Abstract
Objective To assess the effect of bimekizumab on pain, morning stiffness, and fatigue in patients with nonradiographic and radiographic axial spondyloarthritis (axSpA) in the phase III BE MOBILE studies (ClinicalTrials.gov: NCT03928704 and NCT03928743).
Methods Patients were randomized to bimekizumab 160 mg or placebo every 4 weeks; and all patients received bimekizumab from week 16. Patients reported spinal pain, peripheral pain, morning stiffness, and fatigue to week 52. Total and nocturnal spinal pain were each assessed on a 0-10 numerical rating scale (NRS). Individual Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) items (0-10–point NRS) assessed peripheral arthritis pain (question [Q] 3), enthesitis pain/discomfort (Q4), morning stiffness (mean of Q5 and Q6), and fatigue (Q1). Functional Assessment of Chronic Illness Therapy Fatigue subscale score (FACIT-Fatigue) is also reported.
Results At week 16, bimekizumab-treated patients reported lower mean nocturnal spinal pain, total spinal pain, and BASDAI scores (nominal except for nocturnal spinal pain; all P ≤ 0.001), as well as higher FACIT-Fatigue scores (nominal P < 0.05) vs placebo, indicating improved symptom levels. Improvements continued to week 52 in continuous bimekizumab-treated patients and in placebo-bimekizumab switchers. A higher proportion of bimekizumab- vs placebo-randomized patients achieved increasingly stringent thresholds for low spinal and peripheral pain at week 16; this was sustained or improved at week 52. Results were similar for morning stiffness and fatigue. At week 52, over half of patients were considered FACIT-Fatigue responders (≥ 8-point increase in score).
Conclusion Bimekizumab treatment led to rapid improvements in levels of pain and morning stiffness. Substantial improvements were seen in all domains across the full disease spectrum of axSpA and continued to week 52.
Axial spondyloarthritis (axSpA) is a chronic immune-mediated inflammatory disease. The full disease spectrum of axSpA includes axSpA with no radiographic evidence of definite structural damage to the sacroiliac joints, known as nonradiographic (nr)-axSpA, and radiographic (r)-axSpA (ie, ankylosing spondylitis [AS]), defined according to modified New York (mNY) criteria.1 Patients with nr-axSpA and r-axSpA share a similar clinical presentation and disease burden.2,3 Approximately one-third of patients with axSpA experience peripheral manifestations, such as peripheral arthritis and enthesitis.2,4
Pain, morning stiffness, and fatigue are major contributors to axSpA disease burden, described by patients as the features most commonly affecting their health-related quality of life (HRQOL).3,5,6 Relief or improved control of these symptoms is often a treatment goal for patients whose aim is to resume their normal daily activities as much as possible. In a previous Delphi survey, patients considered pain to be the most important domain to measure in clinical trials investigating axSpA treatments, whereas axSpA experts across healthcare, research, pharmaceutical, and regulatory fields were more focused on disease activity (composite measures).7 Stiffness and fatigue were also identified by patients as important targets for treatment.7 These 3 domains can have exacerbating effects on each other, and a recent study highlighted that reduced back pain and morning stiffness could lead to alleviation of fatigue in patients with axSpA.8
In addition to exacerbating effects from stiffness and fatigue, pain can be difficult to manage in patients with axSpA due to its different mechanisms and manifestations. Common comorbidities, such as fibromyalgia or osteoarthritic changes, may contribute to axSpA-related pain.9 Pain hypersensitivity caused by central sensitization has also been proposed as a cause of increased pain beyond the primary area of tissue injury in various rheumatological conditions, which can vary substantially between individuals.10
Although conventional therapies such as nonsteroidal antiinflammatory drugs (NSAIDs) have demonstrated efficacy in treating pain and improving function (as per the Bath Ankylosing Spondylitis Functional Index), they may be less effective at controlling fatigue in patients with AS.11 Residual fatigue has also been reported among those treated with tumor necrosis factor inhibitors (TNFi), despite improvements in disease activity.12
Bimekizumab is a humanized monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F, in addition to IL-17A. IL-17A and IL-17F are key mediators of inflammation that have been implicated in the pathogenesis of axSpA.13,14 In the phase III studies BE MOBILE 1 and 2, bimekizumab demonstrated sustained efficacy and was well tolerated up to 52 weeks in patients with nr-axSpA and r-axSpA.15 In both studies, a greater proportion of bimekizumab-treated patients achieved the primary (Assessment of Spondyloarthritis International Society [ASAS] ≥ 40% improvement) and secondary (Axial Spondyloarthritis Disease Activity Score [ASDAS]) endpoints for disease activity at week 16 than those treated with placebo.15,16
To further explore the effect of bimekizumab, beyond disease activity, on controlling key symptom domains that have been identified as important to patients, we report pain, morning stiffness, and fatigue levels in patients across the full disease spectrum of axSpA during BE MOBILE 1 and 2.
