Received: 31 August 2021 DOI: 10.1002/clt2.12121 ORIGINAL ARTICLE - - Revised: 27 December 2021 Accepted: 25 January 2022 Ligelizumab improves sleep interference and disease burden in patients with chronic spontaneous urticaria Ana Giménez‐Arnau1 | Marcus Maurer2 | Jonathan Bernstein3 | 4 5 6 Petra Staubach | Nathalie Barbier | Eva Hua | Thomas Severin5 | Yolandi Joubert5 | Reinhold Janocha5 | Maria‐Magdalena Balp5 1 Department of Dermatology, Hospital del Mar, Institut Mar d´Investigacions Mèdiques, Abstract Universitat Autònoma, Barcelona, Spain Background: Chronic spontaneous urticaria (CSU) negatively impacts patients' 2 Department of Dermatology and Allergy, sleep, thereby reducing health‐related quality of life (HRQoL). Half of patients with Dermatological Allergology, Allergie‐Centrum‐ Charité, Charité ‐ Universitätsmedizin Berlin, inadequately controlled CSU report sleep interference often or every night, which Berlin, Germany can lead to depression, anxiety, social, and work‐related problems. 3 Bernstein Allergy Group and Bernstein Clinical Research Center, College of Medicine, Methods: This randomized, double‐blind, placebo‐controlled Phase 2b core study Cincinnati, Ohio, USA (NCT02477332) included adult patients ≥18 years with moderate to severe CSU 4 Department of Dermatology, University inadequately controlled with H1‐antihistamines. The current analysis includes pa- Medical Center Mainz, Mainz, Germany 5 tients randomized to receive ligelizumab 72 or 240 mg, omalizumab 300 mg or Novartis Pharma AG, Basel, Switzerland 6 placebo every 4 weeks (q4w) for five injections over 20 weeks with treatment‐free China Novartis Institutes for Biomedical Research Co. Ltd, Shanghai, China 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 Correspondence Ana Giménez‐Arnau, Department of ≥12, which included an open‐label treatment (52 weeks of ligelizumab 240 mg q4w) Dermatology, Hospital del Mar, Institut Mar and a 48‐week post‐treatment follow‐up. Weekly Sleep Interference Scores (SIS7, d´Investigacions Mèdiques, Universitat range 0 [no interference]–21 [substantial interference]), Weekly Activity Interfer- Autònoma, Hospital del Mar, Passeig Maritim 25,29, 08003 Barcelona, Spain. ence Score (AIS7), Dermatology Life Quality Index (DLQI) scores, and Overall Work Email: agimenezarnau@parcdesalutmar.cat; Impairment were assessed. anamariagimenezarnau@gmail.com Results: Mean baseline SIS7 scores were balanced between the treatment arms for Funding information ligelizumab 72 mg (n = 84) and 240 mg (n = 85), omalizumab 300 mg (n = 85), and Novartis Pharma AG 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 Trial registration: Phase 2b core study (NCT02477332) and the open‐label extension study (NCT02649218). This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, pro- vided the original work is properly cited. © 2022 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology. Clin Transl Allergy. 2022;e12121. wileyonlinelibrary.com/journal/clt2 1 of 11 https://doi.org/10.1002/clt2.12121 2 of 11 - GIMÉNEZ‐ARNAU ET AL. placebo, respectively. Improvements in each patient‐reported outcome were sus- tained 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. KEYWORDS daily functioning, quality of life, sleep interference SCHLÜSSELWÖRTER chronische spontane Urtikaria, Lebensqualität, Schlafstörung, tägliches Funktionieren 1 | BACKGROUND 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 The core manifestations of chronic spontaneous urticaria (CSU) pre- a randomized, Phase 2b core study (NCT02477332), the main objec- sent on the skin, however, its negative impact reaches far beyond, tive was to determine a dose–response relationship for ligelizumab for affecting patient's health‐related quality of life (HRQoL).1–5 Significant the complete control of hives (indicated by a weekly hives‐severity sleep interference is associated with CSU, which occurs at almost score of 0) assessed at Week 12. Ligelizumab was compared to double the rate of that seen in age‐ and sex‐matched controls without