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Background: In asthma, clinical response is characterised by disease improvement with treatment, whereas clinical remission is characterised by long-term disease stabilisation with or without ongoing treatment. The proportions of patients receiving tezepelumab who responded to treatment and who achieved on-treatment clinical remission were assessed in the NAVIGATOR (ClinicalTrials.gov identifier NCT03347279) and DESTINATION (ClinicalTrials.gov identifier NCT03706079) studies of severe, uncontrolled asthma., Methods: NAVIGATOR and DESTINATION were phase 3, randomised, double-blind, placebo-controlled studies; DESTINATION was an extension of NAVIGATOR. Complete clinical response was defined as achieving all of the following: ≥50% reduction in exacerbations versus the previous year, improvements in pre-bronchodilator (BD) forced expiratory volume in 1 s (FEV 1 ) of ≥100 mL or ≥5%, improvements in Asthma Control Questionnaire (ACQ)-6 score of ≥0.5 and physician's assessment of asthma improvement. On-treatment clinical remission was defined as an ACQ-6 total score ≤1.5, stable lung function (pre-BD FEV 1 >95% of baseline) and no exacerbations or use of oral corticosteroids during the time periods assessed., Results: Higher proportions of tezepelumab than placebo recipients achieved complete clinical response over weeks 0-52 (46% versus 24%; OR 2.83, 95% CI 2.10-3.82) and on-treatment clinical remission over weeks 0-52 (28.5% versus 21.9%; OR 1.44, 95% CI 0.95-2.19) and weeks >52-104 (33.5% versus 26.7%; OR 1.44, 95% CI 0.97-2.14). Tezepelumab recipients who achieved on-treatment clinical remission versus complete clinical response at week 52 had better preserved lung function and lower inflammatory biomarker levels at baseline, and fewer exacerbations in the 12 months before the study., Conclusions: Among patients with severe, uncontrolled asthma, tezepelumab treatment was associated with an increased likelihood of achieving complete clinical response and on-treatment clinical remission compared with placebo. Both are clinically important outcomes, but may be driven by different patient characteristics., Competing Interests: Conflict of interest: M.E. Wechsler is an employee of National Jewish Health and has received consultancy fees from AstraZeneca, Equillium, Genentech, GSK, Novartis, Regeneron Pharmaceuticals, resTORbio, Sanofi and Teva Pharmaceuticals. G. Brusselle has received fees for participation in advisory boards and/or speaker fees from Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, MSD, Novartis and Sanofi. J.C. Virchow has received grants for research or clinical trials from the German Research Foundation, GSK and MSD, has received consulting fees from Avontec, Boehringer Ingelheim, Chiesi, Essex Schering-Plough, GSK, Janssen-Cilag, MEDA, MSD, Mundipharma, Novartis, Regeneron Pharmaceuticals, Revotar, Roche, Sandoz-Hexal, Sanofi-Aventis, Teva Pharmaceuticals and UCB Schwarz-Pharma, has received fees for lectures from AstraZeneca, Avontec, Bayer, Bencard, Bionorica, Boehringer Ingelheim, Chiesi, Essex Schering-Plough, GSK, Janssen-Cilag, Leti, MEDA, Merck, MSD, Mundipharma, Novartis, Nycomed Altana, Pfizer, Revotar, Sandoz-Hexal, Stallergenes Greer, Teva Pharmaceuticals, UCB Schwarz-Pharma and Zydus Cadila, has received fees for data safety-monitoring board participation from Chiesi, and has received travel support from Boehringer Ingelheim and Sanofi. A. Bourdin has received grants from AstraZeneca, Boehringer Ingelheim, Cephalon/Teva Pharmaceuticals, GSK, Novartis and Sanofi-Regeneron, has provided consultancy for Actelion, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, MedinCell, Merck, Novartis, Roche and Sanofi-Regeneron, and has acted as an investigator or co-investigator for trials sponsored by Actelion, AstraZeneca, Boehringer Ingelheim, Chiesi, Galapagos, GSK, Merck, Novartis, Roche, Sanofi-Regeneron and Vertex Pharmaceuticals. K. Kostikas has received fees for presentations and/or consultancy fees from Alector Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, CSL Behring, Chiesi, ELPEN, Gilead, GSK, Menarini, Novartis, Pfizer, Sanofi, Specialty Therapeutics and WebMD, and his department has received