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For patients with moderate-to-severe persistent allergic asthma, omalizumab is approved for subcutaneous administration according to a recommended dosing table based on weight and total immunoglobulin E (IgE) level. The aim of this analysis was to assess asthma outcomes including quality of life in patients with allergic asthma initiated on omalizumab in the PROSPERO trial; patients were stratified by where their IgE and body weight fell on the approved dosing table. Patient groups were defined as Inside Dosing Table: patients whose IgE and weight fell within the approved dosing table (n = 506); Insufficient Data to Recommend a Dose: patients who fell into the section of the approved dosing table where not enough clinical data were available to make dosing recommendations (n = 72); and Outside Dosing Table: patients who fell outside the approved dosing table due to baseline IgE and/or weight (n = 209). Overall, asthma and quality of life outcomes were improved after omalizumab initiation for both patients who fall within the recommended dosing table or those who fall outside the recommended dosing table. Our results suggest that omalizumab treatment may be effective in a wide range of patients with moderate-to-severe allergic asthma. ClinicalTrials.gov identifier NCT01922037., Competing Interests: Declaration of competing interest NMC: consultant and/or speaker bureau member for Amgen, ARS Pharmaceuticals Inc., AstraZeneca, Blueprint Medicines, Bryn Pharma, Genentech Inc., GlaxoSmithKline, Hikma Pharmaceuticals, Incyte, Novartis, Regeneron, and Sanofi; speaker bureau member for Incyte; consultant for ARS Pharmaceuticals Inc., Bryn Pharma, Genentech, Inc., Hikma Pharmaceuticals, and Novartis Pharmaceuticals Corporation. ML: institution received research grant support on her behalf from Sanofi; received honoraria for serving as a consultant for AstraZeneca. CTJH: former employee of Genentech, Inc. LAM, AS, JWS, BLT: employees of Genentech, Inc.; stockholders of Roche. NAH: received honoraria for serving as advisor or consultant for Amgen, AstraZeneca, Genentech, Inc., GlaxoSmithKline, Novartis Pharmaceuticals Corporation, Regeneron, Sanofi, and Teva. Institution received research grant support on his behalf from AstraZeneca, Genentech, Inc., GlaxoSmithKline, Novartis, Sanofi, and Teva. TBC: consultant and speaker bureau member for Genentech, Inc.; consultant for Novartis Pharmaceuticals Corporation; chief medical advisor for Food Allergy Research & Education., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Chronic spontaneous urticaria (CSU) is a dermatologic condition characterized by spontaneous, pruritic hives and/or angioedema that persists for 6 weeks or longer with no identifiable trigger. Antihistamines and second-line therapies such as omalizumab are effective for some CSU patients, but others remain symptomatic, with significant impact on quality of life. This variable response to treatment and autoantibody levels across patients highlight clinically heterogeneous subgroups., Objective: We aimed to highlight pathways involved in CSU by investigating the genetics of CSU risk and subgroups., Methods: We performed a genome-wide association study (GWAS) of 679 CSU patients and 4446 controls and a GWAS of chronic urticaria (CU)-index, which measures IgG autoantibodies levels, by comparing 447 CU index-low to 183 CU index-high patients. We also tested whether polygenic scores for autoimmune-related disorders were associated with CSU risk and CU index., Results: We identified 2 loci significantly associated with disease risk. The strongest association mapped to position 56 of HLA-DQA1 (P = 1.69 × 10 -9 ), where the arginine residue was associated with increased risk (odds ratio = 1.64). The second association signal colocalized with expression-quantitative trait loci for ITPKB in whole blood (P colocalization  = .997). The arginine residue at position 56 of HLA-DQA1 was also associated with increased risk of CU index-high (P = 6.15 × 10 -5 , odds ratio = 1.86), while the ITKPB association was not (P = .64). Polygenic scores for 3 autoimmune-related disorders (hypothyroidism, type 1 diabetes, and vitiligo) were associated with CSU risk and CU index (P < 2.34 × 10 -3 , odds ratio > 1.72)., Conclusion: A GWAS of CSU identified 2 genome-wide significant loci, highlighting the shared genetics between CU index and autoimmune disorders., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Approximately 5% to 10% of patients with asthma have severe disease, with a consistent preponderance in females. Current asthma guidelines recommend stepwise treatment to achieve symptom control with no differential treatment considerations for either sex., Objective: To examine whether patient sex affects outcomes when using a composite T2-biomarker score to adjust corticosteroid (CS) treatment in patients with severe asthma compared with standard care., Methods: This is a post hoc analysis, stratifying patient outcomes by sex, of a 48-week, multicenter, randomized controlled clinical trial comparing a biomarker-defined treatment algorithm with standard care. The primary outcome was the proportion of patients with a reduction in CS treatment (inhaled and oral corticosteroids). Secondary outcomes included exacerbation rates, hospital admissions, and lung function., Results: Of the 301 patients randomized, 194 (64.5%) were females and 107 (35.5%) were males. The biomarker algorithm led to a greater proportion of females being on a lower CS dose versus standard care, which was not seen in males (effect estimate: females, 3.57; 95% CI, 1.14-11.18 vs males, 0.54; 95% CI, 0.16-1.80). In T2-biomarker-low females, reducing CS dose was not associated with increased exacerbations. Females scored higher in all domains of the 7-item Asthma Control Questionnaire, apart from FEV1, but with no difference when adjusted for body mass index/anxiety and/or depression. Dissociation between symptoms and T2 biomarkers were noted in both sexes, with a higher proportion of females being symptom high/T2-biomarker low (22.8% vs 15.6%; P = .0002), whereas males were symptom low/T2-biomarker high (22.3% vs 11.4%; P < .0001)., Conclusions: This exploratory post hoc analysis identified that females achieved a greater benefit from biomarker-directed CS optimization versus symptom-directed treatment., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Although asthma does not appear to be a risk factor for severe coronavirus disease 2019 (COVID-19), outcomes could vary for patients with different asthma subtypes. The objective of this analysis was to compare COVID-19 outcomes in real-world cohorts in the United States among patients with asthma, with or without evidence of allergy., Methods: In a retrospective analysis of the COVID-19 Optum electronic health record dataset (February 20, 2020-January 28, 2021), patients diagnosed with COVID-19 with a history of moderate-to-severe asthma were divided into 2 cohorts: those with evidence of allergic asthma and those without (nonallergic asthma). After 1:1 propensity score matching, in which covariates were balanced and potential bias was removed, COVID-19 outcomes were compared between cohorts., Results: From a COVID-19 population of 591,198 patients, 1595 patients with allergic asthma and 8204 patients with nonallergic asthma were identified. After propensity score matching (n = 1578 per cohort), risk of death from any cause after COVID-19 diagnosis was significantly lower for patients with allergic vs nonallergic asthma (hazard ratio, 0.48; 95% CI 0.28-0.83; P = 0.0087), and a smaller proportion of patients with allergic vs nonallergic asthma was hospitalized within - 7 to + 30 days of COVID-19 diagnosis (13.8% [n = 217] vs 18.3% [n = 289]; P = 0.0005). Among hospitalized patients, there were no significant differences between patients with allergic or nonallergic asthma in need for intensive care unit admission, respiratory support, or COVID-19 treatment., Conclusions: Asthma subtype may influence outcomes after COVID-19; patients with allergic asthma are at lower risk for hospitalization/death than those with nonallergic asthma., (© 2022. The Author(s).)