omalizumab and placebo in patients with CSU who were inadequately CSU (58.0% vs. 32.7%, p < 0.001),6 and is also linked to CSU disease controlled with standard‐of‐care therapy including H1‐antihistamines activity,7 being worse during urticaria flare‐ups.8 CSU disease state has (H1‐AH). Ligelizumab showed the most effective results by been shown to have a direct and significant impact on sleep interfer- improving urticaria activity, reducing the signs and symptoms of hives, 7 ence scores. An Internet survey of European patients with chronic itch, and angioedema.17 Patients who presented with active disease urticaria (CU) revealed that, importantly, respondents were most after 32 weeks could enter an extension study to assess long‐term commonly bothered by symptoms in the evening (34%) and at night safety (primary endpoint) and long‐term efficacy (secondary (23%). The frequency of sleep affected was three nights per week, on endpoints).19 average, and sleep disturbances from CU were inadequately addressed Here, we present a sub‐analysis from this Phase 2b core study in 48% of patients, meaning it is a standard part of the condition.9 When and the extension study to evaluate sleep, activity interference, compared with other dermatologic conditions, a significantly higher dermatology quality of life, and impact on work in patients with CSU proportion of CU patients reported sleep difficulties in the past treated with ligelizumab and omalizumab versus placebo. 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 2 | METHODS problems are generally not well understood. Possible contributing factors include difficulty in falling asleep and sleeping through the night 2.1 | Study design and patients 11,12 because of the itch associated with hives. Angioedema, which is present in up to 70% of patients with CSU, may also affect sleep.13 The study design has been previously reported in detail.17 Briefly, in Wakefulness promoted by histamine released from mast cells and this randomized, double‐blind, active‐ and placebo‐controlled Phase comorbidities such as sleep apnea14 may also contribute to sleep 2b study, adult patients with moderate to severe CSU (defined by interference. It is clear that sleep loss negatively affects performance weekly urticaria activity score [UAS7] ≥16 on a scale from 0 to 42) at work and daily functioning, significantly impacts social lives, and is were randomized in a 2:2:2:1 ratio to receive ligelizumab 72 or associated with lower life expectancy.15 Even transient sleep loss can 240 mg, or omalizumab 300 mg, or placebo every 4 weeks (q4w) for impair cognitive performance and judgment, and lead to an increased five injections (see Figure 1 for core Phase 2b and extension study 16 risk of other comorbidities, such as cardiovascular disease. design). Patients also received ligelizumab 24 mg q4w or a single Addressing the problem of sleep could have the potential to impact the 120‐mg dose of ligelizumab, but these doses were out of scope and overall health and wellbeing of patients with CSU. not included in our current analyses. Ligelizumab is a next‐generation, high‐affinity 97% (Novartis data The extension study was an open‐label, single‐arm, long‐term on file) humanized monoclonal anti‐IgE antibody that has previously safety Phase 2b extension for all patients who completed the Phase shown dose‐dependent and time‐dependent suppression of free IgE, 2b core study and had a UAS7 ≥12 at Week 32.19 The extension study the expression of its high affinity receptor, FcεRI, and skin‐prick test consisted of an open‐label treatment period (0–52 weeks of ligeli- responses to an allergen, to a greater extent and duration than zumab 240 mg q4w for 13 treatment cycles) and a treatment‐free GIMÉNEZ‐ARNAU ET AL. - 3 of 11 FIGURE 1 Study design of core and extension studies follow‐up period until Week 100.19 The treatment‐free follow‐up recall period.24 The six‐item WPAI‐CU has four subscales, including period started 4 weeks after the last dose and continued for Absenteeism, Presenteeism, Overall Work Impairment (a composite 48 weeks, with visits every 12 weeks, and assessed safety and long‐ score of Absenteeism and Presenteeism), and Activity Impairment, term treatment outcomes, including sustained remission. expressed as impairment percentage (0%–100%), with higher scores In the current analysis, 297 patients were included in the Phase reflecting higher impairment and less productivity. 