METHODS
Study design and patients. The study design, including randomization methods and inclusion criteria for the parallel studies BE MOBILE 1 (ClinicalTrials.gov: NCT03928704) and 2 (NCT03928743) have been reported previously.16 Each study had a 16-week double-blind treatment period, in which patients were randomized 1:1 (BE MOBILE 1) or 2:1 (BE MOBILE 2) to subcutaneous bimekizumab 160 mg or placebo every 4 weeks (Q4W), followed by a 36-week maintenance period. Placebo-randomized patients switched to bimekizumab 160 mg Q4W from week 16 onwards (Supplementary Figure S1, available with the online version of this article).
In BE MOBILE 1, patients were clinically diagnosed with axSpA and fulfilled ASAS classification criteria,17 without radiographic sacroiliitis (nr-axSpA). Patients were also required to have objective inflammation (pelvis magnetic resonance imaging scan showing active sacroiliitis and/or elevated C-reactive protein ≥ 6.0 mg/L). In BE MOBILE 2, patients had clinically diagnosed axSpA and met mNY criteria (r-axSpA). All patients in BE MOBILE 2 also fulfilled the ASAS classification criteria.
Included patients were either biologic disease-modifying antirheumatic drug (bDMARD)-naïve or had no bDMARD use within at least 12 weeks prior to baseline. Patients with prior history of bDMARD treatment were excluded if they had received > 1 TNFi, > 2 non-TNFi bDMARDs, or any IL-17i.16 If a patient had received 1 prior TNFi, they must have been intolerant or experienced an inadequate response to previous treatment given at an approved dose for ≥ 12 weeks.16
Ethics approval statement. Both BE MOBILE studies were conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Guidance for Good Clinical Practice. Ethical approvals were obtained from the relevant institutional review boards or independent ethics committees at participating sites (full list provided in Supplementary Table S1, available with the online version of this article). All patients provided written informed consent in accordance with local requirements.
Outcomes. The predefined primary and secondary endpoints for BE MOBILE 1 and 2 have been reported previously.16 In the present analysis, mean scores and change from baseline are presented over 52 weeks for instruments assessing the following domains: pain (total and nocturnal spinal pain, peripheral arthritis pain, and enthesitis pain/discomfort), morning stiffness, and fatigue.
Total and nocturnal spinal pain were each scored by patients on a numerical rating scale (NRS) of 0-10, with higher scores indicating greater pain. Joint pain and swelling (ie, peripheral arthritis pain) and areas of localized tenderness (a proxy for pain/discomfort caused by enthesitis) were assessed using Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) question (Q) 3 and Q4, respectively. Morning stiffness was evaluated using the mean of BASDAI Q5 (morning stiffness duration) and Q6 (morning stiffness severity) scores. BASDAI items were rated using a 0-10–point NRS, with higher scores indicating greater symptom severity. Spinal pain and BASDAI scores were reported at baseline and weeks 1, 2, 4, 8, 12, 16, 24, 36, and 52.
Fatigue was assessed by BASDAI Q1 and the Functional Assessment of Chronic Illness Therapy Fatigue subscale (FACIT-Fatigue), which consists of 13 items scored from 0 (not at all) to 4 (very much), with a total score ranging from 0-52; higher FACIT-Fatigue scores indicate lower burden of fatigue. FACIT-Fatigue scores were reported at baseline and weeks 4, 16, 24, 36, and 52.