funding and/or grants from AstraZeneca, Boehringer Ingelheim, Chiesi, ELPEN, GSK, Innovis, Menarini, Novartis and NuvoAir. J-P. Llanos is an employee of Amgen and owns stock in Amgen. S.L. Roseti, C.S. Ambrose, G. Hunter and N. Martin are employees of AstraZeneca and may own stock or stock options in AstraZeneca. D.J. Jackson has received consultancy fees and speaker fees from AstraZeneca, GSK, Novartis, Sanofi and Teva Pharmaceuticals. M. Castro reports grants/research support from ALA, AstraZeneca, Gala Therapeutics, Genentech, GSK, Novartis, Patient-Centered Outcomes Research Institute, Pulmatrix, Sanofi-Aventis, Shionogi Theravance and the US National Institutes of Health, consulting fees from Allakos, Amgen, Arrowhead, AstraZeneca, Genentech, Merck, Novartis, OM Pharma, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals, and has received royalties from Aer Therapeutics and Elsevier. N. Lugogo has received consultancy fees for participation in advisory boards from Amgen, AstraZeneca, Genentech, GSK, Novartis, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals, has received fees for non-speaker bureau presentations from AstraZeneca and GSK, has received travel support from AstraZeneca, and her institution has received research support from Amgen, AstraZeneca, Avillion, Genentech, Gossamer Bio, GSK, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals. I.D. Pavord has received speaker fees from Aerocrine AB, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals, has received payments for organisation of educational events from AstraZeneca, GSK, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals, has received consultancy fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Dey Pharma, Genentech, GSK, Knopp Biosciences, Merck, MSD, Napp Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, RespiVert, Sanofi, Schering-Plough and Teva Pharmaceuticals, has received international scientific meeting sponsorship from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Napp Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi and Teva Pharmaceuticals, and has received a research grant from Chiesi. C.E. Brightling has received grants and consultancy fees from 4D Pharma, AstraZeneca, Chiesi, Genentech, Global Access Diagnostics (formerly Mologic), GSK, Novartis, Regeneron Pharmaceuticals, Roche and Sanofi., (Copyright ©The authors 2024.)

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)., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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]).

Background: Tezepelumab is an anti-thymic stromal lymphopoietin mAb. In the PATHWAY phase IIb study (NCT02054130), tezepelumab significantly reduced annualized asthma exacerbation rates (AAERs) versus placebo in adults with severe, uncontrolled asthma., Objective: This post hoc analysis assessed the efficacy of tezepelumab in PATHWAY participants with perennial allergy., Methods: Adults (N = 550) with severe, uncontrolled asthma were randomized to receive tezepelumab (70 mg or 210 mg every 4 weeks or 280 mg every 2 weeks) or placebo, for 52 weeks. The AAER over 52 weeks was analyzed in patients grouped by sensitivity to perennial aeroallergens and by eligibility for omalizumab treatment according to the US or European Union prescribing information. Change from baseline to week 52 in prebronchodilator FEV 1 and type 2 biomarkers was assessed in the perennial allergy subgroups., Results: Across doses, tezepelumab reduced the AAER versus placebo by 66% to 78% in patients with perennial allergy (n = 254) and 67% to 71% in patients without perennial allergy (n = 261). Tezepelumab improved prebronchodilator FEV 1 and reduced blood eosinophil counts and fractional exhaled nitric oxide levels over 52 weeks, irrespective of perennial allergy status. Tezepelumab reduced the AAER versus placebo by 61% to 82% in omalizumab-eligible patients (US, n = 159; European Union, n = 101) and 63% to 70% in omalizumab-ineligible patients (US, n = 372; European Union, n = 440), respectively., Conclusions: Treatment with tezepelumab reduced exacerbations, improved lung function, and reduced type 2 biomarkers versus placebo in patients with severe, uncontrolled asthma with or without perennial