Elsevier

The Lancet

Volume 395, Issue 10217, 4–10 January 2020, Pages 53-64
The Lancet

Articles
Ixekizumab for patients with non-radiographic axial spondyloarthritis (COAST-X): a randomised, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(19)32971-XGet rights and content

Summary

Background

Ixekizumab, a high-affinity interleukin-17A (IL-17A) monoclonal antibody, has previously shown efficacy in radiographic axial spondyloarthritis (also known as ankylosing spondylitis). We aimed to evaluate the efficacy and safety of ixekizumab, an IL-17 inhibitor, in non-radiographic axial spondyloarthritis. Here, we report the primary results of COAST-X.

Methods

COAST-X was a 52-week, randomised, double-blind, placebo-controlled, parallel-group study done at 107 sites in 15 countries in Europe, Asia, North America, and South America. Eligible participants were adults (aged ≥18 years) with active axial spondyloarthritis without definite radiographic sacroiliitis (non-radiographic axial spondyloarthritis), objective signs of inflammation (via MRI or C-reactive protein), and an inadequate response or intolerance to non-steroidal anti-inflammatory drugs (NSAIDs). Patients were randomly assigned (1:1:1) to receive subcutaneous 80 mg ixekizumab every 4 weeks (Q4W) or every 2 weeks (Q2W), or placebo. Changing background medications or switching to open-label ixekizumab Q2W, or both, was allowed after week 16 at investigator discretion. Primary endpoints were Assessment of SpondyloArthritis international Society-40 (ASAS40) response (defined as an improvement of 40% or more and an absolute improvement from baseline of 2 units or more [range 0–10] in at least three of the four domains [patient global, spinal pain, function, and inflammation] without any worsening in the remaining one domain) at weeks 16 and 52. Patients who switched to open-label ixekizumab were imputed as non-responders in logistic regression analysis. This trial is registered with ClinicalTrials.gov, number NCT02757352.

Findings

Between Aug 2, 2016, and Jan 29, 2018, 303 patients were enrolled (105 to placebo, 96 to ixekizumab Q4W, and 102 to ixekizumab Q2W). Both primary endpoints were met: ASAS40 at week 16 (ixekizumab Q4W: 34 [35%] of 96, p=0·0094 vs placebo; ixekizumab Q2W: 41 [40%] of 102, p=0·0016; placebo: 20 [19%] of 105) and ASAS40 at week 52 (ixekizumab Q4W: 29 [30%] of 96, p=0·0045; ixekizumab Q2W: 32 [31%] of 102, p=0·0037; placebo: 14 [13%] of 105). 60 (57%) of 104 patients in the placebo group, 63 (66%) of 96 in the ixekizumab Q4W group, and 79 (77%) of 102 in the ixekizumab Q2W group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events in the ixekizumab groups were nasopharyngitis and injection site reaction. Of the treatment-emergent adverse events of special interest, there was one case of serious infection in the ixekizumab Q4W group. The frequency of serious adverse events was low (four [1%] of 302) and similar across the three groups. There were no malignancies or deaths. No new safety signals were identified.

Interpretation

Ixekizumab was superior to placebo for improving signs and symptoms in patients with non-radiographic axial spondyloarthritis at weeks 16 and 52. Reports of adverse events were similar to those of previous ixekizumab studies. Ixekizumab offers a potential therapeutic option for patients with non-radiographic axial spondyloarthritis who had an inadequate response or were intolerant to NSAID therapy.

Funding

Eli Lilly and Company.

Introduction

Axial spondyloarthritis is a chronic inflammatory disease that predominantly affects the axial skeleton (sacroiliac joints and spine).1 Axial spondyloarthritis is considered a disease continuum distinguished by the presence or absence of structural damage of the sacroiliac joints visible on radiographs: radiographic axial spondyloarthritis (also known as ankylosing spondylitis) and non-radiographic axial spondyloarthritis.2 The clinical manifestations and disease burden are similar across the axial spondyloarthritis disease spectrum.3, 4, 5 The proportion of patients with non-radiographic axial spondyloarthritis among all patients with axial spondyloarthritis is 40–60%, according to national and international referral programmes and prevalence studies.6, 7, 8

First-line pharmacological treatment for axial spondyloarthritis consists of non-steroidal anti-inflammatory drugs (NSAIDs).9, 10, 11 Conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) are not effective for axial involvement in axial spondyloarthritis.12, 13 Treatment with biologic DMARDs (bDMARDs) has been recommended for patients with active disease despite treatment with NSAIDs.9, 10, 11, 14 TNF inhibitors, including adalimumab, certolizumab pegol, etanercept, and golimumab, are the only approved bDMARD treatments for non-radiographic axial spondyloarthritis.15, 16, 17, 18, 19

