Geographic variation in disease burden among patients with severe persistent asthma in the United States.

BACKGROUND: In the United States, a few studies have evaluated geographic variation of severe asthma at the subnational level. OBJECTIVE: To assess state-level geographic variation in the prevalence and characteristics of severe persistent asthma in the United States. METHODS: Patients aged above or equal to 12 years with severe persistent asthma were identified using nationally representative data from IQVIA open-source Medical/Pharmacy Claims and PharMetrics Plus databases (January 2019-December 2020). The index date was defined as the patient's earliest qualifying date for a severe asthma diagnosis. Baseline characteristics were measured during the 12-month pre-index period. Outcomes including exacerbation occurrence, asthma control, and medication use were measured during the 12-month post-index period and compared across states using census-level projections. RESULTS: A total of 2,092,799 patients with asthma were identified; 496,750 (23.7%) met criteria for severe persistent asthma and all inclusion criteria. Mean age was 50.5 years; 68.4% were females. The prevalence of severe persistent asthma varied across states, ranging from 19.6% (New Mexico) to 31.9% (Alaska). Among patients with severe persistent asthma, 40.9% had more than or equal to 1 exacerbation, ranging from 34.2% (Vermont) to 45.6% (Louisiana); 21.1% had uncontrolled disease, ranging from 16.5% (Vermont) to 24.0% (Arizona). Among patients with exacerbations, 13.7% had exacerbation-related emergency department visits or hospitalizations, ranging from 7.0% (North Carolina) to 17.7% (Nevada). Among patients with severe uncontrolled asthma, 15.6% used biologics post-index, ranging from 2.2% (Hawaii) to 27.9% (Mississippi). CONCLUSION: There is significant variability in severe persistent asthma prevalence and disease burden across US states. Reasons for geographic variation may include differences in socioeconomic/environmental factors or asthma management.

Biomarkers and clinical outcomes after tezepelumab cessation: Extended follow-up from the 2-year DESTINATION study.

BACKGROUND: Long-term tezepelumab treatment in the DESTINATION study (NCT03706079) resulted in reduced asthma exacerbations, reduced biomarker levels, and improved lung function and symptom control in patients with severe, uncontrolled asthma. OBJECTIVE: To explore the time course of changes in biomarkers and clinical manifestations after treatment cessation after 2 years of tezepelumab treatment. METHODS: DESTINATION was a 2-year, phase 3, multicenter, randomized, placebo-controlled, double-blind study of tezepelumab treatment in patients (12-80 years old) with severe asthma. Patients received their last treatment doses at week 100 and could enroll in an extended follow-up period from weeks 104 to 140. Change over time in key biomarkers and clinical outcomes were assessed in tezepelumab vs placebo recipients for 40 weeks after stopping treatment. RESULTS: Of 569 patients enrolled in the extended follow-up period, 426 were included in the analysis (289 received tezepelumab and 137 placebo). In the 40-week period after the last tezepelumab dose, blood eosinophil counts, fractional exhaled nitric oxide levels, and Asthma Control Questionnaire-6 scores gradually increased from weeks 4 to 10, with a gradual reduction in pre-bronchodilator forced expiratory volume in 1 second such that blood eosinophil counts, fractional exhaled nitric oxide levels, and clinical outcomes returned to placebo levels; however, none of these outcomes returned to baseline levels. Total IgE levels increased later from week 28 and remained well below placebo and baseline levels during the 40-week period after the last tezepelumab dose. CONCLUSION: This analysis reveals the benefits of continued tezepelumab treatment in the management of patients with severe, uncontrolled asthma, compared with stopping treatment after 2 years. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03706079.

Efficacy of Tezepelumab in Severe, Uncontrolled Asthma: Pooled Analysis of the PATHWAY and NAVIGATOR Clinical Trials.