Rationale: The past 25 years have seen huge progress in understanding of the pathobiology of type-2 (T2) asthma, identification of measurable biomarkers, and the emergence of novel monoclonal antibody treatments. Although present in a minority of patients with severe asthma, very little is known about the mechanisms underlying T2-low asthma, making it a significant unmet need in asthma research. Objectives: The objective of this study was to explore the differences between study exacerbators and nonexacerbators, to describe physiological changes at exacerbation in those who are T2 HIGH and T2 LOW at the time of exacerbation, and to evaluate the stability of inflammatory phenotypes when stable and at exacerbation. Methods: Exacerbation assessment was a prespecified secondary analysis of data from a 48-week, multicenter, randomized controlled clinical study comparing the use of biomarkers and symptoms to adjust steroid treatment in a T2-low severe asthma-enriched cohort. Participants were phenotyped as T2 LOW (fractional exhaled nitric oxide ⩽ 20 ppb and blood eosinophil count ⩽ 150 cells/µl) or T2 HIGH (fractional exhaled nitric oxide > 20 or blood eosinophil count > 150) at study enrollment and at each exacerbation. Here, we report the findings of the exacerbation analyses, including comparison of exacerbators and nonexacerbators, the physiological changes at exacerbation in those who had evidence of T2 biology at exacerbation versus those that did not, and the stability of inflammatory phenotypes when stable and at exacerbation. Measurements and Main Results: Of the 301 participants, 60.8% (183) had one or more self-reported exacerbations (total of 390). Exacerbators were more likely to be female, have a higher body mass index, and have more exacerbations requiring oral corticosteroid and unscheduled primary care attendances for exacerbations. At enrollment, 23.6% (71) were T2 LOW and 76.4% (230) T2 HIGH . The T2 LOW group had more asthma primary care attendances, were more likely to have a previous admission to HDU (high dependency unit)/ICU and to be receiving maintenance oral corticosteroids. At exacerbation, the T2 LOW events were indistinguishable from T2 HIGH exacerbations in terms of lung function (mean fall in T2 LOW FEV 1, 200 [400] ml vs. T2 HIGH 200 [300] ml; P  = 0.93) and symptom increase (ACQ5: T2 LOW , 1.4 [0.8] vs. T2 HIGH , 1.3 [0.8]; P  = 0.72), with no increase in T2 biomarkers from stable to exacerbation state in the T2 LOW exacerbations. The inflammatory phenotype within individual patients was dynamic; inflammatory phenotype at study entry did not have a significant association with exacerbation phenotype. Conclusions: Asthma exacerbations demonstrating a T2 LOW phenotype were physiologically and symptomatically similar to T2 HIGH exacerbations. T2 LOW asthma was an unstable phenotype, suggesting that exacerbation phenotyping should occur at the time of exacerbation. The clinically significant exacerbations in participants without evidence of T2 biology at the time of exacerbation highlight the unmet and pressing need to further understand the mechanisms at play in non-T2 asthma. Clinical trial registered with www.clinicaltrials.gov (NCT02717689).

Background: Lebrikizumab is a monoclonal antibody that modulates activity of interleukin-13. The Phase 3 ACOUSTICS study assessed lebrikizumab efficacy and safety in adolescents with uncontrolled asthma despite standard-of-care treatment., Methods: Adolescents (aged 12-17 years) with uncontrolled asthma, prebronchodilator forced expiratory volume in 1 s 40%-90% predicted, and stable background therapy were randomised 1:1:1 to receive lebrikizumab 125 or 37.5 mg or placebo subcutaneously once every 4 weeks. Primary efficacy endpoint was asthma exacerbation rate over 52 weeks., Results: Between August 2013 and July 2016, 579 patients were screened and 346 were randomised; 224 (65%) completed the study with 52 weeks of treatment. Lebrikizumab 125 mg ( n  = 116) reduced the exacerbation rate at 52 weeks versus placebo ( n  = 117; adjusted rate ratio [RR] 0.49 [95% CI 0.28-0.83]; 51% rate reduction). Lebrikizumab 37.5 mg ( n  = 113) was less effective at reducing exacerbations (RR 0.60 [95% CI 0.35-1.03]; 40% rate reduction). In patients with blood eosinophil counts ≥300 cells/μl, both lebrikizumab doses reduced exacerbations (125 mg: RR 0.44 [95% CI 0.21-0.89]; 37.5 mg: 0.42 [95% CI 0.19-0.93]). Treatment-emergent adverse events, serious adverse events, and adverse events leading to study discontinuation occurred in 155 (68%), 7 (3%), and 5 (2%) of 229 patients who received lebrikizumab (both 125 and 37.5 mg doses) and in 72 (62%), 4 (3%), and 1 (1%) of 117 who received placebo, respectively. No deaths occurred., Conclusion: Lebrikizumab 125 mg reduced asthma exacerbation rates in adolescents with uncontrolled asthma. However, the study was prematurely terminated (sponsor's decision) potentially limiting interpretation of results., Clinical Trial Registration: NCT01875003 (www.ClinicalTrials.gov)., Competing Interests: Stanley J. Szefler reports consultancy during the time of this report and currently for Aerocrine, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Genentech, Inc., Merck, Novartis, Propeller Health, Regeneron, Roche, Sanofi and Teva and research support from the US National Institutes of Health; US National Heart, Lung, and Blood Institute; US National Institute of Allergy and Infectious Diseases; US National Institute of Environmental Health Sciences; US Environmental Protection Agency; Cancer, Cardiovascular and Pulmonary Disease Program; and GlaxoSmithKline. Graham Roberts was the lead investigator in the United Kingdom for this study. Adalberto S. Rubin reports fees from AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Roche, Bristol, and Sanofi. Stefan Zielen reports grants and personal fees from bene‐Arzneimittel GmbH, grants from ALK Arzneimittel, personal fees from Novartis GmbH, Boehringer Ingelheim, Lofarma GmbH, IMS HEALTH GmbH and Co. OHG, GSK, Stallergen, Procter and Gamble, Allergopharma GmbH, AstraZeneca, Sanofi/Pasteur, and Aimmune outside the submitted work. Piotr Kuna reports personal fees from Astra, Boehringer Ingelheim, Berlin Chemie Menarini, GSK, Lekam, Novartis, Polpharma, Mylan, Orion, Teva, Adamed. Oral Alpan reports no disclosures that pertain