Background: Tezepelumab, an mAb inhibiting thymic stromal lymphopoietin, is an upstream-targeted therapy with potential to inhibit multiple pathways in chronic spontaneous urticaria (CSU). Objective: We sought to evaluate tezepelumab efficacy and safety in patients with CSU despite treatment with second-generation H1 antihistamines. Methods: This phase 2b study randomized 183 patients (125 anti-IgE therapy-naive; 58 anti-IgE therapy-experienced) to placebo every 2 weeks, tezepelumab 210 mg every 4 weeks, tezepelumab 420 mg every 2 weeks, or omalizumab 300 mg every 4 weeks (anti-IgE-naive only) for 16-week treatment. The primary end point was change from baseline in weekly Urticaria Activity Score (UAS7) at week 16. Safety and exploratory end points were evaluated through week 32. Results: The 16-week primary end point was not met. In the overall population, tezepelumab 210 mg and 420 mg did not significantly improve UAS7 versus placebo (least squares mean [SE]:-13.5 [1.6] and-14.7 [1.5], respectively, vs-13.6 [1.6], P = .99, nominal and P = .60, nominal, respectively). Greater improvement in UAS7 versus placebo was observed in the anti-IgE-naive tezepelumab-treated populations (nominal significance); a trend toward significance was observed with omalizumab. In the anti-IgE-naive population, there was delayed, sustained, 32-week off-treatment improvement in UAS7 versus placebo with tezepelumab 210 mg (nominally significant) and 420 mg (trend), but not with omalizumab. This effect was larger in patients with lower baseline IgE levels and longer CSU duration and accompanied sustained IL-5 and IL-13 reductions. Tezepelumab and placebo safety findings were balanced. Conclusion: Although the 16-week primary end point was not met, tezepelumab showed post-treatment reductions in CSU activity through week 32, suggesting a delayed, sustained, thymic stromal lymphopoietin blockade treatment effect. (J Allergy Clin Immunol 2025;155:1945-56.)

Annual influenza vaccinations are recommended for adolescents and adults with moderate to severe asthma. This study investigated the effect of tezepelumab, a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin, on the humoral immune response to the quadrivalent seasonal influenza vaccine in patients with moderate to severe asthma. VECTOR was a phase 3b, randomized, multicenter, double-blind, parallel-group, placebo-controlled study. Adolescents (aged 12–17 years) and young adults (aged 18–21 years) with moderate to severe asthma were enrolled across 15 centers in the USA. Patients received tezepelumab 210 mg or placebo subcutaneously at weeks 0, 4, 8, and 12, and a single dose of inactivated quadrivalent seasonal influenza vaccine at week 12 before receiving study treatment. Immediately before vaccination and at 4 weeks postvaccination (week 16), strain-specific antibody responses were assessed for four influenza antigens by hemagglutination inhibition (HAI) and microneutralization (MN) assays. Safety was assessed. Seventy patients were randomized to tezepelumab (n = 35) or placebo (n = 35). There were no meaningful differences in HAI or MN antibody responses between treatment groups at week 16. HAI assay geometric mean fold rises (GMFRs) for influenza strains were 1.76–7.34 for tezepelumab and 1.46–4.75 for placebo. MN assay GMFRs were 4.00–14.56 for tezepelumab and 3.56–10.62 for placebo. In the HAI assay, a fourfold or larger rise in antibody titer from weeks 12 to 16 occurred in 15.2–78.8

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.

Tezepelumab, a monoclonal antibody inhibiting thymic stromal lymphopoietin (TSLP), is an upstream-targeted therapy with potential to inhibit multiple pathways in chronic spontaneous urticaria (CSU). Here, we present the effects of tezepelumab in a subgroup (anti-IgE–naïve) of CSU patients from the phase2b INCEPTION study (NCT04833855).

Aspirin-exacerbated respiratory disease (AERD; Samter's triad) consists of three clinical features: asthma, nasal polyposis, and sensitivity to aspirin or other nonsteroidal anti-inflammatory drugs. In the phase 3 NAVIGATOR (NCT03347279) study, tezepelumab reduced annualized asthma exacerbation rates in patients with severe, uncontrolled asthma, including those with AERD. This post hoc analysis further evaluated the efficacy of tezepelumab in patients with AERD.

In the PATHWAY (NCT02054130) and NAVIGATOR (NCT03347279) studies, tezepelumab reduced the annualized asthma exacerbation rate (AAER) over 52 weeks versus placebo among patients with severe, uncontrolled asthma. The efficacy of tezepelumab in patients with fungal sensitization at baseline was evaluated using pooled data from PATHWAY and NAVIGATOR.

We present the findings of two clinical studies investigating the safety and efficacy of tezepelumab for severe asthma.