Rationale: Tezepelumab reduced exacerbations in patients with severe, uncontrolled asthma across a range of baseline blood eosinophil counts and fractional exhaled nitric oxide levels, and irrespective of allergy status, in the phase 2b PATHWAY (Study to Evaluate the Efficacy and Safety of MEDI9929 [AMG 157] in Adult Subjects With Inadequately Controlled, Severe Asthma; NCT02054130) and phase 3 NAVIGATOR (Study to Evaluate Tezepelumab in Adults & Adolescents With Severe Uncontrolled Asthma; NCT03347279) trials. Objectives: To examine the efficacy and safety of tezepelumab in additional clinically relevant subgroups using pooled data from PATHWAY and NAVIGATOR. Methods: PATHWAY and NAVIGATOR were randomized, double-blind, placebo-controlled trials with similar designs. This pooled analysis included patients with severe, uncontrolled asthma (PATHWAY, 18-75 years old; NAVIGATOR, 12-80 years old) who received tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. The annualized asthma exacerbation rate over 52 weeks and secondary outcomes were calculated in the overall population and in subgroups defined by inflammatory biomarker levels or clinical characteristics. Measurements and Main Results: Overall, 1,334 patients were included (tezepelumab, n = 665; placebo, n = 669). Tezepelumab reduced the annualized asthma exacerbation rate versus placebo by 60% (rate ratio, 0.40 [95% confidence interval, 0.34-0.48]) in the overall population, and clinically meaningful reductions in exacerbations were observed in tezepelumab-treated patients with type 2-high and type 2-low disease by multiple definitions. Tezepelumab reduced exacerbation-related hospitalization or emergency department visits and improved secondary outcomes compared with placebo overall and across subgroups. The incidence of adverse events was similar between treatment groups. Conclusions: Tezepelumab resulted in clinically meaningful reductions in exacerbations and improvements in other outcomes in patients with severe, uncontrolled asthma, across clinically relevant subgroups. Clinical trials registered with www.clinicaltrials.gov (NCT02054130 [PATHWAY], NCT03347279 [NAVIGATOR]).

Efficacy of tezepelumab in patients with evidence of severe allergic asthma: Results from the phase 3 NAVIGATOR study.

BACKGROUND: Allergic asthma is the most common phenotype among patients with severe asthma. In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab significantly reduced the annualized asthma exacerbation rate (AAER) versus placebo in patients with severe, uncontrolled asthma. This exploratory analysis evaluated the efficacy of tezepelumab in NAVIGATOR participants with evidence of severe allergic asthma. METHODS: Patients (12-80 years old) receiving medium- or high-dose inhaled corticosteroids and ≥ 1 additional controller medication, with or without oral corticosteroids, were randomized to tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks in NAVIGATOR. In this analysis, the AAER, forced expiratory volume in 1 second (FEV1 ), patient-reported outcomes (PROs), and type 2 biomarker levels were evaluated in patients grouped by sensitivity to perennial aeroallergens, confirmed symptomatic allergy, and eligibility for omalizumab treatment according to the United States (OMA-US) and the European Union (OMA-EU) prescribing information, including subgroups according to baseline blood eosinophil counts and fractional exhaled nitric oxide (FeNO) levels. RESULTS: Of 1059 patients who received treatment in NAVIGATOR, 680 (64%) had perennial aeroallergen sensitivity and 318 (30%) had confirmed symptomatic allergy; 379 (36%) and 359 (34%) patients were OMA-US- and OMA-EU-eligible, respectively. Tezepelumab reduced the AAER over 52 weeks versus placebo by 58% (95% confidence interval [CI]: 47-67) to 68% (95% CI: 55-77) across these subgroups. Among omalizumab-eligible patients, AAERs were reduced in patients across baseline blood eosinophil counts and FeNO levels. Tezepelumab improved FEV1 and PROs, and reduced type 2 biomarkers, versus placebo in patients with and without perennial allergy. CONCLUSIONS: Tezepelumab was efficacious in patients with severe, uncontrolled asthma with evidence of allergic inflammation, defined by multiple clinically relevant definitions. These findings further support the benefits of tezepelumab in a broad population of patients with severe asthma, including those with severe allergic asthma.

Number of patient-reported asthma triggers predicts uncontrolled disease among specialist-treated patients with severe asthma.

BACKGROUND: Patients with severe asthma (SA) experience a high disease burden, often precipitated by exposure to disease triggers. OBJECTIVE: To evaluate the prevalence and effects of patient-reported triggers on asthma disease burden in a cohort of subspecialist-treated patients with SA in the United States. METHODS: CHRONICLE is an observational study of adults with SA receiving biologics or maintenance systemic corticosteroids or whose disease is uncontrolled on high-dosage inhaled corticosteroids and additional controllers. Data were analyzed for patients enrolled between February 2018 and February 2021. This analysis evaluated patient-reported triggers from a 17-category survey and associations with multiple measures of disease burden. RESULTS: Among 2793 enrolled patients, 1434 (51%) completed the trigger questionnaire. The median trigger number per patient was 8 (interquartile range, 5-10). The most frequent triggers were weather or air changes, viral infections, seasonal allergies, perennial allergies, and exercise. Patients reporting more triggers experienced more poorly controlled disease, worse quality of life, and reduced work productivity. The annualized rates of exacerbations and asthma hospitalizations increased by 7% and 17%, respectively, for each additional trigger (both P < .001). For all measures, trigger number was a stronger predictor of disease burden than blood eosinophil count. CONCLUSION: Among US specialist-treated patients with SA, asthma trigger number was positively and significantly associated with greater uncontrolled disease burden across multiple measures, which highlights the importance of understanding patient-reported triggers in SA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03373045.

