Results of a large phase 3 study show that secukinumab does not offer any advantage over abatacept for patients with active rheumatoid arthritis (RA) who lack or have a suboptimal response to tumor necrosis factor (TNF) inhibitors (Blanco FJ, et al. Arthritis Rheumatol. Feb 19, 2017. Epub ahead of print). Secukinumab was more effective than placebo, but on a variety of measures of efficacy, responses to abatacept were numerically higher than those to secukinumab. The lack of a benefit over abatacept led to premature closing of the trial.
This is the first phase 3 randomized study comparing an interleukin (IL)-17A inhibitor (ie, secukinumab) with abatacept in patients with RA who have had no response to TNF inhibitor therapy. These results in RA are in contradistinction to secukinumab’s demonstrated robust efficacy in spondyloarthropathies, including psoriatic arthritis and ankylosing spondylitis, for which it is approved by the FDA.
“These data, along with data from phase 2 studies and those of other anti-IL-17A agents suggest that IL-17A plays a lesser role in the pathogenesis of RA [compared with the spondyloarthropathies]. Thus, blockade of IL-17A alone may not add to the armamentarium for clinicians in the treatment of patients with RA who have failed anti-TNF therapy,” said Francisco J. Blanco, MD, PhD, Grupo de Investigación Clinica, Instituto Biomédica de Coruña-INIBIC, Spain, and colleagues.
Secukinumab is a humanized, monoclonal antibody that selectively binds to and defuses IL-17A. Previous studies have suggested that this agent may provide a benefit for patients with RA. If so, it would be an alternative to TNF inhibitors, which are the first choice for patients whose disease responses to conventional disease-modifying antirheumatic drugs are suboptimal. Abatacept has a different mechanism of action from that of secukinumab, and from that of TNF inhibitors; it is a selective, co-stimulation modulator that inhibits T-lymphocytes, and is approved for the treatment of RA that does not respond optimally to TNF inhibitors.
Study DesignThe present study sought to compare secukinumab versus abatacept versus placebo in 551 patients with RA who have had an inadequate response or are intolerant to TNF inhibitors. Patients could have been receiving >1 TNF inhibitor. The double-blind, double-dummy, parallel-group, active-comparator, placebo-controlled trial was conducted at 121 centers in 15 countries. Patients with active RA were randomized 1:1:1:1 to intravenous secukinumab 10 mg/kg at baseline and weeks 2 and 4, followed by subcutaneous secukinumab 150 mg or 75 mg every 4 weeks up to week 48 versus abatacept or placebo at the same dosing schedule.
At week 16, patients in the placebo cohort who were nonresponders were rerandomized 1:1 to receive secukinumab 150 mg or 75 mg every 4 weeks. Nonresponders to abatacept at week 16 were rerandomized to receive secukinumab 150 mg or 75 mg every 4 weeks starting at week 24, following an 8-week washout period during which they received placebo in a blinded fashion.
Patients who completed 1 year of treatment with secukinumab were eligible to join an extension study with a planned follow-up of 5 years; mean total follow-up was 1.4 years because of early closure of the extension trial.
OutcomesFor the primary outcome, which was the percentage of patients having ≥20% response rate according to American College of Rheumatology (ACR20) criteria at week 24, ACR20 response rates were 30.7% for secukinumab 150 mg, 28.3% for secukinumab 75 mg, and 42.8% for abatacept, compared with 18.1% for placebo. Secukinumab 150 mg met the primary end point, whereas secukinumab 75 mg did not.
Secukinumab 150 mg—but not 75 mg—met the key secondary objective, which was a significant reduction in Disease Activity Score 28−C-reactive protein from baseline to week 24 (P = .0495). Neither dose of secukinumab met the other main secondary end points, such as the Health Assessment Questionnaire-Disability Index and the proportion of patients with ≥50% response rate (ACR50).
The change from baseline in Disease Activity Score 28−C-reactive protein at week 24 was –1.47 for both secukinumab doses, –2.07 for abatacept, and –1.02 for placebo. At week 24, changes in the Health Assessment Questionnaire-Disability Index from baseline were –0.39 for secukinumab 150 mg, –0.30 for secukinumab 75 mg, –0.61 for abatacept, and –0.26 for placebo.
At week 24, ACR50 response rates were 16.8% for secukinumab 150 mg, 11.6% for secukinumab 75 mg, 27.5% for abatacept, and 9.4% for placebo. A similar trend was observed for ACR70 responses. Abatacept achieved numerically higher ACR50 and ACR70 response rates at week 24 compared with both secukinumab dose groups. ACR20/50/70 responses achieved in both secukinumab dose groups at week 24 were sustained at week 52.
Improvements in Health Assessment Questionnaire-Disability Index score at week 24 were sustained up to week 52 in both secukinumab dose groups, but were further improved with abatacept during this period.
SafetyThe safety profile was similar across active-treatment groups. Treatment-emergent adverse events were reported for a higher proportion of patients in the active-treatment groups versus placebo during the first 16 weeks of treatment. Infections and infestations were the most frequent of these, such as influenza, upper respiratory tract infection, and nasopharyngitis. Rates of musculoskeletal and connective tissue disorders and gastrointestinal disorders were similar in patients treated with secukinumab and abatacept.
The most frequently reported adverse events in the secukinumab groups during the first 16 weeks of treatment were diarrhea, headache, hypertension, and influenza. The incidence of serious adverse events was low and comparable between groups during the first 16 weeks; 9.7 per 100 patient-years in the secukinumab groups and 7.7 per 100 patient-years in the abatacept group.
During the trial’s entirety, 43 patients discontinued treatment because of an adverse event; 38 in the secukinumab groups and 5 in the abatacept group.
