Ligelizumab improves sleep interference and disease burden in patients with chronic spontaneous urticaria

Abstract Background Chronic spontaneous urticaria (CSU) negatively impacts patients' sleep, thereby reducing health‐related quality of life (HRQoL). Half of patients with inadequately controlled CSU report sleep interference often or every night, which can lead to depression, anxiety, social, and work‐related problems. Methods This randomized, double‐blind, placebo‐controlled Phase 2b core study (NCT02477332) included adult patients ≥18 years with moderate to severe CSU inadequately controlled with H1‐antihistamines. The current analysis includes patients randomized to receive ligelizumab 72 or 240 mg, omalizumab 300 mg or placebo every 4 weeks (q4w) for five injections over 20 weeks with treatment‐free follow‐up for 24 weeks. Patients could enter the open‐label extension study (NCT02649218) from Week 32 onwards if their weekly urticaria activity score was ≥12, which included an open‐label treatment (52 weeks of ligelizumab 240 mg q4w) and a 48‐week post‐treatment follow‐up. Weekly Sleep Interference Scores (SIS7, range 0 [no interference]–21 [substantial interference]), Weekly Activity Interference Score (AIS7), Dermatology Life Quality Index (DLQI) scores, and Overall Work Impairment were assessed. Results Mean baseline SIS7 scores were balanced between the treatment arms for ligelizumab 72 mg (n = 84) and 240 mg (n = 85), omalizumab 300 mg (n = 85), and placebo (n = 43). By Week 12, patients experienced large improvements in sleep interference, with least square mean (standard error) changes from baseline (CFB) in SIS7 of −7.84 (0.58), −7.55 (0.61), −6.98 (0.60), and −5.85 (0.81), respectively. By Week 12, CFB in AIS7 were −8.25 (0.57), −8.25 (0.59), −7.30 (0.60), and −5.62 (0.79), DLQI scores were −9.79 (0.77), −9.93 (0.81), −8.35 (0.79), and −6.99 (1.11), and Overall Work Impairment scores were −28.96 (3.73), −30.76 (3.71), −25.74 (3.91), and −20.13 (5.10) for ligelizumab 72 and 240 mg, omalizumab 300 mg and placebo, respectively. Improvements in each patient‐reported outcome were sustained with ligelizumab 240 mg treatment during the extension study. Conclusions Ligelizumab showed effective and sustained responses in managing sleep interference in patients with CSU, and numerically higher responses than with omalizumab and placebo. Treating the symptoms of CSU with ligelizumab improved disease burden, HRQoL, and markedly improved sleep quality.

placebo, respectively. Improvements in each patient-reported outcome were sustained with ligelizumab 240 mg treatment during the extension study.

Conclusions:
Ligelizumab showed effective and sustained responses in managing sleep interference in patients with CSU, and numerically higher responses than with omalizumab and placebo. Treating the symptoms of CSU with ligelizumab improved disease burden, HRQoL, and markedly improved sleep quality.