Effect of tezepelumab on healthcare utilization in patients with severe, uncontrolled asthma: The NAVIGATOR study.

BACKGROUND: Tezepelumab, a human monoclonal antibody, blocks thymic stromal lymphopoietin. In the phase 3 NAVIGATOR study, tezepelumab reduced exacerbations and improved lung function, asthma control, and health-related quality of life compared with placebo in patients with severe, uncontrolled asthma. However, little is known about the impact of tezepelumab on healthcare utilization (HCU) in these patients. OBJECTIVE: To evaluate to what extent tezepelumab reduces patients' HCU. METHODS: In NAVIGATOR, patients were randomized to receive subcutaneous tezepelumab 210 mg or placebo, every 4 weeks for 52 weeks. For this analysis, the main outcomes of interest were asthma-related HCU. A blinded, systematic analysis of the symptoms and HCU recorded in the investigator-reported narratives describing exacerbation-related hospitalizations was also conducted; the narratives included blinded ratings of event intensity, recorded as mild, moderate, or severe. RESULTS: Recipients of tezepelumab (n = 528) required fewer asthma-related unscheduled specialist visits (tezepelumab, 285 events; placebo, 406 events), telephone calls with a healthcare provider (tezepelumab, 234; placebo, 599), ambulance transports (tezepelumab, 5; placebo, 22), emergency department visits (without subsequent hospitalization; tezepelumab, 16; placebo, 37), hospitalizations (tezepelumab, 14; placebo, 78), and intensive care days (tezepelumab, 0; placebo, 31) than did recipients of placebo (n = 531). Among patients with asthma exacerbation-related hospitalizations, 38% of those hospitalized and receiving tezepelumab (5/13) had an event rated as severe, compared with 82% of those hospitalized and receiving placebo (32/39). CONCLUSION: Tezepelumab substantially reduced HCU across all outcomes measured compared with placebo, in addition to the severity of asthma exacerbations requiring hospitalization. Tezepelumab can reduce the overall burden of disease of severe, uncontrolled asthma. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov/ct2/home), identifier: NCT03347279.

Tezepelumab reduces exacerbations across all seasons in patients with severe, uncontrolled asthma (NAVIGATOR).

BACKGROUND: Asthma exacerbation frequencies vary throughout the year owing to seasonal triggers. Tezepelumab is a human monoclonal antibody that targets thymic stromal lymphopoietin. In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab significantly reduced the annualized asthma exacerbation rate (AAER) vs placebo in patients with severe, uncontrolled asthma. OBJECTIVE: To evaluate the effect of tezepelumab on asthma exacerbations across all seasons in NAVIGATOR patients (post hoc). METHODS: NAVIGATOR was a multicenter, randomized, double-blind, placebo-controlled study. Patients (12-80 years old) were randomized 1:1 to tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. AAER over 52 weeks was assessed by season. Data from patients in the Southern Hemisphere were transformed to align with Northern Hemisphere seasons. RESULTS: Tezepelumab reduced the AAER vs placebo by 63% (95% confidence interval [CI], 52-72) in winter, 46% (95% CI, 26-61) in spring, 62% (95% CI, 48-73) in summer, and 54% (95% CI, 41-64) in fall. In matched climates, during the spring allergy season (March 1 to June 15) and ragweed allergy season (September), tezepelumab reduced the AAER vs placebo in patients with seasonal allergy by 59% (95% CI, 29-77) and 70% (95% CI, 33-87), respectively. In patients with perennial allergy and in those with seasonal allergy, tezepelumab reduced the AAER vs placebo across all seasons. CONCLUSION: Tezepelumab reduced exacerbations across all seasons vs placebo in patients with severe, uncontrolled asthma, including patients with seasonal and perennial allergies. These data further support the efficacy of tezepelumab in a broad population of patients with severe, uncontrolled asthma. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03347279 (https://clinicaltrials.gov/ct2/show/NCT03347279).

Clinical and economic burden of severe asthma among US patients treated with biologic therapies.