2b core study as follows: ligelizumab 72 mg (n = 84), ligelizumab Wherever available, data from the Phase 2b core study are 240 mg (n = 85), omalizumab 300 mg (n = 85), and placebo (n = 43). presented from Week 32; however, some endpoints were not Two additional arms included ligelizumab 24 mg q4w and a single measured at Week 32; therefore, we present data from Week 28 dose of 120 mg (to characterize pharmacokinetics and pharmaco- (DLQI and Overall Work Impairment). dynamics); 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. 2.3 | Statistical analysis In this analysis, we present change from baseline (CFB) data for pa- 2.2 | Assessment of patient‐reported outcomes tients across each treatment arm (ligelizumab 72 and 240 mg and omalizumab 300 mg) and placebo at various time points. The Each day during the entire study, patients completed the Urticaria descriptive summary statistics are provided for the SIS7 scores and Patient Daily Diary (UPDD), including the urticaria activity score DLQI scores over time based on the observed data. Mixed models of (UAS), which assessed itch and hives, sleep interference (recorded repeated measures were performed on SIS7 scores, AIS7 scores, every morning), and activity interference (recorded every eve- DLQI and Overall Work Impairment and Presenteeism with UAS7 ning).20,21 Weekly scores were calculated as follows: UAS7 score responder status at each visit, and age, sex and duration of CSU as ranging from 0 to 42, Weekly Sleep Interference Scores (SIS7), and fixed effect factors with subject as a random effect using a compound Weekly Activity Interference Scores (AIS7) both ranging from 0 to symmetry covariance matrix. 21.20,21 Higher scores mean higher interference with sleep and ac- Least square (LS) means are presented together with stan- tivity, respectively. dards errors (SE) overtime for CFB. p‐Values provided are nom- Patients also recorded DLQI at baseline and every 4 weeks. DLQI inal. Week 12 Presenteeism and Overall Work Impairment was has a recall period of 7 days and the total score ranges from 0 to 30 analyzed using Van‐Elteren test with background medication type (higher scores reflect worse HRQoL).22,23 The impact on work due to as the stratification variable. No multiplicity adjustments were CSU was assessed using the Work Productivity and Activity made, therefore, statistical interpretation should be made with Impairment‐Chronic Urticaria (WPAI‐CU version 2.0) with a 7‐day caution. 4 of 11 - GIMÉNEZ‐ARNAU ET AL. T A B L E 1 Demographic and clinical characteristics of patients with chronic spontaneous urticaria in the Phase 2b core study and the Phase 2b extension study Ligelizumab Ligelizumab Omalizumab Placebo Core study total Extension study Characteristics 72 mg (N = 84) 240 mg (N = 85) 300 mg (N = 85) (N = 43) (N = 382) (N = 226) Age (years) 44.3 � 12.4 42.9 � 10.5 41.8 � 13.1 45.4 � 11.2 43.3 � 12.5 44.5 � 12.7 Female sex no. (%) 61 (73) 67 (79) 66 (78) 31 (72) 286 (75) 170 (75) a Body mass index 28.5 � 7.1 27.9 � 6.1 28.1 � 6.4 27.4 � 6.5 27.91 � 6.5 28.8 � 7.3 b Race no. (%) Native American 1 (1) 0 0 0 1 (0.3) 1 (0.4) Asian 20 (24) 19 (22) 12 (14) 9 (21) 76 (20) 51 (23) Black 2 (2) 0 4 (5) 0 8 (2) 3 (1) White 57 (68) 65 (77) 67 (79) 31 (72) 283 (74) 163 (72) Other 3 (3.6) 1 (1) 1 (1) 3 (7) 12 (3) 6 (3) Time since diagnosis of chronic 3.9 � 5.4 4.1 � 5.6 5.1 � 7.5 3.6 � 3.5 4.3 � 6.0 4.75 � 6.2 spontaneous urticaria (years) IgE level IU/ml Median 101.0 74.1 86.2 111.5 87.2 104.5 Range 0–942.0 0–3480.0 0–14,100.0 2.2–870.0 0–14,100.0 0–2000 c Weekly itch‐severity score 13.6 � 4.1 13.0 � 4.3 12.7 � 4.4 13.6 � 4.1 13.1 � 4.1 12.5 � 4.9 c Weekly