to this submission. Cécile T J Holweg, and Wendy S. Putnam are former employees of Genentech, Inc. (a member of the Roche Group). Qiang Chen is an employee of Roche (China) Holding Ltd. Janusz Kaminski is a former employee of Roche Products Ltd. John G. Matthews is a former employee of Genentech, Inc. Judith Anzures‐Cabrera and Nikhil Kamath are employees of Roche Products Ltd., (© 2022 The Authors. Clinical and Translational Allergy published by John Wiley and Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Background: Effectiveness of asthma treatment, including biologics, may be different in patients with higher body mass index (BMI)., Objective: To evaluate response to omalizumab (dosed by serum immunoglobulin E level and weight) by BMI category., Methods: Pooled data from 2 randomized, double-blind, placebo-controlled studies of adults with moderate-to-severe allergic asthma were analyzed by BMI category (<25 kg/m 2 [normal or underweight], n = 397; 25 to <30 kg/m 2 [overweight], n = 330; ≥ 30 kg/m 2 [obese], n = 268). Placebo-adjusted exacerbation rate reductions were evaluated by Poisson regression modeling. Changes from baseline in forced expiratory volume in 1 second, beclomethasone dipropionate (BDP) dose, Total Asthma Symptom Score, and Asthma Quality of Life Questionnaire were evaluated by analysis of covariance., Results: Greater placebo-adjusted exacerbation rate reductions (95% confidence interval) were observed with increasing BMI (normal or underweight, -37.4% [-69.0% to 26.8%]; overweight, -52.7% [-78.4% to 3.7%]; obese, -71.9% [-86.9% to -39.5%]). There were no differences in forced expiratory volume in 1 second improvement between BMI categories at week 16 (normal or underweight, 76.2 [5.3-147.1] mL; overweight, 98.1 [13.9-182.4] mL; obese, 69.1 [-18.9 to 157.2] mL). No differences in BDP dose reduction (µg) were noted between BMI categories (normal or underweight, 23.0 [15.7-30.3]; overweight, 22.5 [13.5-31.5]; obese, 16.6 [5.8-27.3]). Fewer patients in the higher BMI categories eliminated BDP use. There were trends for smaller improvements with higher BMI in Total Asthma Symptom Score (normal/underweight, -0.52 [-0.82 to -0.22]; overweight, -0.50 [-0.80 to -0.20]; obese, -0.39 [-0.77 to 0.00]) and Asthma Quality of Life Questionnaire (normal or underweight, 0.34 [0.16-0.52]; overweight, 0.34 [0.13-0.55]; obese, 0.15 [-0.08 to 0.39])., Conclusion: Omalizumab provides benefit to patients with moderate-to-severe allergic asthma, regardless of BMI., Trial Registration: Studies 008/009 were conducted before clinical trial registration was required, and therefore clinical trial registration numbers are not available., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Genome-wide association studies (GWAS) have identified many common variant loci associated with asthma susceptibility, but few studies investigate the genetics underlying moderate-to-severe asthma risk. Here, we present a whole-genome sequencing study comparing 3181 moderate-to-severe asthma patients to 3590 non-asthma controls. We demonstrate that asthma risk is genetically correlated with lung function measures and that this component of asthma risk is orthogonal to the eosinophil genetics that also contribute to disease susceptibility. We find that polygenic scores for reduced lung function are associated with younger asthma age of onset. Genome-wide, seven previously reported common asthma variant loci and one previously reported lung function locus, near THSD4, reach significance. We replicate association of the lung function locus in a recently published GWAS of moderate-to-severe asthma patients. We additionally replicate the association of a previously reported rare (minor allele frequency < 1%) coding variant in IL33 and show significant enrichment of rare variant burden in genes from common variant allergic disease loci. Our findings highlight the contribution of lung function genetics to moderate-to-severe asthma risk, and provide initial rare variant support for associations with moderate-to-severe asthma risk at several candidate genes from common variant loci., (© 2022. The Author(s).)

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous disease with variable underlying pathophysiologies. Numerous patient factors have been linked to differences in disease severity, control, and response to treatment, including asthma status, aspirin sensitivity, previous sinonasal surgery, and blood eosinophil levels., Objective: The present study examines the efficacy of the anti-immunoglobulin E therapy, omalizumab, versus placebo in patients with CRSwNP from the replicate POLYP 1 (NCT03280550) and POLYP 2 (NCT03280537) trials, grouped by inherent patient characteristics to determine the response to therapy., Methods: Patients in prespecified subgroups from POLYP 1 and POLYP 2 (studies pooled for analysis) were examined. Subgroups included blood eosinophil count at baseline (>300 or ≤300 cells/μL), previous sinonasal surgery (yes or no), asthma status (yes or no), and aspirin sensitivity status (yes or no). Subgroups were examined for subgroup-specific adjusted mean difference (95% confidence interval [CI]) (omalizumab-placebo) in change from baseline at week 24 in Nasal Congestion Score (NCS), Nasal Polyp Score (NPS), Sino-Nasal Outcome Test-22 (SNOT-22), Total Nasal Symptom Score (TNSS), and University of Pennsylvania Smell Identification Test (UPSIT)., Results: Adjusted mean difference (95% CI) (omalizumab-placebo) in NCS, NPS, SNOT-22, TNSS, and UPSIT change from baseline at week 24 consistently favored omalizumab treatment over placebo in patients with blood eosinophil count >300 and ≤300 cells/μL, with or without previous sinonasal surgery, asthma, and aspirin sensitivity., Conclusion: Together, these data suggest broad efficacy of omalizumab across clinical and patient-reported outcomes in patients with CRSwNP, independent of the underlying patient factors examined, including those with high eosinophil levels and those who have undergone previous surgery, which are associated with high recurrence., Clinical Trial Registration: ClinicalTrials.gov identifiers: POLYP 1: ClinicalTrials.gov identifier NCT03280550 (https://clinicaltrials.gov/ct2/show/NCT03280550); POLYP 2: ClinicalTrials.gov identifier NCT03280537 (https://clinicaltrials.gov/ct2/show/NCT03280537).

