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.

Keywords: ASAS40; Ankylosing spondylitis; Axial spondyloarthritis; Fatigue; Inflammation; Ixekizumab; Pain; Sleep.

Figures

Fig. 1

Least-squares mean (LSM) changes from baseline in the ASAS treatment response domains of a, b patient global, c, d spinal pain, e, f inflammation (BASDAI Q5 and Q6), and g function (BASFI) for a, c, e, g bDMARD-naïve patients (COAST-V) and b, d, f TNFi-experienced patients (COAST-W). Comparisons with PBO were made using a mixed-effects model for repeated measures. ***p < 0.001 vs. PBO; **p < 0.01 vs. PBO. The BASFI data for TNFi-experienced patients (COAST-W) were published previously [13]. ADA adalimumab, ASAS Assessment of Spondyloarthritis International Society, BASDAI Bath Ankylosing Spondylitis Disease Activity Index, BASFI Bath Ankylosing Spondylitis Functional Index, bDMARD biologic disease-modifying antirheumatic drugs, IXE ixekizumab, PBO placebo, Q2W, every 2 weeks, Q4W every 4 weeks, TNFi tumor necrosis factor inhibitor

Fig. 2

Least-squares mean (LSM) changes from baseline in patient-reported outcomes of a, b spinal pain at night, c, d fatigue measured by BASDAI Q1, e, f fatigue measured by NRS, and g, h sleep quality measured by JSEQ for a, c, e, g bDMARD-naïve patients (COAST-V) and b, d, f, h TNFi-experienced patients (COAST-W). Comparisons with PBO were made using a mixed-effects model for repeated measures. ***p < 0.001 vs. PBO; **p < 0.01 vs. PBO; *p < 0.05 vs. PBO. ADA adalimumab, BASDAI Bath Ankylosing Spondylitis Disease Activity Index, bDMARD biologic disease-modifying antirheumatic drugs, IXE ixekizumab, JSEQ Jenkins Sleep Evaluation Questionnaire, NRS Numeric Rating Scale, PBO placebo, Q2W, every 2 weeks, Q4W every 4 weeks, TNFi tumor necrosis factor inhibitor

Fig. 3

Least-squares mean (LSM) changes from baseline in a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and b Medical Outcomes Study 36-Item Short-Form Health Survey Physical Component Summary (SF-36 PCS) in bDMARD-naïve patients (COAST-V). Comparisons with PBO were made using a mixed-effects model for repeated measures. ***p < 0.001 vs. PBO; **p < 0.01 vs. PBO. BASDAI and SF-36 PCS data for TNFi-experienced patients (COAST-W) were published previously [13]. ADA adalimumab, bDMARD biologic disease-modifying antirheumatic drug, IXE ixekizumab, PBO placebo, Q2W every 2 weeks, Q4W every 4 weeks, TNFi tumor necrosis factor inhibitor

Fig. 4

Association between ASAS20 and ASAS40 and LSM improvement from baseline for a spinal pain at night, b fatigue (NRS), c sleep quality (JSEQ), and d SF-36 PCS at week 16. Treatment groups, including the placebo and adalimumab arms, were pooled and separated by ASAS20 and ASAS40 achievement. Black bars indicate data from bDMARD-naïve patients (COAST-V); gray bars indicate data from TNFi-experienced patients (COAST-W). §p ≤ 0.001, achieved ASAS20 but not ASAS40 vs. ASAS20 not achieved; *p < 0.0001, ASAS40 achieved vs. ASAS20 not achieved; †p < 0.0001, ASAS40 achieved vs. achieved ASAS20 but not ASAS40. Results were compared using ANCOVA after correcting for baseline value, age, and gender. Missing data were imputed using nonresponder imputation for the ASAS treatment response criteria and using modified baseline observation carried forward for the outcomes at week 16. Numbers shown are LSM improvements from baseline. Fold difference = [(ASAS40 achieved/ASAS20 not achieved) − 1]. ANCOVA analysis of covariance, ASAS Assessment of Spondyloarthritis International Society, bDMARD biologic disease-modifying antirheumatic drug, JSEQ Jenkins Sleep Evaluation Questionnaire, LSM least-squares mean, n, number of non-missing observations, NRS Numeric Rating Scale, SF-36 PCS Medical Outcomes Study 36-Item Short-Form Health Survey Physical Component Summary, TNFi tumor necrosis factor inhibitor