S0140-6736(16)31651-8.
Singh JA, Saag KG, Bridges SL, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis: ACR RA Treatment Recommendations. Arthritis Care Res. 2016;68(1):1-25. doi:10.1002/acr.22783.
Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73(3):492-509. doi:10.1136/annrheumdis-2013-204573.
UCB. The Lancet Publishes First Head-to-Head Study of CIMZIA® (certolizumab pegol) and Humira® (adalimumab) in Bio-Naïve Rheumatoid Arthritis Patients [news release]. http://www.prnewswire.com/news-releases/the-lancet-publishes-first-head-to-head-study-of-cimzia-certolizumab-pegol-and-humira-adalimumab-in-bio-naive-rheumatoid-arthritis-patients-300363191.html. Accessed December 14, 2016.