Background: Although asthma is typically characterized by bronchodilator responsiveness (BDR), fixed airflow obstruction (FAO) occurs in ∼50% of patients with severe asthma., Objective: Do FAO/BDR associate with efficacy of omalizumab, a monoclonal antibody that targets IgE?, Methods: In EXTRA, patients aged 12-75 years with inadequately controlled severe allergic asthma despite high-dose inhaled corticosteroids plus long-acting β 2 -agonists were randomized to omalizumab (n = 427) or placebo (n = 423) for 48 weeks of treatment. In this post hoc analysis, high/low BDR were defined as ≥12%/<12% increases in baseline forced expiratory volume in 1 second (FEV 1 ) after bronchodilator administration, respectively. FAO presence (+)/absence (-) were defined as baseline postbronchodilator FEV 1 /forced vital capacity <70%/≥70%, respectively. Poisson regression/analysis of covariance models were used to estimate exacerbation relative rate reductions (RRRs)/least-squares mean changes in FEV 1 , respectively., Results: In patients with high BDR, omalizumab reduced exacerbations more than placebo over the 48-week treatment period regardless of FAO status (RRR [95% confidence interval (CI)]: FAO+, 59.8% [17.7-80.4%]; FAO-, 44.3% [16.6-62.8%]). Omalizumab improved FEV 1 compared with placebo in the FAO-, high BDR subgroup (FEV 1 change from baseline [95% CI] for omalizumab vs placebo, 0.065 L [-0.071 to 0.201 L] to 0.236 L [0.112-0.359 L]) across 48 weeks. This was not observed in patients with low BDR, irrespective of FAO., Conclusion: Omalizumab was more efficacious than placebo at reducing exacerbations in patients with high, but not low, BDR, regardless of the presence of FAO. Lung function improvement primarily occurred in FAO-, high BDR patients, suggesting that asthma with low BDR may represent a difficult-to-treat phenotype., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale: Blood eosinophil counts are used to inform diagnosis/management of eosinophilic asthma. Objectives: Examine blood eosinophil variability and identify factors affecting eosinophil levels to inform clinical interpretation. Methods: Post hoc analysis to understand eosinophil variability using data from four randomized controlled asthma trials. We examined 1 ) influence of intrinsic/extrinsic factors (comorbidities, medication, and patient history) using baseline data ( n  = 2,612); 2 ) monthly variation using placebo-treated patient data ( n  = 713); 3 ) stability of eosinophil classification (<150, 150-299, and ⩾300 cells/μl) in placebo-treated patients with monthly measurements over a 1-year period ( n  = 751); and 4 ) impact of technical factors (laboratory-to-laboratory differences and time from collection to analysis). Results: Of intrinsic/extrinsic factors examined, nasal polyps increased eosinophil levels by 38%, whereas current smoking decreased levels by 23%. Substantial seasonal differences in eosinophil counts were observed, with differences of ∼20% between July and January. Eosinophil levels between 150 and 299 cells/μl were least stable, with 44% of patients remaining in the same classification for seven of 10 measurements versus 59% and 66% of patients in the <150 and ⩾300 cells/μl subgroups, respectively. Measurements at different laboratories showed high association (Spearman's correlation coefficient, R  = 0.89); however, eosinophil counts were reduced, with longer time from collection to analysis, and variability increased with increasing eosinophil counts. Conclusions: Several intrinsic, extrinsic, and technical factors may influence, and should be considered in, clinical interpretation of eosinophil counts. Additionally, a single measurement may not be sufficient when using eosinophil counts for diagnosis/management of eosinophilic asthma.

Background: Asthma is a heterogeneous disease. Clinical blood parameters differ by race/ethnicity and are used to distinguish asthma subtypes and inform therapies. Differences in subtypes may explain population-specific trends in asthma outcomes. However, these differences in racial/ethnic minority pediatric populations are unclear., Objective: We investigated the association of blood parameters and asthma subtypes with asthma outcomes and examined population-specific eligibility for biologic therapies in minority pediatric populations., Methods: Using data from 2 asthma case-control studies of pediatric minority populations, we performed case-control (N = 3738) and case-only (N = 2743) logistic regressions to quantify the association of blood parameters and asthma subtypes with asthma outcomes. Heterogeneity of these associations was tested using an interaction term between race/ethnicity and each exposure. Differences in therapeutic eligibility were investigated using chi-square tests., Results: Race/ethnicity modified the association between total IgE and asthma exacerbations. Elevated IgE level was associated with worse asthma outcomes in Puerto Ricans. Allergic asthma was associated with worse outcomes in Mexican Americans, whereas eosinophilic asthma was associated with worse outcomes in Puerto Ricans. A lower proportion of Puerto Ricans met dosing criteria for allergic asthma-directed biologic therapy than other groups. A higher proportion of Puerto Ricans qualified for eosinophilic asthma-directed biologic therapy than African Americans., Conclusions: We found population-specific associations between blood parameters and asthma subtypes with asthma outcomes. Our findings suggest that eligibility for asthma biologic therapies differs across pediatric racial/ethnic populations. These findings call for more studies in diverse populations for equitable treatment of minority patients with asthma., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Higher asthma burden is more likely to be experienced by Black than White patients. In clinical research, underrepresentation of minority populations is observed., Objective: To estimate response to omalizumab in Black and White patients in North America with moderate to severe asthma., Methods: Data from placebo-controlled (EXTRA) and single-armed (PROSPERO) omalizumab studies were used for this post hoc analysis. We used a Poisson regression model to examine exacerbation rates. An analysis of covariance model was used to estimate placebo-corrected change in FEV 1 and Asthma Quality of Life Questionnaire (AQLQ) by racial group., Results: This analysis included 631 White and 176 Black patients from EXTRA and 567 White and 130 Black patients from PROSPERO. In EXTRA, placebo-corrected exacerbation rate reductions (relative rate change [95% confidence interval], 22.6% [2.0-38.9%] vs 22.0% [-18.0% to 48.4%]) and FEV 1 improvements were similar for White and Black patients. There was a trend toward greater AQLQ improvements for Black versus White patients (least squares mean treatment differences: 0.0 vs 0.3, 0.6 vs 0.4, and 0.6 vs 0.2 at weeks 16, 32, and 48, respectively) throughout the study. In PROSPERO, on-study exacerbation rates (0.76 [0.65-0.88] vs 0.77 [0.56-1.10]) and AQLQ improvements (least squares mean change from baseline: 1.2 vs 1.2 and 1.3 vs 1.2 at month 6 and end of study, respectively) were similar for White versus Black patients. A trend toward greater FEV 1 improvement was observed in White versus Black patients throughout the study., Conclusions: This analysis of EXTRA and PROSPERO suggests that Black and White patients with moderate to severe asthma experience similar improvements in exacerbations, FEV 1 , and AQLQ with omalizumab., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The anti-immunoglobulin E therapy, omalizumab, improves asthma control and reduces exacerbations in patients with moderate-to-severe allergic asthma. However, it has been suggested that omalizumab should be reserved for highly allergic patients with multiple allergen sensitivities or perennial-only sensitivities., Objective: To examine impact of allergy burden, including number and type of allergen sensitivities, on omalizumab response in a real-world setting., Methods: This post hoc analysis evaluated a subset of omalizumab-treated patients from the Prospective Observational Study to Evaluate Predictors of Clinical Effectiveness in Response to Omalizumab (NCT01922037) who had completed 13 allergen assessments (N=478). Patients were classified by allergen burden (nonsensitized, 1, 2-4, or ≥5 allergen sensitivities) and type of allergen (nonsensitized, seasonal, perennial, or both). Outcome measures included exacerbation rate vs previous year and improvements in lung function and Asthma Quality of Life Questionnaire (AQLQ)., Results: Comparable adjusted exacerbation rates were observed after omalizumab initiation, regardless of number or type of allergen sensitizations (0.56-0.85/y). Improvements in forced expiratory volume in 1 second from baseline at months 6 (0.03-0.09 L) and 12 (-0.08 to 0.08 L) were also similar across subgroups. Least squares mean change in AQLQ from baseline at months 6 (1.0-1.2) and 12 (1.1-1.4) was comparable across patient subgroups, and similar percentages of patients achieved AQLQ minimal clinically important difference of at least a 0.5-point improvement at month 6 (71%-75%), which was maintained or improved to month 12 (71%-89%). In all analyses, 95% confidence intervals overlapped., Conclusion: Overall findings suggest that patients with allergic asthma achieved comparable improvements across distinct outcome measures after omalizumab therapy in a real-world setting, regardless of number and type of allergen sensitizations., Trial Registration: ClinicalTrials.gov Identifier: NCT01922037., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Comorbidities are common in asthma and may complicate treatment response., Objective: To examine response to omalizumab in patients with moderate-to-severe allergic asthma by asthma-related and allergic comorbidities., Methods: Patients aged 12 years or more from placebo-controlled 008/009 (n = 1071), EXTRA (n = 848), and INNOVATE (n = 419), and single-armed PROSPERO (n = 