BACKGROUND: Patients with severe asthma may remain uncontrolled despite biologic therapy in addition to standard therapy, but this disease burden has not been quantified. OBJECTIVE: To estimate the clinical and economic burden in a US national sample. METHODS: Patients who have severe asthma with indicated biologic treatment (earliest use = index date) were selected from the MarketScan database between January 1, 2013, and June 30, 2018. Inclusion criteria were continuous enrollment for 12 months postindex with a minimum of 2 biologic fills, greater than or equal to 12 years of age, evidence of medium- to high-dose inhaled corticosteroids and long-acting ß-agonist combination before the index, and absence of other respiratory diagnoses and malignancies. Disease exacerbations (used to classify asthma control), health care costs, and treatment characteristics were reported during the 12-month postindex period. RESULTS: The sample included 3262 biologic patients; 88% with anti-immunoglobulin E therapy (omalizumab) and 12% non-anti-immunoglobulin E (reslizumab, mepolizumab, benralizumab). The mean age was 49 (±15) years; 64% were women. Prescriptions included inhaled corticosteroids and long-acting ß-agonist (82%), systemic corticosteroids (76%), and leukotriene receptor antagonists (68%). Notably, 63% of patients presented greater than or equal to 1 asthma exacerbation (mean 1.3 per patient/year). Furthermore, 35% of patients were categorized as having controlled asthma, whereas 28% were suboptimally controlled and 29% were uncontrolled. Patients with uncontrolled disease had higher all-cause and asthma-related costs ($69,206 and $45,693, respectively) than patients with suboptimally controlled ($59,407 and $40,793, respectively) or controlled disease ($53,083 and $38,393, respectively). Furthermore, 62% of newly treated patients were persistent with their index biologic. CONCLUSION: Biologic therapies are effective in reducing exacerbations, but a substantial proportion of patients with severe asthma treated with current biologics continue to experience uncontrolled disease, highlighting a remaining unmet need for patients with severe uncontrolled asthma.

Impact of mepolizumab on exacerbations in severe asthma: Results from a U.S. insurance claims data base.

Background: In controlled clinical studies, mepolizumab has been shown to reduce exacerbation rates and the use of oral corticosteroids as well as improve asthma control and health-related quality of life compared with placebo in patients with severe eosinophilic asthma. However, real-world data on the impact of mepolizumab on clinical outcomes are limited. Objective: To evaluate the effect of mepolizumab on asthma exacerbations and asthma exacerbation-related costs in patients with severe asthma in U.S. clinical practice. Methods: This retrospective cohort study used U.S. administrative claims data from patients ages ≥12 years and with severe asthma at mepolizumab treatment initiation (index date; identification period, January 2015-June 2017) who had received two or more mepolizumab administrations within 180 days of the index date and had no evidence of treatment with another asthma biologic. The exacerbation rate and exacerbation-related costs were assessed in both the 12 months before mepolizumab initiation (baseline period) and the following 12 months (follow-up period). A clinical trial-like cohort was identified, defined as patients with two or more baseline exacerbations and ≥10 administrations during follow-up. Results: A total of 201 patients were included in the overall population and 74 patients in the clinical trial-like cohort. Mepolizumab significantly reduced the exacerbation rate between the baseline and follow-up periods in both the overall population and the clinical trial-like cohort (p < 0.001), which corresponded to 33.6% and 48.6% reductions, respectively. The rate of exacerbations in patients who required hospitalization between the baseline and follow-up periods was also reduced by 35.3% (p = 0.080) and 68.2% (p = 0.015) in the overall population and in the clinical trial-like cohort, respectively. Cost data were inconclusive. Conclusion: This study, which used real-world data, demonstrated that mepolizumab is associated with reductions in asthma exacerbations, in line with the findings from controlled clinical studies. These results provided further evidence of the effectiveness of mepolizumab in a real-world setting.

Effects of systemic corticosteroids on blood eosinophil counts in asthma: real-world data.

Introduction: Systemic corticosteroids (SCS) are effective anti-inflammatory therapies for patients with severe or persistent asthma. Use of SCS reduces blood eosinophil counts; the magnitude and duration of reduction in real-world settings needs further investigation. Objective: To examine the SCS effect on blood eosinophil counts over time among patients with asthma in a real-world setting. Methods: This retrospective study used Reliant Medical Group (Worcester, MA) electronic medical records between January 2011 and December 2015. Patients aged ≥12 years with ≥1 SCS prescription (first: index date), ≥1 asthma diagnosis, and ≥1 eosinophil count in each 12-month pre- and post-index periods were included for the study. Endpoints included SCS treatment patterns, time to SCS discontinuation, and changes in index blood eosinophil counts (≥150, ≥300, and ≥400 cells/µL) with SCS initiation and discontinuation. Results: At index visit, 642 of 1198 included patients had a blood eosinophil count ≥150 cells/µL. After an average initial SCS prescription of 35 mg/day, mean (% change) eosinophil counts at month 1 in the ≥150, ≥300, and≥400 cells/µL subgroups decreased from index by 112 (-30%), 202 (-34%), and 290 (-36%) cells/µL, respectively. Of the patients with an eosinophil count ≥150 cells/µL at index, who discontinued SCS within 7, 14, or 21 days after the index date, 21%, 26%, and 25% had an eosinophil count <150 cells/µL 1-month post-index, respectively. Conclusion: Blood eosinophil counts decreased following initiation of SCS therapy and had not returned to index levels several weeks after SCS discontinuation. The time frame of SCS discontinuation is an important consideration when identifying patients with eosinophilic asthma.