hives‐severity score 18.1 � 4.3 17.3 � 4.1 16.6 � 4.7 17.6 � 4.1 17.3 � 4.4 15.7 � 5.3 d Weekly urticaria activity score 31.7 � 7.3 30.3 � 7.3 29.3 � 7.9 31.1 � 6.8 30.4 � 7.4 28.2 � 9.1 Positive chronic urticaria index no. 32 (38) 35 (41) 33 (39) 14 (33) 145 (38) 81 (36) (%)e Background medication Locally approved dose of H1‐ 35 (42) 36 (42) 37 (44) 19 (44) 164 (43) 102 (45) antihistamine Escalated dose of locally approved 49 (58) 49 (58) 48 (56) 24 (56) 218 (57) 124 (55) H1‐antihistamine Note: Plus–minus values are means � SD. There were no notable imbalances among the trial groups regarding the demographic and clinical characteristics of the patients at baseline. a The body‐mass index is the weight in kilograms divided by the square of the height in metres. b Race was reported by the patient or determined by the investigator. c 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. 3 | RESULTS (Table 1).17 In addition, baseline demographics in the core study and for the 226 patients who entered the extension study were 3.1 | Baseline characteristics from the Phase 2b similar. core and extension studies were well balanced Of the 382 patients who were randomly assigned to a treat- 3.2 | Many patients with CSU experienced sleep ment arm in the core study (including the 24 and 120 mg impairment at baseline, some of which was substantial single ligelizumab), 338 patients (88%) completed the treatment phase of the study and all baseline demographics and clinical At baseline of the Phase 2b core study, the mean (standard de- characteristics were balanced between the treatment arms viation [SD]) SIS7 scores were balanced between treatment arms: GIMÉNEZ‐ARNAU ET AL. - 5 of 11 11.13 (5.57), 10.29 (6.00), 10.00 (5.51), and 10.91 (5.00), for 3.3 | Ligelizumab achieved numerically greater ligelizumab 72 mg (n = 84) and 240 mg (n = 85), omalizumab improvements in Weekly Sleep Interference scores 300 mg (n = 85), and placebo (n = 43) arms, respectively. At compared with placebo baseline, almost 12% of patients in each arm had a SIS7 score above 17. At baseline, the majority of patients had SIS7 between 3 By Weeks 12 and 20, patients had achieved numerically greater and ≤17 for each treatment arm, with a rate of between 33.3% CFB responses in the active arms of the Phase 2b core study: the and 44.2%. LS mean (standard error [SE]) CFB in SIS7 scores at Week 12 was (A) Weeks 0 LS mean change from baseline in Weekly Sleep Interference score 0 4 8 12 16 20 24 28 32 -1 -2 -3 -4 -5 -6 -7 -8 -9 -10 Ligelizumab 72 mg (n=84) Ligelizumab 240 mg (n=85) Omalizumab 300 mg (n=85) Placebo (n=43) (B) Weeks 0 0 10 20 30 40 50 60 70 80 90 100 LS mean change from baseline in Weekly Sleep Interference score -1 -2 -3 -4 -5 -6 -7 -8 -9 Ligelizumab 240 mg F I G U R E 2 (A) LS mean change from baseline in Weekly Sleep Interference scores during the Phase 2b core study and treatment‐free follow‐up period and (B) the extension study and treatment‐free follow‐up period 6 of 11 - GIMÉNEZ‐ARNAU ET AL. −7.84 (0.58), −7.55 (0.61), −6.98 (0.60), and −5.85 (0.81), and by respectively. During the treatment‐free follow‐up period (from Week 20, it was −8.25 (0.58), −8.22 (0.60), −7.44 (0.60), and −5.51 Week 20 up to Week 32), the effect on SIS7 was maintained and (0.80) for ligelizumab 72 mg, 240 mg, omalizumab 300 mg and pla- patients in the ligelizumab 240‐mg arm had a slower return to cebo, respectively (Figure 2A). By Week 20, 64.3%, 63.5%, 61.2%, Baseline versus all the other arms (Figure 2A). and 51.2% of patients had no or limited sleep interference in the Patients who entered the extension study experienced sus- ligelizumab 72 and 240 mg, omalizumab 300 mg, and placebo arms, tained improvements in their sleep interference scores from (A) Weekly Activity Interference scores LS mean change from baseline in Weeks 0 -1 0 4 8 12 16 20 24 28 32 -2 -3 -4 -5 -6 -7 -8 -9 -10 Ligelizumab 72 mg (n=84) Ligelizumab 240 mg (n=85) Omalizumab 300 mg (n=85) Placebo (n=43) (B) Weeks Weekly Activity Interference scores 0 LS mean change from baseline in 