801) omalizumab studies were included. Poisson regression/analysis of covariance models were used to estimate adjusted exacerbation rates and forced expiratory volume in 1 second (FEV1) change from baseline after omalizumab initiation for subgroups by number of comorbidities (0, 1 [008/009]; 0, 1, ≥2 [EXTRA and INNOVATE]; 0, 1, 2, ≥3 [PROSPERO]). Self-reported comorbidities included allergic rhinoconjunctivitis, chronic rhinosinusitis, recurrent acute sinusitis, nasal polyps, atopic and contact dermatitis, urticaria, food allergy, anaphylaxis, other allergies, gastroesophageal reflux disease, eosinophilic esophagitis, and eosinophilic granulomatosis with polyangiitis., Results: In the EXTRA and INNOVATE studies, no consistent pattern was observed for placebo-corrected relative rate reduction in normalized asthma exacerbations among omalizumab-treated comorbidity subgroups. In PROSPERO, on-study exacerbation rates in the comorbidity subgroups were similar (0, 0.68; 1, 0.70; 2, 0.77; ≥3, 0.80). FEV1 improvements were observed throughout the study for omalizumab vs placebo for all comorbidity subgroups. There were no consistent differences in FEV1 improvements among comorbidity subgroups in 008/009, EXTRA, or INNOVATE. Similarly, no among-group differences were observed for FEV1 change from baseline at month 12 in PROSPERO (0, 0.05 L; 1, 0.08 L; 2, 0.00 L; ≥3, 0.04 L). The 95% confidence intervals overlapped substantially in all instances., Conclusion: In these analyses of placebo-controlled/single-armed studies, on-study exacerbation rates and FEV1 improvements with omalizumab treatment were similar irrespective of comorbidity burden., Trial Registration: ClinicalTrials.gov identifiers are as follows: EXTRA, NCT00314574 (https://clinicaltrials.gov/ct2/show/NCT00314574); INNOVATE, NCT00046748 (https://clinicaltrials.gov/ct2/show/NCT00046748); and PROSPERO, NCT01922037 (https://clinicaltrials.gov/ct2/show/NCT01922037)., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Current biologic therapies target allergic, eosinophilic or type 2 inflammation phenotypic asthma. However, frequency and degree of overlap among these subtypes is unclear., Objective: To characterize overlap among allergic, eosinophilic and type 2 asthma phenotypes., Methods: Post hoc analyses of baseline data were performed in two adult populations: (a) not selected for any asthma subtype (N = 935) and (b) selected for allergic asthma (N = 1049). Degree of overlap was examined using commonly accepted phenotypic definitions to guide treatment for allergic asthma (skin prick-positive and/or positive serum-specific immunoglobulin E > 0.35 kU/L) and eosinophilic asthma (blood eosinophil high count ≥ 300 cells/µL; low cut-off ≥ 150 cells/µL). Consistent with previous studies, fractional exhaled nitric oxide high level of ≥ 35 ppb and low cut-off of ≥ 25 ppb were selected as local markers of type 2 inflammation and to prevent overlap with the systemic eosinophilic asthma definition., Results: In the non-subtype-selected population, 78.0% had allergic asthma; of these, 39.5% had eosinophilic asthma and 29.5% had type 2 asthma. Within patients with eosinophilic asthma (40.6% of total), 75.8% had allergic asthma and 41.3% had type 2 asthma. Within patients with type 2 asthma (28.3% of total), 81.1% had allergic asthma and 59.2% had eosinophilic asthma. In the allergic asthma-selected population, 38.3% had eosinophilic asthma and 29.2% had type 2 asthma. Within patients with eosinophilic asthma, 46.3% had type 2 asthma. Within patients with type 2 asthma, 60.8% had eosinophilic asthma. Overlaps among subtypes increased at low cut-off values., Conclusions and Clinical Relevance: In this post hoc analysis in adults with moderate-to-severe asthma, allergic asthma was the most prevalent phenotype, followed by eosinophilic and type 2 asthma. Despite observed overlaps, a considerable proportion of patients had only a predominantly allergic subtype. Understanding the degree of overlap across phenotypes will help patient management and guide treatment options., (© 2020 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Background: Asthma treatment guidelines recommend increasing corticosteroid dose to control symptoms and reduce exacerbations. This approach is potentially flawed because symptomatic asthma can occur without corticosteroid responsive type-2 (T2)-driven eosinophilic inflammation, and inappropriately high-dose corticosteroid treatment might have little therapeutic benefit with increased risk of side-effects. We compared a biomarker strategy to adjust corticosteroid dose using a composite score of T2 biomarkers (fractional exhaled nitric oxide [FENO], blood eosinophils, and serum periostin) with a standardised symptom-risk-based algorithm (control)., Methods: We did a single-blind, parallel group, randomised controlled trial in adults (18-80 years of age) with severe asthma (at treatment steps 4 and 5 of the Global Initiative for Asthma) and FENO of less than 45 parts per billion at 12 specialist severe asthma centres across England, Scotland, and Northern Ireland. Patients were randomly assigned (4:1) to either the biomarker strategy group or the control group by an online electronic case-report form, in blocks of ten, stratified by asthma control and use of rescue systemic steroids in the previous year. Patients were masked to study group allocation throughout the entirety of the study. Patients attended clinic every 8 weeks, with treatment adjustment following automated treatment-group-specific algorithms: those in the biomarker strategy group received a default advisory to maintain treatment and those in the control group had their treatment adjusted according to the steps indicated by the trial algorithm. The primary outcome was the proportion of patients with corticosteroid dose reduction at week 48, in the intention-to-treat (ITT) population. Secondary outcomes were inhaled corticosteroid (ICS) dose at the end of the study; cumulative dose of ICS during the study; proportion of patients on maintenance oral corticosteroids (OCS) at study end; rate of protocol-defined severe exacerbations per patient year; time to first severe exacerbation; number of hospital admissions for asthma; changes in lung function, Asthma Control Questionnaire-7 score, Asthma Quality of Life Questionnaire score, and T2 biomarkers from baseline to week 48; and whether patients declined to progress to OCS. A secondary aim of our study was to establish the proportion of patients with severe asthma in whom T2 biomarkers remained low when corticosteroid therapy was decreased to a minimum ICS dose. This study is registered with ClinicalTrials.gov, NCT02717689 and has been completed., Findings: Patients were recruited from Jan 8, 2016, to July 12, 2018. Of 549 patients assessed, 301 patients were included in the ITT population and were randomly assigned to the biomarker strategy group (n=240) or to the control group (n=61). 28·4% of patients in the biomarker strategy group were on a lower corticosteroid dose at week 48 compared with 18·5% of patients in the control group (adjusted odds ratio [aOR] 1·71 [95% CI 0·80-3·63]; p=0·17). In the per-protocol (PP) population (n=121), a significantly greater proportion of patients were on a lower corticosteroid dose at week 48 in the biomarker strategy group (30·7% of patients) compared with the control group (5·0% of patients; aOR 11·48 [95% CI 1·35-97·83]; p=0·026). Patient choice to not follow treatment advice was the principle reason for loss to PP analysis. There was no difference in secondary outcomes between study groups and no loss of asthma control among patients in the biomarker strategy group who reduced their corticosteroid dose., Interpretation: Biomarker-based corticosteroid adjustment did not result in a greater proportion of patients reducing corticosteroid dose versus control. Understanding the reasons for patients not following treatment advice in both treatment strategies is an important area for future research. The prevalence of T2 biomarker-low severe asthma was low., Funding: This study was funded, in part, by the Medical Research Council UK., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Rationale: New approaches are needed to guide personalized treatment of asthma. Objectives: To test if urinary eicosanoid metabolites can direct asthma phenotyping. Methods: Urinary metabolites of prostaglandins (PGs), cysteinyl leukotrienes (CysLTs), and isoprostanes were quantified in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy control participants. Validation was performed internally in 302 participants with SA followed up after 12-18 months and externally in 95 adolescents with asthma. Measurement and Main Results: Metabolite concentrations in healthy control participants were unrelated to age, body mass index, and sex, except for the PGE 2 pathway. Eicosanoid concentrations were generally greater in participants with MMA relative to healthy control participants, with further elevations in participants with SA. However, PGE 2 metabolite concentrations were either the same or lower in male nonsmokers with asthma than in healthy control participants. Metabolite concentrations were unchanged in those with asthma who adhered to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas those with SA treated with omalizumab had lower concentrations of LTE 4 and the PGD 2 metabolite 2,3-dinor-11β-PGF 2α . High concentrations of LTE 4 and PGD 2 metabolites were associated with lower lung function and increased amounts of exhaled nitric oxide and eosinophil markers in blood, sputum, and urine in U-BIOPRED participants and in adolescents with asthma. These type 2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study and were found to be as sensitive to detect T2 inflammation as the established biomarkers. Conclusions: Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new noninvasive approach for molecular phenotyping of adult and adolescent asthma.Clinical trial registered with www.clinicaltrials.gov (NCT01976767).

