Efficacy and Safety of Ixekizumab in the Treatment of Radiographic Axial Spondyloarthritis: Sixteen-Week Results From a Phase III Randomized, Double-Blind, Placebo-Controlled Trial in Patients With Prior Inadequate Response to or Intolerance of Tumor Necrosis Factor Inhibitors

Abstract

Objective: To investigate the efficacy and safety of ixekizumab in patients with active radiographic axial spondyloarthritis (SpA) and prior inadequate response to or intolerance of 1 or 2 tumor necrosis factor inhibitors (TNFi).

Methods: In this phase III randomized, double-blind, placebo-controlled trial, adult patients with an inadequate response to or intolerance of 1 or 2 TNFi and an established diagnosis of axial SpA (according to the Assessment of SpondyloArthritis international Society [ASAS] criteria for radiographic axial SpA, with radiographic sacroiliitis defined according to the modified New York criteria and ≥1 feature of SpA) were recruited and randomized 1:1:1 to receive placebo or 80-mg subcutaneous ixekizumab every 2 weeks (IXEQ2W) or 4 weeks (IXEQ4W), with an 80-mg or 160-mg starting dose. The primary end point was 40% improvement in disease activity according to the ASAS criteria (ASAS40) at week 16. Secondary outcomes and safety were also assessed.

Results: A total of 316 patients were randomized to receive placebo (n = 104), IXEQ2W (n = 98), or IXEQ4W (n = 114). At week 16, significantly higher proportions of IXEQ2W patients (n = 30 [30.6%]; P = 0.003) or IXEQ4W patients (n = 29 [25.4%]; P = 0.017) had achieved an ASAS40 response versus the placebo group (n = 13 [12.5%]), with statistically significant differences reported as early as week 1 with ixekizumab treatment. Statistically significant improvements in disease activity, function, quality of life, and spinal magnetic resonance imaging-evident inflammation were observed after 16 weeks of ixekizumab treatment versus placebo. Treatment-emergent adverse events (AEs) with ixekizumab treatment were more frequent than with placebo. Serious AEs were similar across treatment arms. One death was reported (IXEQ2W group).

Conclusion: Ixekizumab treatment for 16 weeks in patients with active radiographic axial SpA and previous inadequate response to or intolerance of 1 or 2 TNFi yields rapid and significant improvements in the signs and symptoms of radiographic axial SpA versus placebo.

Trial registration: ClinicalTrials.gov NCT02696798.

Figure 1

Disposition of the patients. Details are given according to the Consolidated Standards of Reporting Trials (CONSORT) statement for reporting randomized controlled trials.

Figure 2

Proportion of patients achieving A, 40% improvement in disease activity according to the Assessment of SpondyloArthritis international Society criteria (ASAS40) or B, ASAS20 responses through week 16 when treated with placebo (PBO), ixekizumab every 2 weeks (IXEQ2W), or ixekizumab every 4 weeks (IXEQ4W). * = P < 0.05; † = P < 0.01; ‡ = P < 0.001, all versus placebo by logistic regression analysis, except for week 1 with ASAS40, for which Fisher's exact test was used due to model nonconvergence. Only analyses at week 16 were included in the prespecified multiple testing strategy. n = number of patients in the analysis category; N = number of patients in the analysis population.

Figure 3

Major secondary outcomes investigating disease activity, function, and quality of life among patients treated with placebo (PBO), ixekizumab every 2 weeks (IXEQ2W), or ixekizumab every 4 weeks (IXEQ4W) for 16 weeks. A–D, Ankylosing Spondylitis Disease Activity Score (ASDAS) (A), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (B), ASDAS score <2.1 (C), and Bath Ankylosing Spondylitis Functional Index (BASFI) (D). E and F, Medical Outcomes Study Short Form 36 (SF‐36) health survey, physical component score (PCS) (E) and Assessment of Spondyloarthritis international Society Health Index (ASAS‐HI) (F). * = P < 0.05; † = P < 0.01; ‡ = P < 0.001, all versus placebo by mixed‐effects model of repeated measures (MMRM) or logistic regression analysis (C only). Only analyses at week 16 were included in the prespecified multiple testing strategy. Values shown at week 16 for all measures (except C) are the least squares mean (LSM) ± SE.

Figure 4

Spondyloarthritis Research Consortium of Canada (SPARCC) magnetic resonance imaging (MRI) index spine scores (A) and serum C‐reactive protein (CRP) levels (B) among patients treated with placebo (PBO), ixekizumab every 2 weeks (IXEQ2W), or ixekizumab every 4 weeks (IXEQ4W) through 16 weeks. † = P < 0.01; ‡ = P < 0.001, all versus placebo by analysis of covariance (ANCOVA) and least squares mean (LSM) (A) or mixed‐effects model of repeated measures (MMRM) and LSM (B). Only SPARCC MRI spine score analyses at week 16 were included in the prespecified multiple testing strategy. Values shown are the LSM ± SE. N = number of patients in the analysis population; Nx = number of patients in the MRI addendum population.