0 10 20 30 40 50 60 70 80 90 100 -1 -2 -3 -4 -5 -6 -7 -8 -9 Ligelizumab 240 mg F I G U R E 3 (A) LS mean change from baseline in Weekly Activity Interference score during the Phase 2b core study and treatment‐free follow‐up period and (B) the extension study and treatment‐free follow‐up period GIMÉNEZ‐ARNAU ET AL. - 7 of 11 (A) Weeks 0 0 4 8 12 16 20 24 28 -2 baseline in DLQI score LS mean change from -4 -6 -8 -10 -12 Ligelizumab 72 mg (n=84) Ligelizumab 240 mg (n=85) Omalizumab 300 mg (n=85) Placebo (n=43) (B) Weeks 0 0 10 20 30 40 50 60 70 80 90 100 -2 baseline in DLQI score LS mean change from -4 -6 -8 -10 -12 Ligelizumab 240 mg F I G U R E 4 (A) LS mean change from baseline in Dermatology Life Quality Index score during the Phase 2b core study and treatment‐free follow‐up period and (B) the extension study and treatment‐free follow‐up period baseline (−3.91 [0.31]) throughout the entire treatment period, (−7.87 [0.29]). Scores stayed low during the treatment period, with starting from the first ligelizumab 240 mg dose at Week 0 until a gradual increase of SIS7 scores in the treatment‐free follow‐up Week 52, with the greatest improvement observed at Week 32 period up until Week 100 (Figure 2B). 8 of 11 - GIMÉNEZ‐ARNAU ET AL. TABLE 2 Absolute mean change from baseline in presenteeism Ligelizumab 72 mg (N = 84) Ligelizumab 240 mg (N = 85) Omalizumab 300 mg (N = 85) Placebo (N = 43) Phase 2b Core study Week 12, LS mean (SE) −26.60 (3.43) −28.99 (3.36) −23.54 (3.53) −17.54 (4.54) Week 20, LS mean (SE) −27.97 (3.61) −26.76 (3.39) −24.30 (3.45) −13.36 (4.31) Extension study Week 32, LS mean (SE) NA −35.33 (1.39) NA NA Week 52, LS mean (SE) NA −33.63 (1.62) NA NA Note: Week 12 is the primary endpoint in the Phase 2b core study and Week 20 is the end of the treatment period. Week 52 indicates the end of the treatment period in the extension study. Abbreviations: LS, least square; N, number of patients; NA, not available; SE, standard error. 3.4 | Weekly Activity Interference scores improved Impairment scores of −30.76 (3.71) versus −28.96 (3.73), −25.74 and remained stable throughout treatment with (3.91), and −20.13 (5.10) for ligelizumab 72 mg, omalizumab 300 mg, ligelizumab and placebo, respectively. At Week 12, Presenteeism had signifi- cantly improved for ligelizumab 72 mg (p = 0.004) and 240 mg By Week 12 of the Phase 2b core study, the LS mean (SE) CFB in AIS7 (p = 0.003) versus placebo, and Overall Work Impairment signifi- scores were −8.25 (0.57), −8.25 (0.59), −7.30 (0.60) and −5.62 (0.79), cantly improved (p = 0.003 and p = 0.002, respectively) versus pla- for ligelizumab 72 mg, 240 mg, omalizumab 300 mg, and placebo, cebo; neither parameter improved significantly with omalizumab respectively; by Week 20, AIS7 CFB remained stable at −8.30 (0.56), 300 mg treatment versus placebo. Improvements in Presenteeism −8.74 (0.59), −7.85 (0.59), and −5.38 (0.78), respectively (Figure 3A). and Overall Work Impairment were also experienced by patients in The improvement in AIS7 was sustained throughout the treatment the extension study (Figure 5B). period of the extension study (Figure 3B). 4 | DISCUSSION 3.5 | Dermatology Life Quality Index improvement was numerically greater for patients treated with The analysis presented herein shows the correlations between CSU ligelizumab compared with omalizumab and placebo and various dimensions of HRQoL such as sleep and activity interference, dermatology‐QoL, and impact on work. The results The LS mean (SE) CFB in DLQI scores in the Phase 2b core study suggest that treating the symptoms of CSU also has beneficial ef- was numerically higher in the ligelizumab treatment arms at both fects on these aspects of life. Treatment with ligelizumab, which Week 12 and Week 20: at Week 12, it was −9.79 (0.77), −9.93 improved urticaria activity, was associated with improvements in (0.81), −8.35 (0.79), and −6.99 (1.11), and at Week 20, it was HRQoL (as reflected in DLQI sores) and sleep, as seen through −9.61 (0.78), −10.0 (0.81), −8.25 (0.82), and −6.74 (1.06) for reduced