Disease burden in patients with asthma before initiating biologics: A retrospective cohort database study.

Background: Real-world data on the characteristics and burden of disease among patients with asthma before receiving asthma-specific biologics would improve the understanding of the use of these therapies in a clinical setting. Currently, limited data are available on the use of mepolizumab and omalizumab for the treatment of asthma. Objective: To determine the characteristics and disease burden among patients with asthma before initiating treatment with mepolizumab or omalizumab. Methods: This was a retrospective cohort analysis of commercial and Medicare Advantage Plan members from a medical claims database with a new claim for mepolizumab or omalizumab between January 1, 2015, and March 31, 2017 (GSK ID: HO-17-18283). Eligible patients had a diagnosis of asthma and continuous enrollment in the health plan, with clinical and pharmacy benefits for 12 months before initiating asthma-specific biologic treatment (baseline period), and no diagnosis of chronic idiopathic urticaria during the baseline period. Patient characteristics, exacerbations, and asthma-related health care resource utilization and costs were assessed during the baseline period. Results: Overall, 188 and 901 patients prescribed mepolizumab and omalizumab, respectively, were included. In the 12 months before initiating asthma-specific biologic therapy, the patients prescribed mepolizumab were older, had higher blood eosinophil counts, more-frequent exacerbations (2.9 versus 2.0 exacerbations/year; p < 0.001), and more inhaled corticosteroid and systemic corticosteroid use compared with those prescribed omalizumab. Overall, asthma-related health-care resource utilization and costs were similar across both treatment cohorts, although patients prescribed mepolizumab had more pharmacy fills, higher pharmacy costs, and lower clinic costs compared with patients prescribed omalizumab (20.8 versus 16.9 fills, $4504 versus $3102, and $1816 versus $2709, respectively; all p < 0.001). Conclusion: In the 12 months before initiating asthma-specific biologic therapy, the patients prescribed mepolizumab may have a greater disease burden than those prescribed omalizumab. Overall, health-care resource utilization and costs were broadly similar across both treatment cohorts.

Association of depressive symptoms with health status and markers of uncontrolled severe asthma.

Background: There are limited data that describe the association between markers of asthma control and depressive symptoms in severe asthma. Objective: To evaluate the association between depressive symptoms and markers of asthma control in patients with uncontrolled severe eosinophilic asthma. Methods: Baseline data from the MENSA and SIRIUS studies (N = 681) of mepolizumab intervention in severe eosinophilic asthma was used. We analyzed the relationships between depressive symptom severity by using the Beck Depression Inventory (BDI-II) and quality of life by using the St. George's Respiratory Questionnaire (SGRQ), asthma control questionnaire-5 (ACQ-5), polypharmacy, and sleep symptoms. Results: When compared with patients with less severe depressive symptoms, patients with more severe depressive symptoms were predominantly female (81% versus 54%), had a higher mean body mass index (30.56 versus 27.67 kg/m²), were more likely to have a blood eosinophil count of ≥300 cells/uL within the previous 12 months (81% versus 68%), and to have experienced a near-fatal asthma event (16% versus 7%). The mean SGRQ score was higher in the severe BDI-II category compared with the minimal depressive symptoms category, which indicated a worse quality of life (71.6 versus 41.4, p < 0.001). Eighty-nine percent of the patients in the severe BDI-II category had poorly controlled asthma (ACQ-5 score ≥ 1.5) compared with 63% in the minimal category (p < 0.001). Conclusion: Increased severity of depressive symptoms was associated with worse respiratory-related quality of life and asthma control in the patients with severe eosinophilic asthma. These findings highlight the need for a multidimensional approach for the management of uncontrolled asthma, including timely identification of depressive symptoms. Additional research is needed to further explore the interactions between the two common conditions.Clinical trials NCT01691521 and NCT01619508, www.clinicaltrials.gov.