Research in context

Evidence before this study

We searched PubMed for research articles published in English between database inception and Sept 4, 2019, using the terms: “non-radiographic axial spondyloarthritis” AND “biologic”. Of the 28 articles that resulted from the search, we selected those that described the disease and current treatments. Axial spondyloarthritis is a chronic inflammatory disease that predominately affects the sacroiliac joints and spine. For classification purposes, axial spondyloarthritis has been separated into radiographic and non-radiographic categories on the basis of whether or not a patient has definite sacroiliitis visible on radiographs. Tumour necrosis factor inhibitors are the only class of biologic drugs approved for the treatment of non-radiographic axial spondyloarthritis. Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin 17A (IL-17A), has been approved in the USA for the treatment of patients with radiographic axial spondyloarthritis. However, to our knowledge, this study is the first to investigate the efficacy and safety of an IL-17 inhibitor in patients with non-radiographic axial spondyloarthritis.

Added value of this study

The COAST-X study met the primary endpoints, showing superiority of ixekizumab over placebo for achievement of Assessment of SpondyloArthritis international Society-40 response at weeks 16 and 52 in patients with non-radiographic axial spondyloarthritis and objective signs of inflammation. The major secondary endpoints were also met, with ixekizumab showing efficacy in reducing disease activity and sacroiliac joint inflammation and improving patient function and quality of life. The safety profile of ixekizumab in COAST-X was consistent with studies of ixekizumab in patients with moderate-to-severe psoriasis, psoriatic arthritis, and radiographic axial spondyloarthritis. COAST-X is the first study to show efficacy of an IL-17 inhibitor in patients with non-radiographic axial spondyloarthritis, where only evidence for TNF inhibitors previously existed.

Implications of all the available evidence

The COAST-X study shows that IL-17A has a role in the pathogenesis of non-radiographic axial spondyloarthritis. Treatment with ixekizumab resulted in significant improvements in disease activity, physical function, quality of life, and inflammation in the sacroiliac joints compared with placebo. Overall, our findings indicate that ixekizumab could be a new treatment option for patients with non-radiographic axial spondyloarthritis.

Although most TNF inhibitors are approved in the European Union and many countries worldwide,15, 16, 17, 18, 20 the first bDMARD for non-radiographic axial spondyloarthritis (certolizumab pegol) was approved in the USA in March, 2019.19 Thus, there remains an unmet need globally for patients with non-radiographic axial spondyloarthritis. Ixekizumab is a high-affinity monoclonal antibody against interleukin 17A (IL-17A) that was approved in August, 2019, for the treatment of patients with radiographic axial spondyloarthritis based on the efficacy shown in both biologic-naive and TNF inhibitors-exposed patients.21, 22 We aimed to investigate the efficacy and safety of ixekizumab in patients with non-radiographic axial spondyloarthritis.

Section snippets

Study design

COAST-X was a multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial, followed by an optional 2-year extension trial (COAST-Y). The study was done over 52 weeks by 109 investigators at 107 sites in 15 countries in Europe, Asia, North America, and South America. Investigators and sites are listed in the appendix (pp 5–11).

At week 0, patients were randomly assigned to receive placebo (placebo group), 80 mg subcutaneous ixekizumab every 4 weeks (Q4W; ixekizumab

Results

Between Aug 2, 2016, and Jan 29, 2018, 781 patients were screened, of whom 436 (56%) failed screening (figure 1). 303 patients were enrolled and allocated to treatment: 105 to placebo, 96 to ixekizumab Q4W, and 102 to ixekizumab Q2W. 290 (96%) of 303 patients completed the first 16 weeks and 265 (87%) completed the whole 52 weeks, including patients that switched to open-label ixekizumab Q2W. At week 52, 34 (32%) of 105 patients in the placebo group had completed the full 52-week period on

Discussion

This 52-week placebo-controlled trial of ixekizumab showed clinically relevant and statistically significant differences versus placebo in the primary and major secondary endpoints covering various disease aspects (clinical disease activity, physical function, and quality of life) in patients with active non-radiographic axial spondyloarthritis and objective signs of inflammation. Although changes in CRP concentrations between treatment groups did not differ at week 16 or 52, a significant

Data sharing

Eli Lilly and Company provides access to all individual participant data collected during the trial, after anonymisation, with the exception of pharmacokinetic or genetic data. Data are available on request 6 months after the indication studied has been approved in the USA and European Union and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an

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