SIS7 scores. In addition, interference with daily activities ligelizumab 72 and 240 mg, omalizumab 300 mg, and placebo, was reduced (reflected by improvement in AIS7 scores) as well as a respectively (Figure 4A). positive impact on work components (Presenteeism and Overall Patients in the extension study experienced sustained improve- Work Impairment scores). These improvements with ligelizumab ments in DLQI scores throughout the treatment period with the occurred as early as after the initial treatment (Week 4 of the core greatest improvement measured at Week 52 (−9.52 [0.36]). Im- study, as shown in the figures), with continued improvements up to provements continued until Week 100 (−5.92 [0.62]) but were not as the end of the treatment period (Week 20) of the core study. high during the treatment‐free follow‐up (Figure 4B). During the treatment‐free follow‐up period of the Phase 2b core study (Week 32), patients from the ligelizumab treatment arms maintained low SIS7 scores, with sleep interference relapse taking 3.6 | Ligelizumab led to numerically greater longer with ligelizumab 240 mg. Low SIS7 scores were maintained improvements in Presenteeism and Overall Work throughout treatment during the extension study. The mean DLQI Impairment compared with omalizumab and placebo scores continued to improve until the end of treatment in the Phase 2b core study and extension study, with the largest change The LS mean CFB in Presenteeism and Overall Work Impairment was observed in the ligelizumab 240 mg group. It has previously been numerically higher in the ligelizumab treatment arms compared to shown that a DLQI score of between 3.3 and 4 relates to a minimal omalizumab 300 mg and placebo (see Table 2 and Figure 5A). clinically important difference (MCID).25 DLQI scores for all arms in By Week 12 of the Phase 2b core study, patients on ligelizumab this study achieved an MCID after 12 weeks, but were higher for 240 mg achieved the highest improvement in Overall Work the ligelizumab arms: scores reduced (improved) by −9.79, −9.93, GIMÉNEZ‐ARNAU ET AL. - 9 of 11 (A) 0 LS mean change from baseline in -5 Overall Work Impairment -10 -15 -20 -25 -30 -35 0 4 8 12 16 20 24 28 -40 Weeks Ligelizumab 72 mg (n=84) Ligelizumab 240 mg (n=85) Omalizumab 300 mg (n=85) Placebo (n=43) (B) Weeks 0 LS mean change from baseline in 0 10 20 30 40 50 60 70 80 90 100 -5 Overall Work Impairment -10 -15 -20 -25 -30 -35 -40 Ligelizumab 240 mg F I G U R E 5 (A) LS mean change from baseline in Overall Work Impairment score during the Phase 2b core study and treatment‐free follow‐up period and (B) the extension study and treatment‐free follow‐up period −8.35, and −6.99 and by Week 12, and −9.61, −10.0, −8.25, and presented from both the core and extension studies support pre- −6.74 by Week 20 for ligelizumab 72 and 240 mg, omalizumab vious findings of sleep interference and the relationship on work 300 mg, and placebo, respectively. In the extension study, the MICD productivity and HRQoL.1–5 The effect of treatment on work ac- in DLQI scores were sustained with ligelizumab 240 mg, with values tivity was significant at Week 12 for both doses of ligelizumab; of −9.52 at Week 52, and −5.92 at Week 100. The results Presenteeism and Overall Work Impairment significantly improved 10 of 11 - GIMÉNEZ‐ARNAU ET AL. for both ligelizumab doses versus placebo at Week 12; neither CSU improves urticaria activity and HRQoL, and thereby also has the parameter improved significantly with omalizumab 300 mg treat- potential to improve sleep (through decreased interference),28 which ment versus placebo. Mirroring the changes in other HRQoL pa- should be confirmed in further Phase 3 studies. Sleep interference is rameters, the improvements in AIS7 scores were also notably drastically underappreciated as a severe and clinically relevant reduced by Week 12 and 20, again with the largest change in the symptom of CSU. Patient assessments of the effect of therapy on ligelizumab 240 mg arm by Week 20 (end of treatment period). sleep quality should