Background: The anti-interleukin 13 (IL-13) monoclonal antibody lebrikizumab improves lung function in patients with moderate-to-severe uncontrolled asthma, but its effects on airway inflammation and remodelling are unknown. CLAVIER was designed to assess lebrikizumab's effect on eosinophilic inflammation and remodelling., Objective: To report safety and efficacy results from enrolled participants with available data from CLAVIER., Methods: We performed bronchoscopy on patients with uncontrolled asthma before and after 12 weeks of randomized double-blinded treatment with lebrikizumab (n = 31) or placebo (n = 33). The pre-specified primary end-point was relative change in airway subepithelial eosinophils per mm 2 of basement membrane (cells/mm 2 ). Pre-specified secondary and exploratory outcomes included change in IL-13-associated biomarkers and measures of airway remodelling., Results: There was a baseline imbalance in tissue eosinophils and high variability between treatment groups. There was no discernible change in adjusted mean subepithelial eosinophils/mm 2 in response to lebrikizumab (95% CI, -82.5%, 97.5%). As previously observed, FEV 1 increased after lebrikizumab treatment. Moreover, subepithelial collagen thickness decreased 21.5% after lebrikizumab treatment (95% CI, -32.9%, -10.2%), and fractional exhaled nitric oxide, CCL26 and SERPINB2 mRNA expression in bronchial tissues also reduced. Lebrikizumab was well tolerated, with a safety profile consistent with other lebrikizumab asthma studies., Conclusions & Clinical Relevance: We did not observe reduced tissue eosinophil numbers in association with lebrikizumab treatment. However, in pre-specified exploratory analyses, lebrikizumab treatment was associated with reduced degree of subepithelial fibrosis, a feature of airway remodelling, as well as improved lung function and reduced key pharmacodynamic biomarkers in bronchial tissues. These results reinforce the importance of IL-13 in airway pathobiology and suggest that neutralization of IL-13 may reduce asthmatic airway remodelling., Clinical Trial Registration: NCT02099656., (© 2020 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Introduction: Asthma exacerbations spike in the spring and autumn months, yet the seasonal variation of asthma symptoms and lung function is poorly studied., Methods: Seasonal variation of lung function, rescue medication use and patient-reported symptoms was evaluated by post hoc analyses of the Phase III lebrikizumab (anti-IL-13) LAVOLTA I and II studies in 2148 subjects with uncontrolled asthma. Lung function measurements (prebronchodilator FEV 1 , forced vital capacity (FVC) and peak expiratory flow (PEF)), rescue medication use and Standardised Asthma Quality of Life Questionnaire (AQLQ(S)) were measured every 4 weeks over 52 weeks. By-month estimates normalised by hemispheric season were based on mixed-effect models with repeated measures (MMRM), adjusted by study stratification factors as covariates when appropriate. The dependency of clinical outcomes with seasonal variability was assessed by employing linear contrasts comparing hemisphere normalised December versus July group means from an MMRM regression and presented as the difference in means (adjusted 95% CI)., Results: FEV 1 , FVC and PEF, rescue medication use and AQLQ(S) progressively worsened towards winter, unlike spring and autumn surges in asthma exacerbations. The December versus July mean differences were: (1) PEF=-6.5 (-8.7 to -4.2) L/min, 2) prebronchodilator FEV 1 =-42 (-57 to -27) mL, (3) FVC=-41 (-59 to -23) mL and (4) AQLQ(S)=-0.15 (-0.19 to -0.1) units. Among AQLQ questions, discomfort or distress related to cough was most variable with respect to season (-0.33 (-0.42 to -0.24) units)., Discussion: Interpretation of interventional studies biased by seasonal exposures may be confounded by seasonal variability., Trials Registration Numbers: NCT01867125 and NCT01868061., Competing Interests: Competing interests: RB, XY, TS, JO, CTJH, JA and DFC are employees of Genentech, Inc and hold Roche stocks and/or options. JGM was previously an employee of Genentech at the time of this study., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Type-2 biomarkers and related cytokines (IL-5, IL-13), lung function and asthma symptoms were measured in 44 poorly-controlled severe oral corticosteroid (OCS)-dependent asthmatics for up to 88 days after a 7-day prednisolone boost (0.5 mg/kg). High-dose OCS reduced median blood eosinophils (-60 cells/µl; 95% CI -140 to 10), periostin (-8.4 ng/mL; -11.6 to -2.8), FeNO (-19.0 ppb; -28.5 to -4.0), IL-5 (-0.17 pg/mL; -0.28 to -0.08) and IL-13 (-0.15 pg/mL; -0.27 to -0.03). There were small improvements in mean FEV 1 (0.16 L; 0.05 to 0.27) and (Asthma Control Questionnaire) ACQ-7 score (0.3; 0.0 to 0.7). Study measures returned to baseline 1-month postintervention. Following rescue OCS, 1 month is sufficient before using type-2 biomarkers to guide long-term treatment. TRIAL REGISTRATION NUMBER: NCT01948401., Competing Interests: Competing interests: CH, AC, JGM, TS are (or were at time of study) employees of Genentech Inc., a Member of the Roche Group and own Roche stock. RC has attended Advisory Board Meetings for AstraZeneca, GSK, Novartis and Teva and been a speaker at meetings for AstraZeneca. She has attended conferences supported by Boehringer, Teva, AstraZeneca and received educational grants from Novartis and Aerocrine. AHM received personal and department funds for talks and advisory board meetings and was sponsored to attend national and international conferences from pharmaceutical companies that include GlaxoSmithKline, Astra Zeneca, Novartis, NAPP, Boehringer Ingelheim, Roche, Chiesi. AM-G has attended advisory boards with GlaxoSmithKline, Novartis, AstraZeneca, Boehringer Ingelheim and Teva. He has received speaker fees from Novartis, AstraZeneca, Vectura, Boehringer Ingelheim, Sanofi and Teva. He has participated in research with Hoffman La Roche, GlaxoSmithKline, Boehringer Ingelheim and Astra Zeneca. He has attended international conferences with Teva and Boehringer Ingelheim and has consultancy agreements with AstraZeneca, Sanofi and Vectura. RN has received an unrestricted grant of £10,000 from Novartis in 2010 towards development of clinical services at the University Hospital of South Manchester. He has run preceptorship programmes in 2015 and 2016. These programmes have resulted in payment to the University Hospital of south Manchester for amounts not exceeding £10,000. He has also performed lecturing at Pharmaceutically sponsored meetings for the following pharmaceutical companies in the last 3 years: Astra Zeneca (<£1000), Boehringer Ingelheim (<£2000) Boston scientific (<£5000) Chiesi (<£1000), Novartis < £10,000, Napp (<£2000), Teva (<£2000). He has sat on advisory boards for the following companies in the last 3 years (Astra Zeneca, Boehringer Ingelheim, Boston scientific, Chiesi, GSK, Novartis Vectura and Teva), receiving reimbursement not exceeding £5000 per company. He has received sponsorship support to attend international academic meetings from Astra Zeneca, Boehringer ingelheim, Novartis, GSK, Chiesi and TEVA. RN (or any members of his family) has no shares or any pecuniary interest in any pharmaceutical industry and has no shareholdings or dividends and is not a paid consultant for any company. LGH is Academic Lead for the Medical Research Council Stratified Medicine UK Consortium in Severe Asthma which involves industrial partnerships with a number of pharmaceutical companies., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