The proportion of patients achieving increasingly stringent score thresholds (≤ 4 to 0) for total and nocturnal spinal pain and individual BASDAI items are reported based on the BE MOBILE 1 and 2 study inclusion criteria of back pain ≥ 4, according to BASDAI Q2, and 0, corresponding with an absence of symptoms or complete resolution of spinal pain. Patients achieving scores of ≤ 3 and 0 are highlighted in the results.
The proportion of patients achieving a meaningful improvement in fatigue (FACIT-Fatigue responders) is also reported, defined as an ≥ 8-point increase from baseline among patients who could achieve such an improvement (ie, those with a baseline score of ≤ 44 out of 52), as proposed by a recently published thorough psychometric assessment of FACIT-Fatigue in patients with axSpA.18 In addition, the proportions of patients with FACIT-Fatigue scores in each of the following severity bands to week 52 are reported: none or minimal (> 40), mild (> 30 to ≤ 40), moderate (> 21 to ≤ 30), and severe (≤ 21).18
Statistical analysis. The statistical analyses used in BE MOBILE 1 and 2 have been described previously.16 Analyses were performed on the randomized set. Missing data were imputed using multiple imputation for mean scores over time and change from baseline, and as nonresponse for dichotomous analyses (patients achieving score thresholds or FACIT-Fatigue responders). The proportions of patients with scores in each FACIT-Fatigue severity band over time are reported as observed case.
Least square mean differences between treatment arms and P values were calculated at week 16 using an analysis of covariance model for change from baseline in pain (total and nocturnal spinal pain score, BASDAI Q3, and BASDAI Q4), morning stiffness (mean of BASDAI Q5 and Q6), and fatigue (BASDAI Q1 and FACIT-Fatigue scores). Except for nocturnal spinal pain, which was a key secondary endpoint of both BE MOBILE trials at week 16, all P values reported are considered nominal and are not controlled for multiplicity.15,16
RESULTS
Patient disposition and baseline characteristics. Overall, 220/254 (86.6%) patients with nr-axSpA and 298/332 (89.8%) with r-axSpA completed treatment to week 52 (Supplementary Figure S1, available with the online version of this article). In each study, baseline demographics and disease characteristics were similar between treatment arms, although the percentage of patients with prior TNFi exposure was slightly lower for patients with nr-axSpA randomized to bimekizumab compared with placebo (Table).
Patient demographics and baseline characteristics.
Pain.
• Spinal pain. Across both bimekizumab and placebo-randomized patients with nr-axSpA and r-axSpA, mean total and nocturnal spinal pain scores at baseline were between 7.1-7.3 and 6.6-6.9 (NRS range 0-10), respectively (Table).
For both total and nocturnal spinal pain, separation of bimekizumab-treated patients from those receiving a placebo was visible from week 4 of BE MOBILE 1 and 2 (Figure 1). At week 16, patients receiving bimekizumab vs placebo had lower mean total spinal pain (nr-axSpA: 4.0 [95% CI 3.5-4.4] vs 5.5 [95% CI 5.0-5.9]; r-axSpA: 3.8 [95% CI 3.5-4.1] vs 5.3 [95% CI 4.8-5.7]) and nocturnal spinal pain scores (nr-axSpA: 3.3 [95% CI 2.8-3.8] vs 5.1 [95% CI 4.6-5.5]; r-axSpA: 3.3 [95% CI 3.0-3.6] vs 4.9 [95% CI 4.4-5.4]), corresponding to a greater change from baseline with bimekizumab vs placebo (nominal P < 0.001 for total spinal pain and P < 0.001 for nocturnal spinal pain; Supplementary Figure S2, available with the online version of this article).
Absolute mean and change from baseline in (A) total spinal pain and (B) nocturnal spinal pain to week 52 (MI). Randomized set. Error bars indicate 95% CI. a P values were calculated at week 16 using an analysis of covariance model for change from baseline. P values for nocturnal spinal pain were calculated using reference-based MI (in which the MI model was based on data from the placebo group) and were controlled for multiplicity; P values for total spinal pain are considered nominal P values and should not be used as an indication of statistical significance. BKZ: bimekizumab; BL: baseline; CfB: change from baseline; MI: multiple imputation; nr-axSpA: nonradiographic axial spondyloarthritis; PBO: placebo; Q: question; Q4W: every 4 weeks; r-axSpA: radiographic axial spondyloarthritis.