Efficacy of Tezepelumab in Patients with Severe, Uncontrolled Asthma Across Multiple Clinically Relevant Subgroups in the NAVIGATOR Study.

INTRODUCTION: Many patients with severe asthma continue to experience symptoms and exacerbations despite treatment with standard-of-care therapy. In the phase 3 NAVIGATOR study, tezepelumab significantly reduced exacerbations over 52 weeks compared with placebo in patients with severe, uncontrolled asthma. This analysis assessed the efficacy of tezepelumab in reducing asthma exacerbations in various clinically relevant subgroups of patients in NAVIGATOR. METHODS: NAVIGATOR was a phase 3, multicentre, randomized, double-blind, placebo-controlled study. Participants (12-80 years old) with severe, uncontrolled asthma were randomized 1:1 to receive tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. Pre-specified and post hoc analyses were performed to evaluate the annualized asthma exacerbation rate (AAER) over 52 weeks in clinically relevant subgroups of patients defined by baseline patient characteristics, medical history, exacerbation triggers, medication eligibility and medication use before and during the study. RESULTS: Tezepelumab reduced the AAER over 52 weeks compared with placebo across a wide range of patient subgroups assessed. Reductions in exacerbations were similar across subgroups defined by baseline patient characteristics, ranging from 48% (95% confidence interval [CI]: 21, 65) to 60% (95% CI: 44, 71) in subgroups analysed by sex, smoking history and body mass index. Among the asthma-related comorbidity subgroups investigated, patients with aspirin or NSAID sensitivity had the greatest reductions in AAER with tezepelumab compared with placebo (83%; 95% CI: 66, 91). In patients eligible to receive dupilumab, tezepelumab reduced exacerbations compared with placebo by 64% (95% CI: 54, 71). Reductions in the AAER with tezepelumab compared with placebo were also observed irrespective of exacerbation trigger category and the number of asthma controller medications patients were receiving at baseline. CONCLUSION: These findings further support the benefits of tezepelumab in patients with severe, uncontrolled asthma and can help to inform healthcare providers' treatment decisions. CLINICAL TRIAL REGISTRATION: NAVIGATOR (NCT03347279).

Efficacy of Biologics in Patients with Allergic Severe Asthma, Overall and by Blood Eosinophil Count: A Literature Review.

Patients with uncontrolled, allergic severe asthma may be prescribed biologic therapies to reduce exacerbations and improve disease control. Randomized controlled trials (RCTs) of these therapies have differed in design, with varying results overall and by baseline blood eosinophil count (BEC). This study describes published annualized asthma exacerbation rate (AAER) reductions from RCTs in patients with allergic severe asthma, overall and by baseline BEC category. A literature search was performed to identify published phase 3 RCT data of US Food and Drug Administration-approved biologics for severe asthma in patients with severe, uncontrolled asthma and confirmed sensitization to perennial aeroallergens. Analyses focused on AAER reduction versus placebo in the overall population and/or in those with an elevated or low BEC at baseline or screening. Baseline serum total immunoglobulin E levels varied between RCT populations. In patients with allergic severe asthma across all BEC categories, data were available for tezepelumab, dupilumab, benralizumab and omalizumab only; the greatest AAER reduction was observed with tezepelumab. In patients with allergic severe asthma and BECs of ≥ 260 cells/µL or ≥ 300 cells/µL, AAER reductions were observed with all biologics (tezepelumab, dupilumab, mepolizumab, benralizumab and omalizumab); the greatest AAER reduction was observed with tezepelumab and the smallest AAER reduction was observed with omalizumab. In patients with allergic severe asthma and BECs of < 260 cells/µL or < 300 cells/µL (regardless of historical BEC), an AAER reduction was observed with tezepelumab but not with benralizumab or omalizumab. Differential mechanisms of action may explain the differences in results observed between biologics. Among patients with allergic severe asthma, the efficacy of biologics in RCTs varied considerably overall and by BEC. Tezepelumab was the only biologic to demonstrate AAER reductions consistently across all subgroups. These differences can inform provider treatment decisions when selecting biologic treatments for patients with allergic severe asthma.

Efficacy of Biologics in Severe, Uncontrolled Asthma Stratified by Blood Eosinophil Count: A Systematic Review.