Background: In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab gradually decreased serum total immunoglobulin (Ig)E levels in patients with severe, uncontrolled asthma over 52 weeks. In the phase 3 DESTINATION study (NCT03706079), this reduction continued to end of treatment (EOT; week 104). Objective: To assess serum total IgE during the off-treatment extended follow-up (EFU) in DESTINATION, following tezepelumab cessation. Methods: Patients (12–80 years) who completed NAVIGATOR could enrol in DESTINATION, a multicentre, randomized, placebo-controlled, double-blind, extension study. Patients previously randomized to tezepelumab continued treatment (tezepelumab only; 210 mg every 4 weeks). Those previously randomized to placebo were re-randomized 1:1 to placebo (placebo only) or tezepelumab. At EOT, eligible patients could enter a 36-week off-treatment EFU. Change in serum total IgE over time was assessed. Results: Overall, 569 patients entered the EFU. Mean baseline serum total IgE was 586.18 and 625.19 IU/mL for the tezepelumab only and placebo only subgroups. After tezepelumab cessation, serum total IgE remained low; there was a partial increase from week 122, but levels remained below baseline (Figure). Conclusion: Serum total IgE levels reductions achieved with tezepelumab during NAVIGATOR and DESTINATION were maintained for 36 weeks after tezepelumab cessation, suggesting a maintained immunological effect.

Background: Tezepelumab reduced the annualized asthma exacerbation rate in adolescents with severe, uncontrolled asthma in the phase 3 NAVIGATOR (NCT03347279) and the phase 3 long-term extension DESTINATION (NCT03706079) studies. Objective: To more completely describe the safety and efficacy of tezepelumab (210 mg every 4 weeks) in adolescents (≥12–<18 years) over 2 years. Methods: Patients (12–80 years old) who completed NAVIGATOR could enrol in DESTINATION, a multicentre, randomized, placebo-controlled, double-blind, extension study. Patients previously randomized to tezepelumab continued treatment with tezepelumab. Those previously randomized to placebo were re-randomized 1:1 to placebo or tezepelumab. Exposure-adjusted incidence rates of adverse events and serious adverse events and the annualized asthma exacerbation rate were assessed over 104 weeks in adolescents who received ≥1 dose of tezepelumab or placebo. Pre-bronchodilator forced expiratory volume in 1 second and Asthma Control Questionnaire-6 score were assessed over 104 weeks in adolescents who received tezepelumab only or placebo only. Results Results are summarized in Table 1. Conclusion: In addition to reducing asthma exacerbations, tezepelumab was well tolerated for 2 years and improved lung function and asthma control from baseline in adolescents with severe, uncontrolled asthma.

Background: Tezepelumab improved pre-bronchodilator percent predicted FEV1 (pre-BD ppFEV1) versus placebo in patients with severe, uncontrolled asthma in the phase 2b PATHWAY (NCT02054130) and phase 3 NAVIGATOR (NCT03347279) studies. Objective: This post hoc pooled analysis assessed the effect of tezepelumab on pre-BD ppFEV1 in patients grouped by baseline pre-BD ppFEV1 in PATHWAY and NAVIGATOR. Methods: Included patients (12–80 years) received tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. Patients had post-BD FEV1 reversibility ≥12% and a pre-BD ppFEV1 <80% (<90% for adolescents) before enrolment. Pre-BD FEV1 was assessed by baseline pre-BD ppFEV1 (<80% and ≥80%). Results: Overall, 665 and 669 patients received tezepelumab or placebo; 563 (84.7%) and 569 (85.1%) had baseline pre-BD ppFEV1 <80%, respectively. Of these, 18.1% and 10.0% had pre-BD ppFEV1 ≥80% at week 52 with tezepelumab and placebo (Table). In those with baseline pre-BD ppFEV1 ≥80%, fewer tezepelumab than placebo recipients had pre-BD ppFEV1 <80% at week 52 (19.8% vs 29.0%). Tezepelumab improved pre-BD FEV1 at week 52 versus placebo by 0.14 L (95% CI: 0.09, 0.19) and 0.13 L (95% CI: 0.01, 0.24) in patients with baseline pre-BD ppFEV1 <80% and ≥80%, respectively. Conclusion: In patients with severe, uncontrolled asthma and baseline pre-BD ppFEV1 <80%, more tezepelumab than placebo recipients achieved pre-BD ppFEV1 ≥80% at week 52.

IntroductionTezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin (TSLP). In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab reduced blood eosinophil counts and fractional exhaled nitric oxide levels from week 2 and serum total immunoglobulin E (IgE) levels from week 12 compared with placebo in patients with severe, uncontrolled asthma. Given the gradual reductions in IgE levels observed with tezepelumab, this post hoc analysis assessed the timing of exacerbations with tezepelumab in patients with and without confirmed symptomatic perennial allergy to dust mite or animal allergens.MethodsNAVIGATOR 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. The cumulative number of exacerbations was assessed over 52 weeks in patients grouped by confirmed symptomatic perennial allergy status. Symptomatic perennial allergy status was defined as investigator-reported history of allergy to dust mite or animal allergens and a positive fluorescence enzyme immunoassay test result for serum-specific IgE to the corresponding allergen at baseline.ResultsIn patients with (n = 318) and without (n = 741) confirmed symptomatic perennial allergy, tezepelumab reduced the cumulative number of exacerbations compared with placebo over 52 weeks. Reductions with tezepelumab compared with placebo were observed early in patients with and without confirmed symptomatic perennial allergy (Figure).ConclusionIn patients with severe, uncontrolled asthma, tezepelumab treatment resulted in early and sustained reductions in the cumulative number of exacerbations compared with placebo, irrespective of confirmed symptomatic perennial allergy status.