We investigated the time course of change of type-2 asthma biomarkers after a severe asthma exacerbation. Blood eosinophils were lowest immediately after treatment was initiated (0.07 vs 0.33×10 9 /L, p<0.001) while serum IgE levels were at their highest (339 vs 249 U/L, p<0.001). Fractional exhaled Nitric Oxide levels were lowest 2 weeks after treatment (23 vs 33 ppb, p=0.06) and serum periostin levels were lowest 1 week after treatment (45·9 vs 50·9 ng/mL, p<0.001). A delay of 4-8 weeks following a severe exacerbation is required if these biomarkers are used to guide the ongoing management of patients with asthma. TRIAL REGISTRATION NUMBER: Post-results; The Australia New Zealand Trial Registry, >ACTRN12614000443695., Competing Interests: Competing interests: CH and JM are employees of Genentech Inc., a member of the Roche group. RB reports grants from Genentech during the conduct of the study; personal fees from Health Research Council of New Zealand, Glaxo Smith Kline, AstraZeneca, and Novartis outside the submitted work; grants from AstraZeneca, Chiese, Cephalon, Genentech, Novartis and Sanofi Aventis outside the submitted work. Other authors have no competing interests to declare., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Identification of a biomarker for disease activity in eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss) remains an unmet need. This study examined the value of serum periostin, a marker of type 2 inflammation, as a measure of disease activity in patients with EGPA., Methods: Participants enrolled in a multicenter, prospective cohort of patients with EGPA were included in this study if they had disease activity (defined as Birmingham Vasculitis Activity Score [BVAS] > 0) during follow-up. Serum levels of periostin were measured at flare visit as well as two pre- and two post-flare visits, if available. The outcome of disease activity was assessed either with BVAS or Physician Global Assessment (PGA). Mixed-effect models were used to examine the association between periostin levels and disease activity. Comparisons were made with a historical cohort of healthy individuals and patients with asthma., Results: In the 49 patients included in the study, the median periostin level was 60 ng/ml (IQR 50 to 73) in all visits and did not significantly change across visits. Multivariate analyses found no association between periostin level and presence or absence of flare according to the BVAS (adjusted OR 1.00 [95% CI 0.98 to 1.02], p = 0.98) but an increase in periostin level was significantly associated with greater disease severity during a flare according to the PGA (adjusted beta-coefficient 0.02 [95% CI 0.004 to 0.03], p = 0.01). Periostin levels in EGPA were significantly higher than previously studied healthy controls and patients with asthma., Conclusion: In EGPA serum periostin level is modestly associated with greater disease severity during a flare but does not discriminate active from inactive disease. Periostin levels in EGPA are higher than in other previously studied cohorts, including healthy populations and patients with asthma, and are relatively stable over time., Competing Interests: CTJH and KW are full-time employees of Genentech Inc. We confirm that CTJH and KW’s employment at Genentech, Inc does not alter our adherence to the journal’s policies on data sharing.

Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) was initiated in the first year of the Innovative Medicines Initiative (IMI). It was an ambitious plan to tackle the understanding of asthma through an integration of clinical and multi-'omics approaches that necessitated the bringing together of industry, academic, and patient representatives because it was too large to be managed by any one of the partners in isolation. It was a novel experience for all concerned. In this review, we describe the main features of the U-BIOPRED experience from the industry perspective. We list some of the key advantages and learnings from the perspective of the authors, and also improvements that we feel could be made in future projects., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Asthma is a heterogeneous and complex disease in both its clinical course and response to treatment. IL-13 is central to Type 2 inflammation and contributes to many features of asthma. In a previous Phase 2 study, lebrikizumab, an anti-IL-13 monoclonal antibody, did not significantly improve FEV 1 in mild-to-moderate asthma patients not receiving ICS therapy. This Phase 3 study was designed to further assess the efficacy and safety of lebrikizumab in adult patients with mild-to-moderate asthma treated with daily short-acting β 2 -agonist therapy alone., Methods: Adult patients with mild-to-moderate asthma were randomised to receive lebrikizumab 125 mg subcutaneously (SC), placebo SC, or montelukast 10 mg orally for 12 weeks, with an 8-week follow-up period. The primary efficacy endpoint was absolute change in pre-bronchodilator FEV 1 from baseline at Week 12., Findings: A total of 310 patients were randomised and dosed in the study. The mean absolute change in FEV 1 from baseline at Week 12 was higher in the lebrikizumab-treated arm compared with placebo (150 mL versus 67 mL); however, this improvement did not achieve statistical significance (overall adjusted difference of 83 mL [95% CI: -3, 170]; p = .06). Montelukast did not improve FEV 1 as compared with placebo. Lebrikizumab was generally safe and well tolerated during the study., Interpretation: Lebrikizumab did not significantly improve FEV 1 in mild-to-moderate asthma patients at a dose expected to inhibit the IL-13 pathway. Inhibiting IL-13 in this patient population was not sufficient to improve lung function. These data support the findings of a previous trial of lebrikizumab in patients not receiving ICS., Clinical Trials Registry Number: This trial was registered under NCT02104674 at http://www.clinicaltrials.gov., (Copyright © 2017. Published by Elsevier Ltd.)