Mean spinal pain scores reported by patients who switched to bimekizumab at week 16 (placebo-bimekizumab switchers) approached those of continuous bimekizumab-treated patients by week 24 (Figure 1). Scores remained comparable between treatment arms to week 52 for total and nocturnal spinal pain (Figure 1).
The proportion of patients with nr-axSpA or r-axSpA achieving increasingly stringent thresholds for low total and nocturnal spinal pain increased over time with bimekizumab treatment (Figure 2; Supplementary Figure S3, available with the online version of this article). For example, at week 16 (Supplementary Figure S3), the proportion of patients achieving total spinal pain score ≤ 3 with bimekizumab vs placebo was 47.7% vs 27.8% (nr-axSpA) and 46.2% vs 25.2% (r-axSpA), whereas the proportion achieving score = 0 at week 16 was 7.8% vs 1.6% (nr-axSpA) and 5.9% vs 2.7% (r-axSpA). Similar differences between treatment groups were seen for patients achieving nocturnal spinal pain score ≤ 3 (nr-axSpA: 59.4% vs 31.7%; r-axSpA: 52.9% vs 30.6%) and 0 (nr-axSpA: 17.2% vs 4%; r-axSpA: 14.5% vs 5.4%).
Proportion of patients achieving increasingly stringent thresholds for (A) total spinal pain and (B) nocturnal spinal pain at week 52 (NRI). Randomized set. BKZ: bimekizumab; nr-axSpA: nonradiographic axial spondyloarthritis; NRI: nonresponder imputation; PBO: placebo; Q4W: every 4 weeks; r-axSpA: radiographic axial spondyloarthritis.
By week 52, over half of patients across the full disease spectrum of axSpA achieved total or nocturnal spinal pain scores ≤ 3, regardless of treatment arm (Figure 3). Achievement of complete resolution was also comparable between treatment arms at week 52.
Absolute mean and change from baseline in (A) morning stiffness (mean of BASDAI Q5 and Q6) and (B) fatigue (BASDAI Q1) to week 52 (MI). Randomized set. Error bars indicate 95% CI. a P values were calculated at week 16 using an analysis of covariance model for change from baseline. All P values reported here are considered nominal P values and should not be used as an indication of statistical significance. BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; BKZ: bimekizumab; BL: baseline; CfB: change from baseline; MI: multiple imputation; nr-axSpA: nonradiographic axial spondyloarthritis; PBO: placebo; Q: question; Q4W: every 4 weeks; r-axSpA: radiographic axial spondyloarthritis.
• Peripheral pain. Mean peripheral arthritis pain (BASDAI Q3) and enthesitis pain/discomfort (BASDAI Q4) scores were between 5.7 and 6.7 at baseline (Table).
At week 16, patients with nr-axSpA receiving bimekizumab vs placebo had lower mean peripheral arthritis pain (3.7 [95% CI 3.2–4.2] vs 4.9 [95% CI 4.4–5.4]) and enthesitis pain/discomfort scores (3.9 [95% CI 3.4–4.4] vs 4.8 [95% CI 4.4–5.3]), with nominal P < 0.001 for change from baseline in both scores. Results were similar for r-axSpA (Supplementary Figure S2, Supplementary Figure S4, available with the online version of this article).
After week 16, placebo-bimekizumab switchers rapidly approached similarly low levels of peripheral pain compared to continuous bimekizumab-treated patients; low levels were sustained in both treatment arms to week 52 (Supplementary Figure S4, available with the online version of this article).
These trends were reflected in the proportion of patients achieving increasingly stringent score thresholds for peripheral arthritis pain (Supplementary Figure S5, available with the online version of this article) and enthesitis pain/discomfort (Supplementary Figure S6). At week 16, the proportion of patients receiving bimekizumab vs placebo achieving peripheral arthritis pain score ≤ 3 was 52.3% vs 31% (nr-axSpA) and 54.8% vs 41.4% (r-axSpA), whereas the proportion achieving score = 0 was 10.9% vs 7.1% (nr-axSpA) and 13.6% vs 10.8% (r-axSpA). Similar differences between treatment groups were seen for patients achieving enthesitis pain/discomfort score ≤ 3 (nr-axSpA: 47.7% vs 32.5%; r-axSpA: 57% vs 39.6%) and 0 (nr-axSpA: 10.2% vs 2.4%; r-axSpA: 13.1% vs 8.1%).