INTRODUCTION: Randomized controlled trials (RCTs) of biologics in patients with severe, uncontrolled asthma have shown differential results by baseline blood eosinophil count (BEC). In the absence of head-to-head trials, we describe the effects of biologics on annualized asthma exacerbation rate (AAER) by baseline BEC in placebo-controlled RCTs. Exacerbations associated with hospitalization or an emergency room visit, pre-bronchodilator forced expiratory volume in 1 s, Asthma Control Questionnaire score, and Asthma Quality of Life Questionnaire score were also summarized. METHODS: MEDLINE (via PubMed) was searched for RCTs of biologics in patients with severe, uncontrolled asthma and with AAER reduction as a primary or secondary endpoint. AAER ratios and change from baseline in other outcomes versus placebo were compared across baseline BEC subgroups. Analysis was limited to US Food and Drug Administration-approved biologics. RESULTS: In patients with baseline BEC ≥ 300 cells/µL, AAER reduction was demonstrated with all biologics, and other outcomes were generally improved. In patients with BEC 0 to < 300 cells/µL, consistent AAER reduction was demonstrated only with tezepelumab; improvements in other outcomes were inconsistent across biologics. In patients with BEC 150 to < 300 cells/µL, consistent AAER reduction was demonstrated with tezepelumab and dupilumab (300 mg dose only), and in those with BEC 0 to < 150 cells/µL, AAER reduction was demonstrated only with tezepelumab. CONCLUSION: The efficacy of all biologics in reducing AAER in patients with severe asthma increases with higher baseline BEC, with varying profiles across individual biologics likely due to differing mechanisms of action.

Incremental cost burden among patients with severe uncontrolled asthma in the United States.

BACKGROUND: The economic burden of severe asthma and severe uncontrolled asthma (SUA) is significant. Updated assessments of health care resource utilization (HCRU) and cost are needed given the increase in treatment options and updates to guidelines in recent years. OBJECTIVE: To describe all-cause and asthma-related HCRU and costs among patients with SUA vs patients with nonsevere asthma in the United States using real-world data. METHODS: MarketScan administrative claims databases were used to select adults with persistent asthma for this retrospective analysis between January 1, 2013, and December 31, 2019. Asthma severity status was defined using the Global Initiative for Asthma step 4/5 criteria (index is the earliest date qualifying patients as severe or randomly assigned for nonsevere patients). Patients with SUA were a subset of the severe cohort meeting the following criteria: those who were hospitalized with asthma as the primary diagnosis or had at least 2 emergency department or outpatient visits with an asthma diagnosis and a steroid burst within 7 days. HCRU, costs (allcause and asthma-related defined as medical claims with an asthma diagnosis and pharmacy claims for asthma treatment), work loss, and indirect costs due to absenteeism and short-term disability (STD) were compared between patients with SUA, severe, and nonsevere asthma. Outcomes were reported during a fixed 12-month post-index period using chi-square and t-tests where appropriate. RESULTS: 533,172 patients with persistent asthma were identified (41.9% [223,610]) severe and 58.1% [309,562] nonsevere). Of the severe patients, 17.6% (39,380) had SUA. The mean (SD) all-cause total health care costs were significantly higher in patients with SUA ($23,353 [$40,817]) and severe asthma ($18,554 [$36,147]) compared with those with nonsevere asthma ($16,177 [$37,897], P < 0.001 vs nonsevere asthma). The results were consistent for asthma-related costs. In addition, although patients with severe asthma made up 41.9% of the total study population, they contributed disproportionately higher costs (60.5%) to the total asthma-related direct costs, with the effect more evident among patients with SUA (7.4% of study population contributed 17.7% of the total asthma-related costs). For the subset of patients with asthma with workplace absenteeism, patients with SUA lost more time from work (259.3 vs 236.2 hours lost, P = 0.002; 7.8 vs 5.3 STD days, P < 0.001), and had higher corresponding indirect costs ($5,944 vs $5,415, P = 0.002 for absenteeism related; $856 vs $582, P < 0.001 for STD related) compared with patients with nonsevere asthma. CONCLUSIONS: Patients with SUA have significantly higher asthma-related economic burden compared with patients with nonsevere asthma and contribute a disproportionally higher percentage of asthma-related costs. DISCLOSURES: This study was funded by Amgen and AstraZeneca. The design and analysis for this study was conducted primarily by Merative. Amgen and AstraZeneca provided funding to support protocol development, data analysis, and manuscript development activities associated with this study. Dr Burnette is on the advisory board and a consultant for GSK, a consultant and member of the advisory boards and speakers' bureaus of Sanofi, Genzyme, Regeneron, AstraZeneca, and Amgen Inc. Dr Wang, Dr Rane, Dr Lindsley, and Dr Llanos are employees and shareholders of Amgen Inc. Dr Chung and Dr Ambrose are employees and shareholders of AstraZeneca. Ms Princic and Ms Park are employees of Merative, which received funding from Amgen to conduct this study.