Lebrikizumab is a humanized monoclonal antibody that binds to interleukin-13 and has been evaluated as a treatment for moderate-to-severe asthma. Objectives of this work were to characterize lebrikizumab pharmacokinetics (PK), identify influential covariates, and graphically explore exposure-response relationships in moderate-to-severe asthmatics. Pooled PK data from 11 studies were used in the population PK model development. Full covariate modeling was used to evaluate the impact of pre-specified covariates. Response data (exacerbation rate, forced expiratory volume in 1 s [FEV 1 ], and fractional exhaled nitric oxide [FeNO]) were obtained from moderate-to-severe asthmatics (n = 2148) who received placebo, lebrikizumab 37.5 mg or 125 mg every 4 weeks (Q4W) in two replicate phase 3 studies. Graphical exposure-response analyses were stratified by numerous covariates, including biomarker subgroups defined by serum periostin level and blood eosinophil count at baseline. Lebrikizumab PK was described by a two-compartment model with first-order absorption. Population typical values were estimated as 0.156 L/day for clearance (CL), 4.10 L for central volume (Vc), and 0.239 day -1 for absorption rate (ka), 85.6% for bioavailability (inter-subject variability: CL, 33.3%; Vc, 36.3%; ka, 40.8%). The estimated mean terminal half-life was 25.7 days. Body weight was the most influential covariate. Generally, the exposure-response analyses of FEV 1 and FeNO showed increased response at higher exposure quartiles, while flat or unclear exposure-response relationships were observed in exacerbation rate. Lebrikizumab PK is as expected for a typical immunoglobulin G4 monoclonal antibody. Results from the exposure-response analyses suggested that, compared to 125 mg Q4W, the 37.5 mg Q4W dose did not achieve the maximum responses for FEV 1 and FeNO, although it appeared to maximize the effect on exacerbation reduction. This suggests that the antibody levels needed to improve these outcomes may not be the same. In addition, the role of IL-13 in airflow obstruction/airway inflammation and asthma exacerbations might be different and targeting multiple pathways may be required to treat this heterogeneous disease and provide clinically meaningful benefits to asthma patients., (Copyright © 2017 Genentech, Inc. Published by Elsevier Ltd.. All rights reserved.)

Asthma is characterized by episodic, reversible airflow obstruction associated with variable levels of inflammation. Over the past several decades, there has been an increasing appreciation that the clinical presentation of asthma comprises a diverse set of underlying pathologies. Rather than being viewed as a single disease entity, asthma is now thought of as a clinical syndrome with the involvement of multiple pathological mechanisms. While it is appreciated that eosinophilia is present in only a subset of patients, it remains a key feature of asthma and other eosinophilic disorders such as atopic dermatitis, eosinophilic esophagitis, and chronic rhinosinusitis with nasal polyps. Eosinophils are bone marrow-derived leukocytes present in low numbers in health; however, during disease the type 2 cytokines [interleukins (IL)-4, -5, and -13] can induce rapid eosinophilopoiesis, prolonged eosinophil survival, and trafficking to the site of injury. In diseases such as allergic asthma there is an aberrant inflammatory response leading to eosinophilia, tissue damage, and airway pathology. IL-13 is a pleiotropic type 2 cytokine that has been shown to be integral in the pathogenesis of asthma and other eosinophilic disorders. IL-13 levels are elevated in animal models of eosinophilic inflammation and in the blood and tissue of patients diagnosed with eosinophilic disorders. IL-13 signaling elicits many pathogenic mechanisms including the promotion of eosinophil survival, activation, and trafficking. Data from preclinical models and clinical trials of IL-13 inhibitors in patients have revealed mechanistic insights into the role of this cytokine in driving eosinophilia. Promising results from clinical trials further support a key mechanistic role of IL-13 in asthma and other eosinophilic disorders. Here, we provide a perspective on the role of IL-13 in asthma and other eosinophilic disorders and describe ongoing clinical trials targeting this pathway in patients with significant unmet medical needs.

Blood eosinophil counts and serum periostin levels are biomarkers of type 2 inflammation. Although serum levels of HDL and apoA-I have been associated with less severe airflow obstruction in asthma, it is not known whether serum lipids or lipoprotein particles are correlated with type 2 inflammation in asthmatics. Here, we assessed whether serum lipids and lipoproteins correlated with blood eosinophil counts or serum periostin levels in 165 atopic asthmatics and 163 nonasthmatic subjects with and without atopy. Serum lipids and lipoproteins were quantified using standard laboratory assays and NMR spectroscopy. Absolute blood eosinophils were quantified by complete blood counts. Periostin levels were measured using the Elecsys® periostin assay. In atopic asthmatics, blood eosinophils negatively correlated with serum HDL cholesterol and total HDL particles measured by NMR spectroscopy (HDL NMR ). Serum periostin levels negatively correlated with total HDL NMR In contrast, blood eosinophil counts positively correlated with serum triglyceride levels. This study demonstrates for the first time that HDL particles were negatively correlated, whereas serum triglycerides were positively correlated, with blood eosinophils in atopic asthmatics. This supports the concept that serum levels of HDL and triglycerides may be linked to systemic type 2 inflammation in atopic asthma., (Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.)

Background: Biomarkers, preferably noninvasive, that predict asthma inception in children are lacking., Objective: Little is known about biomarkers of type 2 inflammation in early life in relation to asthma inception. We evaluated aeroallergen sensitization, peripheral blood eosinophils, and serum periostin as potential biomarkers of asthma in children., Methods: Children enrolled in the Childhood Origins of ASThma study were followed prospectively from birth. Blood samples were collected at ages 2, 4, 6, and 11 years, and serum-specific IgE levels, blood eosionophil counts, and periostin levels were measured in 244 children. Relationships among these biomarkers, age, and asthma were assessed., Results: Serum periostin levels were approximately 2- to 3-fold higher in children than previously observed adult levels. Levels were highest at 2 years (145 ng/mL), and did not change significantly between 4 and 11 years (128 and 130 ng/mL). Age 2 year periostin level of 150 ng/mL or more predicted asthma at age 6 years (odds ratio [OR], 2.3; 95% CI, 1.3-4.4). Eosinophil count of 300 cells/μL or more and aeroallergen sensitization at age 2 years were each associated with increased risk of asthma at age 6 years (OR, 3.1; 95% CI, 1.7-6.0 and OR, 3.3; 95% CI, 1.7-6.3). Children with any 2 of the biomarkers had a significantly increased risk of developing asthma by school age (≥2 biomarkers vs none: OR, 6.6; 95% CI, 2.7-16.0)., Conclusions: Serum periostin levels are significantly higher in children than in adults, likely due to bone turnover, which impairs clinical utility in children. Early life aeroallergen sensitization and elevated blood eosinophils are robust predictors of asthma development. Children with evidence of activation of multiple pathways of type 2 inflammation in early life are at greatest risk for asthma development., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)