Over half of placebo-bimekizumab switchers and continuous bimekizumab-treated patients achieved peripheral arthritis pain or enthesitis pain/discomfort scores ≤ 3 at week 52, across the full disease spectrum of axSpA (Supplementary Figure S5 and Supplementary Figure S6, available with the online version of this article). Achievement of complete resolution was also comparable between treatment arms at week 52.
Morning stiffness. Overall mean morning stiffness scores (the mean of scores for BASDAI Q5 and Q6) were between 6.7 and 7.0 at baseline (Table).
Separation of bimekizumab-treated patients from placebo was observed from week 4 of BE MOBILE 1 and 2 (Figure 3A). At week 16, patients receiving bimekizumab vs placebo reported a lower mean morning stiffness score (nr-axSpA: 3.3 [95% CI 2.9-3.8] vs 5.0 [95% CI 4.6-5.5]; r-axSpA: 3.5 [95% CI 3.2-3.8] vs 4.6 [95% CI 4.2-5.1]). Nominal P < 0.001 for change from baseline (Figure 3A; Supplementary Figure S2, available with the online version of this article). Mean morning stiffness score for placebo-bimekizumab switchers rapidly approached that of continuous bimekizumab-treated patients after week 16 (Figure 3A); scores remained similar between treatment arms to week 52.
At week 16, the proportion of patients with morning stiffness score ≤ 3 after treatment with bimekizumab vs placebo was 51.6% vs 26.2% (nr-axSpA) and 49.8% vs 30.6% (r-axSpA; Supplementary Figure S7A, available with the online version of this article), whereas 15.6% vs 3.2% (nr-axSpA) and 6.8% vs 2.7% (r-axSpA) achieved complete resolution (score 0). By week 52, over half of patients had morning stiffness score ≤ 3 regardless of treatment arm; the achievement of complete resolution was also comparable between treatment arms (Figure 4A).
Proportion of patients achieving increasingly stringent thresholds for (A) morning stiffness (mean of BASDAI Q5 and Q6) and (B) fatigue (BASDAI Q1) at week 52 (NRI). Randomized set. BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; BKZ: bimekizumab; nr-axSpA: nonradiographic axial spondyloarthritis; NRI: nonresponder imputation; PBO: placebo; Q: question; Q4W: every 4 weeks; r-axSpA: radiographic axial spondyloarthritis.
Fatigue.
• BASDAI Q1. Mean fatigue (BASDAI Q1) scores were between 6.4 and 6.7 at baseline (Table).
At week 16, mean fatigue scores for patients with bimekizumab vs placebo were 4.1 (95% CI 3.6-4.5) vs 5.4 (95% CI 5.0-5.8) for nr-axSpA, and 3.9 (95% CI 3.6-4.2) vs 4.7 (95% CI 4.3-5.1) for r-axSpA (Figure 3B). Nominal P < 0.001 for change from baseline (Supplementary Figure S2, available with the online version of this article).
Placebo-bimekizumab switchers rapidly approached similar levels of fatigue compared to continuous bimekizumab-treated patients between week 16 and week 24 (Figure 3B). Scores remained similar between treatment arms up to week 52.
At week 16, the proportion of patients achieving fatigue score ≤ 3 with bimekizumab vs placebo was 45.3% vs 23.8% (nr-axSpA) and 46.6% vs 33.3% (r-axSpA; Supplementary Figure S7B, available with the online version of this article). Approximately half of patients achieved score ≤ 3 at week 52, regardless of treatment arm (Figure 4B).
• FACIT-Fatigue. Baseline FACIT-Fatigue scores are reported in the Table. Patients were relatively evenly distributed across FACIT-Fatigue severity bands at baseline, with around half reporting moderate-to-severe fatigue18; a slightly higher proportion of patients with r-axSpA randomized to bimekizumab vs placebo had severe fatigue at baseline (Figure 5A).