Introduction and ObjectivesTezepelumab reduces both blood eosinophil counts (BECs) and fractional exhaled nitric oxide (FeNO) levels versus placebo in patients with severe, uncontrolled asthma. The proportion of patients achieving low type 2 biomarker levels with tezepelumab treatment has not been previously evaluated. To assess the proportion of patients who achieved biomarker levels below those associated with an increased risk of asthma-related morbidity (BEC <150 cells/µL or <300 cells/µL; FeNO <25 ppb or <50 ppb) with tezepelumab versus placebo in the phase 3 NAVIGATOR study (NCT03347279).MethodsNAVIGATOR was a multicentre, randomized, double-blind, placebo-controlled study. Patients (12–80 years old) received tezepelumab 210 mg or placebo subcutaneously every 4 weeks for up to 52 weeks. BECs and FeNO levels were compared at baseline and week 52.ResultsOverall, 528 and 531 patients received tezepelumab and placebo, respectively. At week 52, a greater proportion of tezepelumab recipients achieved BEC <150 cells/µL and <300 cells/µL, and FeNO levels <25 ppb and <50 ppb versus placebo recipients (figure 1).ConclusionAt week 52, most tezepelumab recipients in NAVIGATOR had maintained or reduced their biomarker levels to below those associated with an increased risk of asthma-related morbidity. Please refer to page A295 for declarations of interest related to this abstract.

WHAT IS THIS SUMMARY ABOUT?:This is a summary of the results of 2 clinical studies that looked at a medicine called tezepelumab. Tezepelumab is approved in the United States of America (USA), the European Union (EU) and several other countries for the treatment of severe, uncontrolled asthma in people aged 12 and above. The results of these 2 studies, called PATHWAY and NAVIGATOR, formed the basis for tezepelumab's approval for use. Tezepelumab is a type of biologic treatment called an antibody. Biologics are treatments that target certain cells or proteins in the body and often in the immune system - the body's natural defence system against infections and diseases - to reduce patients' disease. It works by blocking a key first step in the body's chain reaction leading to inflammation in the airways of people with severe asthma. The clinical studies were done to learn if tezepelumab can be used to treat people with severe, uncontrolled asthma and to find out about its safety. In both studies, tezepelumab was compared to placebo. A placebo is a dummy treatment that looked like tezepelumab but did not have any medicine in it. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?:In both studies, tezepelumab reduced the number of severe asthma attacks that the participants had per year compared with placebo. It also increased the volume of air that the participants could breathe out in 1 second compared with placebo. Tezepelumab was well-tolerated, and a similar number of participants had health issues in the tezepelumab and placebo treatment groups. The most common health issues that the participants had during the PATHWAY study were: Worsening of asthma, common cold, headache, and inflammation of the airways. The most common health issues that the participants had during the NAVIGATOR study were: Common cold, infection of the sinuses, throat and airways, headache, worsening of asthma, and inflammation of the airways. WHAT ARE THE KEY TAKEAWAYS?:The results showed that participants who had monthly doses of tezepelumab had fewer severe asthma attacks and better lung function than those who had placebo. In both studies, the health issues that the participants had were similar between the tezepelumab and placebo treatment groups. Overall, the studies showed that tezepelumab worked in a broad population of people with severe asthma and that the study participants had an acceptable level of health issues during the studies. These results led to the approval of tezepelumab for people with severe asthma aged 12 and above in the USA, EU and other countries. Clinical Trial Registration: PATHWAY study: NCT02054130; NAVIGATOR study: NCT03347279 (ClinicalTrials.gov).

Background: Tezepelumab significantly reduced the annualized asthma exacerbation rate by 56% versus placebo in patients with severe, uncontrolled asthma in the phase 3 NAVIGATOR study (NCT03347279). Objective: This post hoc analysis evaluated exacerbation characteristics in tezepelumab versus placebo recipients. Methods: NAVIGATOR was a multicentre, randomized, double-blind, placebo-controlled study. Patients (12–80 years old) receiving medium- or high-dose inhaled corticosteroids and ≥1 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. Sites documented patient-reported symptoms, and medication use during exacerbations. Results: Of 1059 patients, 231/528 (43.8%) and 319/531 (60.1%) reported ≥1 exacerbation in the tezepelumab and placebo groups, respectively. Most exacerbation symptoms occurred in slightly fewer participants receiving tezepelumab versus placebo (range of differences: 4.2–10.7%); cough was similar between groups. Medication use during exacerbations and the duration of systemic corticosteroid use was similar or slightly reduced for tezepelumab versus placebo (Table). Conclusion: Compared with placebo, tezepelumab recipients had fewer exacerbations. When exacerbations occurred, symptoms and medication use were similar or slightly reduced among tezepelumab recipients.