explicitly be included as part of an integrated Similar to the results seen in our study, the previous ASSURE trial treatment approach. showed that CSU markedly interferes with sleep and daily activities, and >20% of patients reported ≥1 h per week of missed work.3 All A CK NO W L ED GM E NT S of these effects worsened with increasing disease activity. The authors thank Gillian Brodie, MSc, and Hayley Furlong, PhD, of Patients' responses to treatment can alter their sleep quality and Novartis Ireland Ltd. for editorial and medical writing support, which levels of fatigue, and produce undesirable effects, as observed was funded by Novartis Pharma AG, Basel, Switzerland, in accor- through the use of first‐generation H1‐AH. The global EAACI/ dance with the Good Publication Practice (GPP3) guidelines (http:// GA2LEN/EDF/WAO (European Academy of Allergology and Clinical www.ismpp.org/gpp3). We also wish to thank Bharat Suryawanshi Immunology/Global Allergy and Asthma European Network/Euro- and Sandip Acharya of Novartis Pharma AG for their support in the 26 analysis. This investigation was sponsored by Novartis Pharma AG, pean Dermatology Forum/World Allergy Organization) guidelines on the management of urticaria are clear; they state that second‐ Basel, Switzerland. generation, non‐sedating H1‐AH should be used for first‐line treat- ment of CSU, with a dosage increase up to fourfold as second‐line CO N F L I CT O F I N T ER E S T treatment. Comorbidities and the effect of H1‐AHs were not stud- Ana Giménez‐Arnau reports roles as a Medical Advisor for Uriach ied in our Phase 2b core or extension studies and warrant further Pharma, Sanofi and Genentech, Novartis, FAES, GSK, Thermo Fisher, investigation. Some patients experience daytime sedation as a Almirall, Amgen, and has research grants supported by Uriach Pharma, consequence of using H1‐AH to control CSU symptoms. One of the Novartis, and Instituto Carlos III‐ FEDER; she also participates in objectives when choosing a treatment is to provide complete symp- educational activities for Uriach Pharma, Novartis, Genentech, tom control, including avoidance of sleep disturbances induced by the Menarini, LEO‐PHARMA, GSK, MSD, Almirall, Avene, and Sanofi. disease or treatments. Using appropriate biologic treatments, which Marcus Maurer is or recently was a speaker and/or advisor for and/or are unlikely to interfere with the sleep cycle, should be considered in has received research funding from Allakos, Amgen, Aralez, ArgenX, the right patients based upon a physician's diagnosis. AstraZeneca, Celldex, Centogene, CSL Behring, FAES, Genentech, Sleep improvements have also been experienced in patients with GIInnovation, Innate Pharma, Kyowa Kirin, Leo Pharma, Lilly, Menarini, CSU after treatment with omalizumab, as shown by the results from Moxie, Novartis, Roche, Sanofi/Regeneron, Third HarmonicBio, UCB, three randomized, placebo‐controlled trials.27 Sleep improvements and Uriach. Jonathan Bernstein reports grants and personal fees from were observed after the first dose of omalizumab, which mirrored the Celldex, Amgen, Sanofi Regeneron, Novartis, Astra Zeneca, Allakos, efficacy in disease activity, a positive effect that continued with and Genentech. Petra Staubach has received research funding and/or subsequent doses, and improved throughout treatment. When dis- fees for consulting and/or lectures from Novartis, CSL Behring, Shire, continued, CSU symptoms returned along with rebounding sleep MSD, Schering‐Plough, Abbvie, Viropharma, Leo Pharma, Leti Pharma, 27 Pohl‐Boskamp GmbH, Astella, Allergika, Karrer, Allmirall, Sanofi, problems. Additionally, improvement in itch was associated with decreases in somnolence and sleep disturbances. Octapharma, Pfleger GmbH, Beiersdorf, L'Oreal, Lilly, Janssen, Cel- This study was limited by the relatively low number of patients gene, Hermal, UCB, Allmirall, Astelas, Sobi, and Pfizer. Eva Hua is an and short trial duration of the core study, although the extension employee of China Novartis Institutes for Biomedical Research