Proportion of patients (A) in each FACIT-Fatigue severity band to week 52 (OC); and (B) achieving an ≥ 8-point improvement in FACIT-Fatigue score from baseline (FACIT-Fatigue responders; NRI). Randomized set. a Patients with baseline FACIT-Fatigue score ≤ 44 only; b P values were calculated at week 16 using an analysis of covariance model for change from baseline. P values reported here are considered nominal P values and should not be used as an indication of statistical significance. BKZ: bimekizumab; FACIT-Fatigue: Functional Assessment of Chronic Illness Therapy Fatigue scale; nr-axSpA: nonradiographic axial spondyloarthritis; NRI: nonresponder imputation; OC: observed case; PBO: placebo; Q4W: every 4 weeks; r-axSpA: radiographic axial spondyloarthritis.
A greater mean FACIT-Fatigue score, indicating less severe fatigue, was reported at week 16 with bimekizumab vs placebo (Supplementary Figure S8, available with the online version of this article) in patients with both nr-axSpA (38.0 [95% CI 36.2-39.8] vs 34.6 [95% CI 32.6-36.5]) and r-axSpA (39.0 [95% CI 37.7-40.3] vs 38.1 [95% CI 36.3-39.8]). Nominal P values for change from baseline were P < 0.001 and P = 0.02 for patients with nr-axSpA and r-axSpA, respectively (Supplementary Figure S2). After week 16, mean FACIT-Fatigue score for placebo-bimekizumab switchers rapidly approached or surpassed that of continuous bimekizumab-treated patients (Supplementary Figure S8); mean scores remained similar between treatment arms to week 52.
A greater proportion of patients achieved an ≥ 8-point improvement in score by week 16 with bimekizumab vs placebo (nr-axSpA: 50.8% vs 29.8%, nominal P = 0.001; r-axSpA: 53.4% vs 37.4%, nominal P = 0.009; Figure 5B). By week 52, over half of placebo-bimekizumab switchers with nr-axSpA and r-axSpA also reached this threshold.
From baseline to week 16, the proportion of patients reporting no or minimal fatigue more than doubled in patients randomized to bimekizumab (nr-axSpA: 18.8% to 44.9%; r-axSpA: 22.6% to 54.3%). The difference in patients randomized to placebo was 21.4% to 35.6% (nr-axSpA) and 28.8% to 49.1% (r-axSpA). By week 52, the majority of patients across indications and treatment arms reported no or minimal fatigue (Figure 5A).
DISCUSSION
In this analysis of results from 2 phase III studies (BE MOBILE 1 and 2), inhibition of IL-17A and IL-17F with bimekizumab led to rapid, substantial, and sustained improvements in levels of spinal and peripheral pain and morning stiffness to week 52 across the full disease spectrum of axSpA. Substantial improvements were also seen in levels of fatigue (BASDAI Q1 and FACIT-Fatigue) with bimekizumab, although from our clinical experience, fatigue tends to have a more delayed response to treatment in practice. This analysis expands on previous publications demonstrating the efficacy of bimekizumab treatment on disease activity and objective measures of inflammation in BE MOBILE 1 and 2.15,16
Inflammatory mediators can directly or indirectly influence pain in axSpA, and morning stiffness has been shown to result from musculoskeletal inflammation.19,20 The pathology of fatigue is less understood; however, inflammation is likely a contributing factor.19 Therefore, patients’ experience of pain, stiffness, and fatigue is important to consider when monitoring disease improvements.
There is often a disparity in the priorities of patients and their physicians when it comes to managing axSpA, with rheumatologists and other healthcare professionals placing a higher importance on disease activity (composite measures), whereas patients identified pain, stiffness, and fatigue as important targets for treatment.7 Due to this difference in priorities, some physicians may consider a patient’s disease to be stable, improving, or in remission when the patient may continue to report high levels of symptoms such as pain or fatigue.19
When assessing total spinal pain, by week 16, approximately 45% of the patients receiving bimekizumab (vs ~25% with placebo) no longer met the threshold for study inclusion (spinal pain score ≥ 4); this percentage increased to approximately 50% to 60% at week 52. By the end of the study, around 10% to 20% of patients reported complete absence (score = 0) of each of the domains of spinal pain, peripheral pain, and morning stiffness.
Similarly, both mean score and the proportion of patients achieving increasingly stringent thresholds for fatigue (BASDAI Q1) indicated lower levels of fatigue in patients receiving bimekizumab at week 16 compared with placebo.
