Translating Improvements with Ixekizumab in Clinical Trial Outcomes into Clinical Practice: ASAS40, Pain, Fatigue, and Sleep in Ankylosing Spondylitis

Abstract

Introduction Ixekizumab, a humanized interleukin-17A antibody, has shown efficacy in ankylosing spondylitis (AS), with a greater proportion of ixekizumab-treated patients achieving an ASAS40 (Assessment of Spondyloarthritis International Society 40) endpoint compared to placebo. An ASAS40 response is a high standard that is not routinely used in clinical practice. The goals of this study were (a) to measure improvement in ixekizumab-treated patients in the four ASAS treatment response domains and in other patient-reported outcomes, and (b) to determine how the ASAS response was associated with changes in spinal pain at night, fatigue, sleep, and the Short Form 36-Item Physical Component Summary (SF-36 PCS). Methods The COAST-V and COAST-W trials were randomized, double-blind, controlled trials examining ixekizumab efficacy in patients with AS who were biologic disease-modifying antirheumatic drug (bDMARD)-naïve and tumor necrosis factor inhibitor (TNFi)-experienced, respectively. Data for the ASAS treatment response domains and other outcomes were collected through 16 weeks. Comparisons between treatment groups were made using a mixed-effects model for repeated measures. To determine how the ASAS response was associated with the changes in spinal pain at night, fatigue, sleep, and SF-36 PCS, comparisons were made between patient groups according to their level of treatment response (ASAS40 vs. ASAS20 vs. ASAS20 nonresponse) using analysis of covariance. Results Compared with placebo, patients treated with ixekizumab reported significantly greater improvement in the four ASAS treatment response domains and other outcomes ( p < 0.05). Results were consistent for bDMARD-naïve and TNFi-experienced patients. Compared to ASAS20 nonresponders, patients who achieved ASAS40 reported significantly greater mean changes in spinal pain at night (1.0 vs. 5.1 for bDMARD-naïve; 0.5 vs. 5.4 for TNFi-experienced), fatigue (0.6 vs. 3.8 for bDMARD-naïve; 0.2 vs. 3.9 for TNFi-experienced), sleep quality (1.1 vs. 4.0 for bDMARD-naïve; 0.8 vs. 4.9 for TNFi-experienced), and SF-36 PCS (2.6 vs. 11.6 for bDMARD-naïve; 1.2 vs. 12.6 for TNFi-experienced) ( p < 0.0001). Conclusion Patients with AS who were treated with ixekizumab reported greater improvements in multiple patient-reported outcomes than patients who received placebo. Importantly, achieving ASAS40 was associated with a 2.6-fold to 5.3-fold greater improvement in pain, fatigue, sleep, and quality of life for bDMARD-naïve patients, and a 5.1-fold to 18.5-fold greater improvement for TNFi-experienced patients, compared to ASAS20 nonresponders. Trial Registration ClinicalTrials.gov identifiers: NCT02696785 and NCT02696798. Funding Eli Lilly and Company.

Ixekizumab Improves Patient-Reported Outcomes in Non-Radiographic Axial Spondyloarthritis: Results from the Coast-X Trial

“…In the current analysis of data from the COAST-X clinical trial of patients with nr-axSpA, we demonstrate that ixekizumab is effective at improving spinal PROs in patients with nr-axSpA. This analysis from COAST-X along with the previously reported results from COAST-V and COAST-W in r-axSpA indicate that treatment with ixekizumab is effective in improving the most impactful symptoms across the axSpA disease spectrum (r-axSpA and nr-axSpA) [15]. As previously reported in the r-axSpA trials assessing ixekizumab (COAST-V and COAST-W), here we also show that ASAS40 responders report greater improvements in PtGA, spinal pain, function, and stiffness, fatigue, and spinal pain at night compared with ASAS20 responders, and ASAS20 responders also report greater improvements in PROs than ASAS20 non-responders.…”

“…The Assessment of Spondyloarthritis International Society (ASAS) responses, ASAS20 and ASAS40 (defined by criteria including improvements of 20% and 40%, respectively) and partial remission, are primary endpoints in axSpA randomized controlled trials (RCTs). While ASAS responses are valuable in the context of RCTs, physicians in clinical practice focus on individual patient symptoms, such as patient global disease activity (PtGA), spinal pain, function, stiffness, fatigue, and spinal pain at night [14,15]. The present study used data from the COAST-X trial to assess the impact of ixekizumab treatment over 52 weeks and explore how ASAS40 responses correlate with improvements in patient-reported outcomes (PROs).…”

Assessing the effect of interventions for axial spondyloarthritis according to the endorsed ASAS/OMERACT core outcome set: a meta-research study of trials included in Cochrane reviews

“…As with previous findings, this meta-epidemiological study found that pain and PGA are important predictors for treatment responses in axSpA trials [79], thus emphasizing the value of reporting core domains separately.…”

Efficacy and safety of IL-17 inhibitors for the treatment of ankylosing spondylitis: a systematic review and meta-analysis

“…For patients who do not respond to or tolerate NSAIDs, biological disease-modifying antirheumatic drugs (bDMARDs), mainly tumor necrosis factor inhibitors (TNFis), have been recommended since the early 2000s [4,5]. However, approximately 30 to 40% of patients have disease that remains active after standardized treatment with NSAIDs and/or bDMARDs [7][8][9]. The emergence of interleukin (IL)-17 inhibitors has changed the treatment landscape of active ankylosing spondylitis [10].…”