Effect of Tezepelumab on Lung Function in Patients With Severe, Uncontrolled Asthma in the Phase 3 NAVIGATOR Study.

INTRODUCTION: Severe asthma is associated with airway inflammation and airway obstruction. In the phase 3 NAVIGATOR study, tezepelumab treatment significantly improved pre-bronchodilator forced expiratory volume in 1 s (FEV1) compared with placebo in patients with severe, uncontrolled asthma. This analysis assessed the effect of tezepelumab versus placebo on additional lung function parameters in patients from NAVIGATOR. METHODS: NAVIGATOR was a multicenter, randomized, double-blind, placebo-controlled study. Patients (12-80 years old) receiving medium- or high-dose inhaled corticosteroids and at least one additional controller medication, with or without oral corticosteroids, were randomized 1:1 to tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. Changes from baseline to week 52 in pre-bronchodilator FEV1, post-bronchodilator FEV1, forced vital capacity (FVC), pre-bronchodilator FEV1/FVC ratio, pre-bronchodilator forced expiratory flow between 25 and 75% of vital capacity (FEF25-75), and morning and evening peak expiratory flow (PEF) were assessed. RESULTS: Tezepelumab treatment improved all evaluated lung function parameters over 52 weeks compared with placebo [least-squares mean difference (95% confidence interval): pre-bronchodilator FEV1, 0.13 (0.08, 0.18) L; post-bronchodilator FEV1, 0.12 (0.07, 0.16) L; FVC, 0.13 (0.07, 0.19) L; FEV1/FVC ratio, 2.06% (1.22%, 2.90%); FEF25-75, 0.13 (0.07, 0.19) L/s; morning PEF, 16.6 (8.1, 25.1) L/min; and evening PEF, 14.9 (6.3, 23.4) L/min]. Improvements were observed as early as weeks 1-2 and were maintained over 52 weeks. Greater improvements in lung function compared with placebo were observed in patients with a disease duration of less than 20 years, those with baseline post-bronchodilator FEV1 reversibility of at least 20%, and in patients with a baseline post-bronchodilator FEV1/FVC ratio of less than 0.7. CONCLUSION: These findings further support the benefits of tezepelumab treatment in improving airflow limitation in patients with severe, uncontrolled asthma. CLINICAL TRIAL REGISTRATION: NAVIGATOR (NCT03347279).

Tezepelumab Efficacy in Patients with Severe, Uncontrolled Asthma with Comorbid Nasal Polyps in NAVIGATOR.

Purpose: Tezepelumab, a human monoclonal antibody, blocks thymic stromal lymphopoietin. In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab reduced annualized asthma exacerbation rates (AAERs) versus placebo, irrespective of baseline disease characteristics, and improved lung function and symptom control versus placebo in adults and adolescents with severe, uncontrolled asthma. We assessed the efficacy of tezepelumab in patients with severe asthma with or without nasal polyps (NPs) in the 2 years before randomization in NAVIGATOR. Methods: Patients with severe asthma (N=1059) were randomized (1:1) and received tezepelumab 210 mg or placebo every 4 weeks subcutaneously for 52 weeks. Prespecified exploratory analyses included: AAER over 52 weeks and changes from baseline to week 52 in pre-bronchodilator forced expiratory volume in 1 second, Sino-Nasal Outcome Test (SNOT)-22 scores, and asthma control and health-related quality life (HRQoL) outcomes in NP subgroups. Changes from baseline in fractional exhaled nitric oxide (FeNO), blood eosinophil counts, total immunoglobulin E (IgE), eosinophil-derived neurotoxin (EDN), matrix metalloproteinase-10 (MMP-10), and serum interleukin (IL)-5, IL-6, IL-8 and IL-13 were assessed (post hoc). Results: Tezepelumab reduced the AAER over 52 weeks versus placebo by 85% (95% confidence interval [CI]: 72, 92; n=118) and 51% (95% CI: 40, 60; n=941) in patients with and without NPs, respectively. At week 52, tezepelumab improved lung function, asthma control and HRQoL versus placebo in patients with and without NPs. Tezepelumab reduced SNOT-22 total scores (least-squares mean difference versus placebo [95% CI]) in patients with NPs at 28 weeks (-12.57 points [-19.40, -5.73]) and 52 weeks (-10.58 points [-17.75, -3.41]). At week 52, tezepelumab reduced blood eosinophil counts and FeNO, IgE, IL-5, IL-13, EDN and MMP-10 levels versus placebo, irrespective of NP status. Conclusion: Tezepelumab resulted in clinically meaningful improvements in sino-nasal symptoms and asthma outcomes in patients with severe asthma with comorbid NPs.