An ≥ 8-point improvement in FACIT-Fatigue score has recently been proposed to identify FACIT-Fatigue responders.18 Over half of patients with nr-axSpA and r-axSpA were considered FACIT-Fatigue responders by the end of the BE MOBILE studies, showing a consistent response following bimekizumab treatment in patients across the full axSpA disease spectrum. Although approximately 16% to 25% of patients had severe fatigue at baseline, < 6% of patients had severe fatigue at week 52 and the majority were considered to have no or minimal fatigue.
There continues to be an unmet need for axSpA treatments that effectively manage the most burdensome symptoms for patients, such as residual pain and fatigue.21 NSAIDs can be effective for managing pain, but less effective at controlling fatigue.11 Even in treatments that were shown to alleviate fatigue, severe fatigue persisted in some patients after treatment.12,22 Additionally, fatigue can be affected by poor sleep quality and depression, which are often experienced by patients with axSpA.5,23 Sleep function in patients in BE MOBILE 1 and 2 has been evaluated in a separate publication.24 Further research is required to investigate the relationships between the potential effect of bimekizumab on fatigue, sleep function, and depression.
Even without complete resolution, sustained control of axSpA symptoms could lead to the increased ability of patients to perform their daily activities and improved HRQOL. Recent studies have demonstrated how pain, morning stiffness, and fatigue interact with and exacerbate each other, which may contribute to the difficulty of achieving complete resolution in any single domain. The Janus kinase inhibitor tofacitinib was shown to alleviate fatigue indirectly, through combined effects on morning stiffness and pain; however, it did not meaningfully affect fatigue directly or through other indirect pathways.8 Despite the strong relationship between pain and fatigue,25 it has also been reported that fatigue is not reliably controlled by pain management alone.19
Here we demonstrated consistent, sustained control of pain, morning stiffness, and fatigue in patients across the full axSpA disease spectrum, although further investigation is warranted to understand the interactions between these symptoms and bimekizumab treatment. The BE MOBILE studies also did not explore other causes of pain in axSpA, such as comorbidities and central sensitization, which can make it difficult for patients to achieve complete pain resolution in clinical practice.9,10
A strength of this analysis is that it evaluated outcomes over 1 year from 2 parallel studies with similar designs and a crossover screening approach, enabling data to be presented across the full disease spectrum of axSpA. Baseline demographics and disease characteristics were generally consistent across treatment groups and studies and were typical of the general nr-axSpA and r-axSpA populations.26
However, as in all clinical trials, the results may not be generalizable to all patients with axSpA due to the eligibility criteria. Real-world evidence is needed to fully evaluate the effect of bimekizumab on axSpA symptoms and their effect on patients’ lives.
Another limitation is the absence of established thresholds for meaningful within-patient change in spinal pain score or BASDAI items. The proposed thresholds were intended to represent reductions that would be meaningful to patients, with a focus on those achieving scores below the back pain score threshold for inclusion in BE MOBILE 1 and 2 (≥ 4 according to BASDAI Q2), and 0, corresponding with an absence of symptoms.
Patient responses may have been affected by the coronavirus disease 2019 (COVID-19) pandemic, possibly due to increased stress or social isolation,27,28 or reduced access or ability to exercise to alleviate symptoms.29-31 However, no indication of negative effects on disease activity and HRQOL during this period was found in patients with AS in the open-label extension of the phase IIb BE AGILE study (ClinicalTrials.gov: NCT02963506).32 Overall, despite possible behavioral changes related to the pandemic, these analyses were able to detect improved outcomes among patients with nr-axSpA and r-axSpA who were treated with bimekizumab.
In summary, inhibition of IL-17A and IL-17F with bimekizumab resulted in rapid, substantial improvements compared with placebo in levels of pain, morning stiffness, and fatigue across the full disease spectrum of axSpA, which were sustained or which continued to improve to week 52. These findings, alongside previously published results,15,16 support the benefit of bimekizumab for managing clinical symptoms that are central to the patient experience and have significant impact on their daily lives.
