Background: Several biologics are now available as add-on treatment for severe asthma but, currently there are no universally accepted criteria to measure the response to these therapies. This survey aims to establish consensus criteria to use in practice for the initial evaluation of response to biologics after four months of treatment. Method: Using Delphi methodology, a questionnaire including ten items was developed and validated by a 13-member panel of international experts in asthma. The electronic survey circulated within the INterasma Scientific Network platform, Global Asthma Association membership, contact list of the co-authors, national associations for specialists, and social media. For each item, five answers were proposed graduated from “no importance” to “very high importance” and by a score (A=2 points; B=4 points; C=6 points; D=8 points; E=10 points). The final criteria were selected if the median score for the item was ≥7 and >60% of responses accorded “high importance” and “very high importance”. All selected criteria were validated by the thirteen experts. Results: Four criteria were identified to evaluate the efficacy of biologics in asthma: to reduce daily systemic corticosteroids dose by ≥50% (ideally complete withdrawal); to decrease the number of asthma exacerbations requiring systemic corticosteroids by ≥50%, (ideally no asthma exacerbation); to have no/minimal side-effects and to obtain asthma control according validated questionnaires. The consensual decision was that ≥3 criteria are needed to conclude a good response to biologics. Conclusions: Specific criteria were defined by an international panel of experts and could be used as tool in clinical practice.
Treatment of Chronic Spontaneous Urticaria With Benralizumab: Report of Primary Endpoint Per Protocol Analysis, and Exploratory EndpointsStandard treatments for chronic spontaneous urticaria (CSU) including the second-generation H1-antihistamines (SGAH) are often ineffective even with four-times the FDA-recommended dose.1,2Eosinophilic infiltrates and an abundance of interleukin-5 (IL5) in CSU lesions (hives) support a role for IL5 in the pathomechanism of CSU.3 Thus, the use of biologic therapies, e.g. benralizumab targeting IL5-receptor-α, in treating SGAH-resistant CSU was hypothesized.A repeated-measures, 24-week study was designed and conducted at an urticaria clinic to determine clinical efficacy of benralizumab in CSU. Twelve SGAH-unresponsive CSU patients (3 males, 9 females; 2 blacks, 10 whites; between ages 32-65 years) having a median daily Urticaria Activity Score (UAS7)4 of 4, and pruritus severity ≥2 were enrolled. After a baseline run-in period, subjects were treated with a subcutaneous placebo dose followed by benralizumab 30mg subcutaneously every month (×3 doses) followed by two off-medication monthly-visits. Subject-reported responses to UAS7 and CU-QoL questionnaires were recorded at the monthly visits. The primary and exploratory endpoints were the change in UAS7 and Chronic Urticaria Quality-of-Life Total Score (CUQoLTS) respectively, from 4 weeks after placebo dose (visit 2) to 4 weeks after last dose of benralizumab (visit 5). Nine subjects completed the study; three withdrew after the first benralizumab dose. An intent-to-treat (ITT) analysis (n=12) of the primary endpoint has been reported previously.5Per-protocol (PP) analysis (n=9) of the primary endpoint, and PP vs. ITT of the exploratory endpoint are reported here. It was presumed that lesions were not self-limiting, and any improvement in outcomes during the study were because of intervention. Non-responders to benralizumab were identified if at any time during the 16 weeks after the first benralizumab dose there was <40% improvement in UAS7 from baseline vs. responders if UAS7 was ≤6.The average duration of urticarial symptoms was 7.0 years. Baseline UAS7 and CUQoLTS ranged between 22-42 and 36-95 respectively. Both outcomes significantly improved at visit 5 vs. visit 2 in 7 of 9 (78%) subjects completing the study. The average difference (95% CL) between visit 2 and visit 5 for UAS7, was -15.5 (-4.1, -26.8, p=0.003) and for CUQoLTS, using ITT analysis, was-13.2 (-2.4, -24.0, p=0.0005) or, using PP analysis, was -11.6 (-0.8, -22.4, p=0.03) (Figure-1 ). Five responders reported no hives/pruritus (UAS7=0) at visit 5 or 6.Between responders and non-responders, the average age (51.6 vs. 53, p=0.9) and symptom duration (5 vs. 9 years, p=0.5) did not differ significantly. However, the adjusted mean UAS7 percentage difference, adjusted for symptom duration, age, and blood eosinophils (eos%), from visit 2 till visit 5 was -84% for responders and +7.5% for non-responders, p=0.0009 (Table-1) . The average baseline UAS7 was not statistically significant (27 vs. 37.5, p=0.5) between groups however, the baseline mean difference for eos% was -6±1 (p=0.001), and for basophil% was -1.2±0.2, p=0.02), which were not observed at visit 5 (eos%: 0±1, p=0.9; basophil%: 0.2±0.2, p=0.8) (Table-1 ). Thus, clinical improvement among responders was independent of baseline disease severity. Non-responsiveness to benralizumab, measured by changes in UAS7, are likely due to other mechanistic factors unrelated to eos% which are eliminated by blocking IL-5R with benralizumab(S-Figure-1) .UAS7 and CU-QoLTS values were significantly correlated (r2=0.9, p<0.0001) (S-Table-3) . CU-QoL components that improved significantly were the pruritus/wheal scores, urticarial interference with physical activities, sleep and spare time (S-Table-4) .This study supports the use of benralizumab for treatment of SGAH-unresponsive CSU. Benralizumab-related improvements in UAS7 and CUQoLTS reported here are similar to the efficacy of omalizumab in CSU reported in a previous study (S-Table-5) .6The sustained significant improvement in urticarial lesions based on subject-reported outcomes by benralizumab warrants further investigation of underlying biologic pathways to better elucidate the role of IL-5 in CSU.
Background. Standard of care for chronic spontaneous urticaria (CSU) includes second-generation H1-antihistamines (SGAH) but is often ineffective even with four-times the FDA-recommended dose. Urticarial lesions are commonly characterized by increased lymphocytes with perivascular eosinophilic infiltrates implying a role for the interleukin-5 (IL5). Objective. This study investigated the effects of benralizumab, an anti-IL5-receptor-alpha monoclonal antibody, in human subjects with SGAH-unresponsive CSU that completed all study visits. Methods. A repeated-measures, 24-week study was conducted at an urticaria specialist clinic where SGAH-unresponsive CSU patients (3 males and 9 females; age range, 32-65 years) having a median weekly Urticaria Activity Score (UAS7) of 4 and pruritus severity ≥2 were enrolled. After a baseline run-in period, subjects were treated with a subcutaneous placebo dose followed by benralizumab 30mg subcutaneously every month (×3 doses) followed by two off-medication monthly-visits. The primary and exploratory endpoints were the change from baseline in UAS7 and Chronic Urticaria Quality-of-Life Score (CU-QoLTS) respectively. Secondary endpoints included peripheral blood eosinophils (eos%) and basophils, skin eosinophilia, and differentially expressed genes (DEGs) in blood before- and after benralizumab. Results. UAS7 and CU-QoLTS significantly improved post-benralizumab compared to baseline scores in 7 of 9 subjects completing the study. Clinical improvements correlated with reduction in eos% and inflammatory cell infiltrates in skin lesions. Biologic pathways, regulated by DEGs, involved IL-5R activity, tryptophan metabolism and Siglec-8 expression. Conclusion. Benralizumab was clinically efficacious in the treatment of subjects with SGAH-refractory CSU which correlated with several DEGs in blood. This study supports the use of benralizumab for CSU treatment.