| BACKGROUND
The core manifestations of chronic spontaneous urticaria (CSU) present on the skin, however, its negative impact reaches far beyond, affecting patient's health-related quality of life (HRQoL). [1][2][3][4][5] Significant sleep interference is associated with CSU, which occurs at almost double the rate of that seen in age-and sex-matched controls without CSU (58.0% vs. 32.7%, p < 0.001), 6 and is also linked to CSU disease activity, 7 being worse during urticaria flare-ups. 8 CSU disease state has been shown to have a direct and significant impact on sleep interference scores. 7 An Internet survey of European patients with chronic urticaria (CU) revealed that, importantly, respondents were most commonly bothered by symptoms in the evening (34%) and at night (23%). The frequency of sleep affected was three nights per week, on average, and sleep disturbances from CU were inadequately addressed in 48% of patients, meaning it is a standard part of the condition. 9 When compared with other dermatologic conditions, a significantly higher proportion of CU patients reported sleep difficulties in the past 12 months versus patients with any severity of psoriasis (40.8% for mild, 47.2% for moderate/severe psoriasis, and 55.7% for CU patients, p < 0.001). 10 In patients with CSU, sleep is understudied, and sleep problems are generally not well understood. Possible contributing factors include difficulty in falling asleep and sleeping through the night because of the itch associated with hives. 11,12 Angioedema, which is present in up to 70% of patients with CSU, may also affect sleep. 13 Wakefulness promoted by histamine released from mast cells and comorbidities such as sleep apnea 14 may also contribute to sleep interference. It is clear that sleep loss negatively affects performance at work and daily functioning, significantly impacts social lives, and is associated with lower life expectancy. 15 Even transient sleep loss can impair cognitive performance and judgment, and lead to an increased risk of other comorbidities, such as cardiovascular disease. 16 Addressing the problem of sleep could have the potential to impact the overall health and wellbeing of patients with CSU.
Ligelizumab is a next-generation, high-affinity 97% (Novartis data on file) humanized monoclonal anti-IgE antibody that has previously shown dose-dependent and time-dependent suppression of free IgE, the expression of its high affinity receptor, FcεRI, and skin-prick test responses to an allergen, to a greater extent and duration than omalizumab. 17 The interaction of ligelizumab with IgE has been shown to be around 88-fold stronger than the IgE binding of omalizumab. 18 In a randomized, Phase 2b core study (NCT02477332), the main objective was to determine a dose-response relationship for ligelizumab for the complete control of hives (indicated by a weekly hives-severity score of 0) assessed at Week 12. Ligelizumab was compared to omalizumab and placebo in patients with CSU who were inadequately controlled with standard-of-care therapy including H 1 -antihistamines (H 1 -AH). Ligelizumab showed the most effective results by improving urticaria activity, reducing the signs and symptoms of hives, itch, and angioedema. 17 Patients who presented with active disease after 32 weeks could enter an extension study to assess long-term safety (primary endpoint) and long-term efficacy (secondary endpoints). 19 Here, we present a sub-analysis from this Phase 2b core study and the extension study to evaluate sleep, activity interference, dermatology quality of life, and impact on work in patients with CSU treated with ligelizumab and omalizumab versus placebo.

| Study design and patients
The study design has been previously reported in detail. 17 Briefly, in this randomized, double-blind, active-and placebo-controlled Phase 2b study, adult patients with moderate to severe CSU (defined by weekly urticaria activity score [UAS7] ≥16 on a scale from 0 to 42) were randomized in a 2:2:2:1 ratio to receive ligelizumab 72 or 240 mg, or omalizumab 300 mg, or placebo every 4 weeks (q4w) for five injections (see Figure 1 for core Phase 2b and extension study design). Patients also received ligelizumab 24 mg q4w or a single 120-mg dose of ligelizumab, but these doses were out of scope and not included in our current analyses.
The extension study was an open-label, single-arm, long-term safety Phase 2b extension for all patients who completed the Phase 2b core study and had a UAS7 ≥12 at Week 32. 19 The extension study consisted of an open-label treatment period (0-52 weeks of ligelizumab 240 mg q4w for 13 treatment cycles) and a treatment-free follow-up period until Week 100. 19 The treatment-free follow-up period started 4 weeks after the last dose and continued for 48 weeks, with visits every 12 weeks, and assessed safety and longterm treatment outcomes, including sustained remission.
Two additional arms included ligelizumab 24 mg q4w and a single dose of 120 mg (to characterize pharmacokinetics and pharmacodynamics); however, these treatment arms are not reported in the current analysis. In the extension study, 226 patients entered and were treated with ligelizumab 240 mg.

| Assessment of patient-reported outcomes
Each day during the entire study, patients completed the Urticaria Patient Daily Diary (UPDD), including the urticaria activity score (UAS), which assessed itch and hives, sleep interference (recorded every morning), and activity interference (recorded every evening). 20,21 Weekly scores were calculated as follows: UAS7 score ranging from 0 to 42, Weekly Sleep Interference Scores (SIS7), and Weekly Activity Interference Scores (AIS7) both ranging from 0 to 21. 20,21 Higher scores mean higher interference with sleep and activity, respectively.
Patients also recorded DLQI at baseline and every 4 weeks. DLQI has a recall period of 7 days and the total score ranges from 0 to 30 (higher scores reflect worse HRQoL). 22,23 The impact on work due to CSU was assessed using the Work Productivity and Activity Impairment-Chronic Urticaria (WPAI-CU version 2.0) with a 7-day recall period. 24 The six-item WPAI-CU has four subscales, including Absenteeism, Presenteeism, Overall Work Impairment (a composite score of Absenteeism and Presenteeism), and Activity Impairment, expressed as impairment percentage (0%-100%), with higher scores reflecting higher impairment and less productivity.
Wherever available, data from the Phase 2b core study are presented from Week 32; however, some endpoints were not measured at Week 32; therefore, we present data from Week 28 (DLQI and Overall Work Impairment).