Co. Ltd, 19 China. Nathalie Barbier, Thomas Severin, Yolandi Joubert, and Maria study showed longer‐term effects. Ligelizumab is being investigated in an ongoing clinical trial program that includes the Phase 3 PEARL 1 Magdalena‐Balp are full‐time employees of Novartis Pharma AG, (NCT03580369) and PEARL 2 (NCT03580356) trials, which aim to Basel, Switzerland. Reinhold Janocha is a former Novartis employee recruit more than 2000 patients with CSU across 48 countries glob- and holds Novartis shares. ally. The complex relationship between patients with CSU and sleep is imperative to study and these studies will help further our under- A UT HO R C O NT RI B U T I O N S standing and provide invaluable insights. Ana Giménez‐Arnau: Conceptualization; Data curation; Formal anal- ysis; Investigation; Supervision; Validation; Writing ‐ review & editing. Marcus Maurer: Conceptualization; Formal analysis; Investigation; 5 | CONCLUSIONS Supervision; Validation; Writing ‐ review & editing. Jonathan Bern- stein: Investigation; Supervision; Validation; Writing ‐ review & editing. Overall, ligelizumab treatment has benefits beyond relief from urti- Petra Staubach: Investigation; Validation; Writing ‐ review & editing. caria symptoms and can impact HRQoL, highlighting the importance Nathalie Barbier: Data curation; Formal analysis; Methodology; Proj- of targeting complete urticaria control. Treating the symptoms of ect administration; Resources; Validation; Writing ‐ review & editing. GIMÉNEZ‐ARNAU ET AL. - 11 of 11 Eva Hua: Data curation; Formal analysis; Methodology; Resources; 13. Sussman G, Abuzakouk M, Berard F, et al. Angioedema in Supervision; Validation; Writing ‐ review & editing. Thomas Severin: chronic spontaneous urticaria is underdiagnosed and has a sub- stantial impact: analyses from ASSURE‐CSU. Allergy. 2018;73: Data curation; Formal analysis; Funding acquisition; Methodology; 1724‐1734. Project administration; Resources; Supervision; Validation; Writing ‐ 14. Alatas ET, Unal Y, Demir Pektas S, Kutlu G. Obstructive sleep apnea review & editing. Yolandi Joubert: Data curation; Formal analysis; syndrome in patients with chronic idiopathic urticaria. Dermatol Ther. Methodology; Supervision; Validation; Writing ‐ review & editing. 2020;33:e14060. https://doi.org/10.1111/dth.14060 15. Capezuti EA. The power and importance of sleep. Geriatr Nurs. Reinhold Janocha: Data curation; Formal analysis; Methodology; 2016;37:487‐488. Validation; Writing ‐ review & editing. Maria‐Magdalena: Conceptu- 16. Bertisch SM, Pollock BD, Mittleman MA, et al. Insomnia with alization; Data curation; Formal analysis; Methodology; Supervision; objective short sleep duration and risk of incident cardiovascular Validation; Writing ‐ review & editing. disease and all‐cause mortality: Sleep Heart Health Study. Sleep. 2018;41:zsy047. 17. Maurer M, Gimenez‐Arnau AM, Sussman G, et al. Ligelizumab O RC ID for chronic spontaneous urticaria. N Engl J Med. 2019;381: Ana Giménez‐Arnau https://orcid.org/0000-0001-5434-7753 1321‐1332. Marcus Maurer https://orcid.org/0000-0002-4121-481X 18. Gasser P, Tarchevskaya SS, Guntern P, et al. The mechanistic and Jonathan Bernstein https://orcid.org/0000-0002-3476-1196 functional profile of the therapeutic anti‐IgE antibody ligelizumab differs from omalizumab. Nat Commun. 2020;11:165. Nathalie Barbier https://orcid.org/0000-0001-8052-7862 19. Maurer M, Giménez‐Arnau A, Bernstein JA, et al. Sustained safety Eva Hua https://orcid.org/0000-0001-5781-170X and efficacy of ligelizumab in patients with chronic spontaneous urticaria: a one‐year extension study. Allergy. 2021. https://doi.org/ REFERENCES 10.1111/all.15175 20. Mathias SD, Crosby RD, Rosen KE, Zazzali JL. The minimal important 1. Weller K, Maurer M, Grattan C, et al. ASSURE‐CSU: a real‐world difference for measures of urticaria disease activity: updated find- study of burden of disease in patients with symptomatic chronic ings. Allergy Asthma Proc. 2015;36:394‐398. spontaneous urticaria. 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