allergy, further supporting its efficacy in a broad population of patients with severe, uncontrolled asthma., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale: IL-13 is a potential therapeutic target for idiopathic pulmonary fibrosis (IPF); preclinical data suggest a role in tissue fibrosis, and expression is increased in subjects with rapidly progressing disease., Objectives: Investigate efficacy and safety of tralokinumab, a human anti-IL-13 monoclonal antibody, in subjects with mild to moderate IPF., Methods: Subjects received tralokinumab (400 or 800 mg), or placebo, intravenously every 4 weeks for 68 weeks. The primary endpoint was change from baseline to Week 52 in percent predicted FVC in the intention-to-treat population. Exploratory analyses included assessment of clinical response in subgroups with baseline serum periostin concentration above/below median., Measurements and Main Results: The study was stopped due to lack of efficacy after interim analysis. Neither tralokinumab 400 mg nor tralokinumab 800 mg met the primary endpoint; least-squares mean difference (95% confidence interval) percent predicted FVC from baseline to Week 52: -1.77 (-4.13 to 0.59) (P = 0.140) and -1.41 (-3.73 to 0.91) (P = 0.234), respectively. The primary endpoint was also not met in either treatment group in subgroups defined by periostin baseline concentration. The percentage of subjects with decline in percent predicted FVC greater than or equal to 10% at Week 52 was numerically greater for tralokinumab-treated subjects compared with placebo. The most common treatment-emergent adverse events for tralokinumab 400 mg, tralokinumab 800 mg, and placebo were cough (17.5, 30.5, 22.8%), IPF progression and exacerbation (21.1, 16.9, 22.8%), and upper respiratory tract infection (17.5, 20.3, 12.3%), respectively., Conclusions: Tralokinumab demonstrated an acceptable safety and tolerability profile but did not achieve key efficacy endpoints. Clinical trial registered with www.clinicaltrials.gov (NCT01629667).

Background: In some patients with moderate-to-severe asthma, particularly those with noneosinophilic inflammation, the disease remains uncontrolled. This trial evaluated the efficacy and safety of tezepelumab (AMG 157/MEDI9929), a human monoclonal antibody specific for the epithelial-cell-derived cytokine thymic stromal lymphopoietin (TSLP), in patients whose asthma remained uncontrolled despite treatment with long-acting beta-agonists and medium-to-high doses of inhaled glucocorticoids., Methods: In this phase 2, randomized, double-blind, placebo-controlled trial, we compared subcutaneous tezepelumab at three dose levels with placebo over a 52-week treatment period. The primary end point was the annualized rate of asthma exacerbations (events per patient-year) at week 52., Results: The use of tezepelumab at a dose of 70 mg every 4 weeks (low dose; 145 patients), 210 mg every 4 weeks (medium dose; 145 patients), or 280 mg every 2 weeks (high dose; 146 patients) resulted in annualized asthma exacerbation rates at week 52 of 0.26, 0.19, and 0.22, respectively, as compared with 0.67 in the placebo group (148 patients). Thus, exacerbation rates in the respective tezepelumab groups were lower by 61%, 71%, and 66% than the rate in the placebo group (P<0.001 for all comparisons). Similar results were observed in patients regardless of blood eosinophil counts at enrollment. The prebronchodilator forced expiratory volume in 1 second at week 52 was higher in all tezepelumab groups than in the placebo group (difference, 0.12 liters with the low dose [P=0.01], 0.11 liters with the medium dose [P=0.02], and 0.15 liters with the high dose [P=0.002]). A total of 2 patients in the medium-dose group, 3 in the high-dose group, and 1 in the placebo group discontinued the trial regimen because of adverse events., Conclusions: Among patients treated with long-acting beta-agonists and medium-to-high doses of inhaled glucocorticoids, those who received tezepelumab had lower rates of clinically significant asthma exacerbations than those who received placebo, independent of baseline blood eosinophil counts. (Funded by MedImmune [a member of the AstraZeneca Group] and Amgen; PATHWAY ClinicalTrials.gov number, NCT02054130 .).