ACKNOWLEDGMENT
The authors thank the patients and their caregivers, in addition to all the investigators and their teams who contributed to these studies. The authors also acknowledge Natasha de Peyrecave, DPhil, UCB, Brussels, Belgium, for substantial contributions to this publication; Celia Menckeberg, PhD, UCB, Breda, the Netherlands, for publication coordination and editorial assistance; and Tara Groves, BSc, Costello Medical, Cambridge, UK, and Kaity McCafferty Layte, BSc, Costello Medical, London, UK, for medical writing and editorial assistance.
Footnotes
This article was based on the original studies, BE MOBILE 1 (NCT03928704) and BE MOBILE 2 (NCT03928743), which were sponsored by UCB. Support for third party writing assistance for this article was funded by UCB in accordance with Good Publication Practice 2022 guidelines (https://www.ismpp.org/gpp-2022). HMO is supported by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (LBRC). The views expressed here are those of the authors and not necessarily those of the UK National Health Service (NHS), the NIHR, or the UK Department of Health.
VNC has served on speakers’ bureaus for AbbVie, Eli Lilly, Fresenius Kabi, Janssen, MSD, Novartis, Pfizer, and UCB; has been a consultant for AbbVie, Eli Lilly, Galapagos, MoonLake, MSD, Novartis, Pfizer, and UCB; and has received grant/research support from AbbVie and Novartis. MR has served on speakers’ bureaus for AbbVie, Boehringer Ingelheim, Chugai, Eli Lilly, Janssen, Novartis, Pfizer, and UCB; and has been a consultant for AbbVie, Eli Lilly, Novartis, and UCB. M. Dubreuil has received consulting fees from Amgen and UCB; and an educational grant from Pfizer, paid to institution. MM has received consultancy fees from AbbVie, BMS, Eli Lilly, Novartis, Pfizer, and UCB; and research grants from AbbVie, BMS, and UCB. HMO has received speaking honoraria and/or consultancy fees from AbbVie, Amgen, Biogen, Eli Lilly, Janssen, MoonLake, Novartis, Pfizer, Takeda, and UCB; and research grants from Janssen, Novartis, Pfizer, and UCB. PJM has served on the speakers’ bureau for AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer, and UCB; has received consultancy fees from AbbVie, Acelyrin, Aclaris, Amgen, BMS, Boehringer Ingelheim, Eli Lilly, Galapagos, Gilead, GSK, Janssen, MoonLake, Novartis, Pfizer, Sun Pharma, Takeda, UCB, and Ventyx; and received research grants from AbbVie, Acelyrin, Amgen, BMS, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Sun Pharma, and UCB. JAW has served as a consultant for and/or received grant support from AbbVie, Amgen, Eli Lilly, Janssen, Merck, Novartis, Pfizer, and UCB. M. Dougados has received consultancy fees, speaker fees, and/or research grants from AbbVie, Eli Lilly, Merck, Novartis, Pfizer, and UCB. CdlL has served as a consultant for UCB. CF and VT are employees and shareholders of UCB. UM and TV are employees of UCB. AD has been a speaker for Eli Lilly, Janssen, Novartis, Pfizer, and UCB; has been a consultant for BMS, Eli Lilly, Janssen, MoonLake, Novartis, Pfizer, and UCB; and has received grant/research support from BMS, Celgene, Eli Lilly, Novartis, Pfizer, and UCB.
- Accepted for publication August 16, 2024.
- Copyright © 2024 by the Journal of Rheumatology
This is an Open Access article, which permits use, distribution, and reproduction, without modification, provided the original article is correctly cited and is not used for commercial purposes.
REFERENCES
DATA AVAILABILITY
Underlying data from this manuscript may be requested by qualified researchers 6 months after product approval in the US and/or Europe, or global development is discontinued, and 18 months after study completion. Investigators may request access to anonymized individual patient-level data and redacted trial documents, which may include the following: analysis-ready datasets, trial protocols, annotated case report forms, statistical analysis plans, dataset specifications, and clinical study reports. Prior to use of the data, proposals need to be approved by an independent review panel at www.vivli.org and a signed data sharing agreement will need to be executed. All documents are available in English only, for a prespecified time, typically 12 months, on a password-protected portal.
PLAIN LANGUAGE SUMMARY
A plain language summary of this article (text or graphical) is included as online supplementary material.
SUPPLEMENTARY DATA
Supplementary material accompanies the online version of this article.