| Statistical analysis
In this analysis, we present change from baseline (CFB) data for pa-

| Baseline characteristics from the Phase 2b core and extension studies were well balanced
Of the 382 patients who were randomly assigned to a treatment arm in the core study (including the 24 and 120 mg single ligelizumab), 338 patients (88%) completed the treatment phase of the study and all baseline demographics and clinical characteristics were balanced between the treatment arms (Table 1). 17 In addition, baseline demographics in the core study and for the 226 patients who entered the extension study were similar.

| Many patients with CSU experienced sleep impairment at baseline, some of which was substantial
At baseline of the Phase 2b core study, the mean (standard deviation [SD]) SIS7 scores were balanced between treatment arms:  The weekly itch-severity and hives-severity scores measure the severity of itch and hives, respectively, over a period of 7 days on scales ranging from 0 to 21, with higher scores indicating greater severity. d The weekly urticaria activity score is a composite of the weekly itch-severity and hives-severity scores. Scores range from 0 to 42, with higher scores indicating greater severity. e A positive Chronic Urticaria (CU) Index (scores range from 1 to 50, with scores ≥10 representing a positive result) indicates that the patient has either an autoimmune basis for the urticaria or an alternative histamine-releasing factor that has been associated with greater disease severity than that in patients with a negative CU Index. The 120 mg single-dose arm was chosen to characterize the pharmacokinetics/pharmacodynamics; the ligelizumab 120 and 24 mg arms are not included in the table but are included in the total column.  The improvement in AIS7 was sustained throughout the treatment period of the extension study ( Figure 3B).

| Dermatology Life Quality Index improvement was numerically greater for patients treated with ligelizumab compared with omalizumab and placebo
The LS mean (SE) CFB in DLQI scores in the Phase 2b core study was numerically higher in the ligelizumab treatment arms at both Week 12 and Week 20: at Week 12, it was −9.79 (0.77), −9.93

| Ligelizumab led to numerically greater improvements in Presenteeism and Overall Work Impairment compared with omalizumab and placebo
The LS mean CFB in Presenteeism and Overall Work Impairment was numerically higher in the ligelizumab treatment arms compared to omalizumab 300 mg and placebo (see Table 2 and Figure 5A). and Overall Work Impairment were also experienced by patients in the extension study ( Figure 5B).

| DISCUSSION
The analysis presented herein shows the correlations between CSU and various dimensions of HRQoL such as sleep and activity interference, dermatology-QoL, and impact on work. The results suggest that treating the symptoms of CSU also has beneficial effects on these aspects of life. Treatment with ligelizumab, which improved urticaria activity, was associated with improvements in HRQoL (as reflected in DLQI sores) and sleep, as seen through reduced SIS7 scores. In addition, interference with daily activities    Sleep improvements have also been experienced in patients with CSU after treatment with omalizumab, as shown by the results from three randomized, placebo-controlled trials. 27 Sleep improvements were observed after the first dose of omalizumab, which mirrored the efficacy in disease activity, a positive effect that continued with subsequent doses, and improved throughout treatment. When discontinued, CSU symptoms returned along with rebounding sleep problems. 27 Additionally, improvement in itch was associated with decreases in somnolence and sleep disturbances.
This study was limited by the relatively low number of patients and short trial duration of the core study, although the extension study showed longer-term effects. 19 Ligelizumab is being investigated in an ongoing clinical trial program that includes the Phase 3 PEARL 1 (NCT03580369) and PEARL 2 (NCT03580356) trials, which aim to recruit more than 2000 patients with CSU across 48 countries globally. The complex relationship between patients with CSU and sleep is imperative to study and these studies will help further our understanding and provide invaluable insights.

| CONCLUSIONS
Overall, ligelizumab treatment has benefits beyond relief from urticaria symptoms and can impact HRQoL, highlighting the importance of targeting complete urticaria control. Treating the symptoms of CSU improves urticaria activity and HRQoL, and thereby also has the potential to improve sleep (through decreased interference), 28 which should be confirmed in further Phase 3 studies. Sleep interference is drastically underappreciated as a severe and clinically relevant symptom of CSU. Patient assessments of the effect of therapy on sleep quality should explicitly be included as part of an integrated treatment approach.