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.

Tezepelumab for the treatment of severe asthma: a plain language summary of the PATHWAY and NAVIGATOR studies.

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).

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).

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.

Tezepelumab and Mucus Plugs in Patients with Moderate-to-Severe Asthma.

BACKGROUND: Mucus plugs in asthmatic airways are associated with airway obstruction and the activity of inflammatory cytokines, specifically interleukin (IL)-5 and IL-13, and they may provide an opportunity for targeted therapy. This analysis of the CASCADE (Study to Evaluate Tezepelumab on Airway Inflammation in Adults With Uncontrolled Asthma) placebo-controlled trial used computed tomography (CT) imaging to assess mucus plugs in patients with moderate-to-severe, uncontrolled asthma who received tezepelumab or placebo. METHODS: CASCADE was an exploratory, double-blind, placebo-controlled trial examining the anti-inflammatory effect of tezepelumab. Patients (aged 18 to 75 years old) were randomly assigned 1:1 to 210 mg tezepelumab or placebo every 4 weeks subcutaneously for at least 28 weeks. An expert radiologist, blinded to treatment groups and time points, objectively scored 18 lung segments for the presence of mucus plugs in CT scans obtained before and after treatment; greater numbers of mucus plugs resulted in higher mucus plug scores. RESULTS: Absolute change from baseline (mean [±standard deviation]) in mucus plug score was −1.7±2.6 in patients receiving tezepelumab (n=37) and 0.0±1.4 in patients receiving placebo (n=45). At baseline, mucus plug scores correlated positively with levels of inflammatory biomarkers (blood eosinophils, eosinophil-derived neurotoxin, fractional exhaled nitric oxide, IL-5, and IL-13) and negatively with lung function measures (prebronchodilator forced expiratory volume in 1 second and forced mid-expiratory flow). In tezepelumab recipients, reductions in mucus plug scores were correlated with improvements in lung function and reductions in blood eosinophil count and levels of eosinophil-derived neurotoxin, a biomarker of eosinophilic degranulation. CONCLUSIONS: Tezepelumab was associated with a reduction in occlusive mucus plugs versus placebo in a randomized controlled trial in patients with moderate-to-severe, uncontrolled asthma. (Funded by AstraZeneca and Amgen Inc.; ClinicalTrials.gov number, NCT03688074.)

Feno differentiates epithelial gene expression clusters: Exploratory analysis from the MESOS randomized controlled trial.

BACKGROUND: Understanding how asthma biomarkers relate to gene expression signatures could help identify drivers of pathogenesis. OBJECTIVE: This post hoc exploratory analysis of the phase II tralokinumab trial MESOS (ClinicalTrials.gov identifier NCT02449473) aimed to profile baseline airway inflammation in patients with moderate-to-severe asthma. METHODS: The T2 and T17 gene expression signatures, 3-gene mean and 5-gene mean, were calculated through transcriptomic analysis of baseline bronchial brushing samples. Clustering analysis using these signatures identified 3 distinct inflammatory subgroups: T2LOW/T17HIGH (n = 33), T2HIGH/T17LOW (n = 10), and T2LOW/T17LOW (n = 27). RESULTS: Fractional exhaled nitric oxide (Feno) levels were highest for T2HIGH/T17LOW and lowest for T2LOW/T17HIGH (median = 52.0 [range 42.5-116.3] and median = 18.8 [range 6.6-128.6] ppb, respectively; P = .003). High Feno levels were strongly correlated with high T2 gene expression (Spearman ρ = 0.5537; P < .001). Individual genes differentially expressed in patients with elevated levels of Feno, blood and bronchial submucosal eosinophil counts, and IgE level were explored, with cystatin SN (CST1) being the most upregulated gene in all subgroups (4.49- to 34.42-fold upregulation across clinically defined subgroups with high biomarker expression). CONCLUSION: Feno level may be useful to differentiate patients with T2 or T17 gene expression. Elevated Feno levels are associated with high CST1 expression.

Evaluation of the oral corticosteroid-sparing effect of tezepelumab in adults with oral corticosteroid-dependent asthma (SOURCE): a randomised, placebo-controlled, phase 3 study.

BACKGROUND: Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin. SOURCE evaluated the oral corticosteroid-sparing effect of tezepelumab in adults with oral corticosteroid-dependent asthma. METHODS: We conducted this phase 3, multicentre, randomised, double-blind, placebo-controlled study across 60 sites in seven countries. Participants aged 18-80 years with physician-diagnosed asthma, who had been receiving medium-dose or high-dose inhaled corticosteroids and had at least one asthma exacerbation in the 12 months before screening were eligible. Patients who were receiving medium-dose inhaled corticosteroids must have had their dose increased to a high dose for at least 3 months before screening. After an oral corticosteroid optimisation phase of up to 8 weeks, participants were randomly assigned according to a computer-generated fixed block randomisation sequence to receive tezepelumab 210 mg or placebo subcutaneously every 4 weeks during a 48 week treatment period (4 week induction phase, 36 week oral corticosteroid reduction phase, and 8 week maintenance phase). Randomisation was stratified by region. Participants, investigators, and site staff were masked to treatment assignment. The primary endpoint was the categorised percentage reduction from baseline in daily oral corticosteroid dose at week 48 without the loss of asthma control. Efficacy and safety endpoints were assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03406078. FINDINGS: Between March 5, 2018, and Sept 27, 2019, 150 participants were randomly assigned to receive tezepelumab 210 mg (n=74) or placebo (n=76). The cumulative odds of achieving a category of greater percentage reduction in an oral corticosteroid dose for daily maintenance at week 48 were similar with tezepelumab or placebo in the overall population (odds ratio [OR] 1·28 [95% CI 0·69-2·35], p=0·43; the primary endpoint was not met). The cumulative odds were higher with tezepelumab than with placebo in participants with baseline blood eosinophil counts of at least 150 cells per µL (2·58 [1·16-5·75]), but not in participants with counts below 150 cells per µL (0·40 [0·14-1·13]). Tezepelumab was well tolerated, with no safety concerns identified. 53 (72%) of 74 tezepelumab-assigned participants and 65 (86%) of 76 placebo-assigned participants reported an adverse event. Serious adverse events were reported in 12 (16%) participants in the tezepelumab group and 16 (21%) participants in the placebo group. INTERPRETATION: We did not observe a significant improvement in oral corticosteroid dose reduction with tezepelumab versus placebo in the overall population of this oral corticosteroid-sparing study, although an improvement was observed in participants with baseline blood eosinophil counts of at least 150 cells per µL. FUNDING: AstraZeneca and Amgen.

Baseline type 2 biomarker levels and response to tezepelumab in severe asthma.

BACKGROUND: Tezepelumab is a human monoclonal antibody that blocks activity of thymic stromal lymphopoietin (TSLP). In the phase IIb PATHWAY study (NCT02054130), tezepelumab significantly reduced annualized asthma exacerbation rates (AAERs) versus placebo in adults with severe, uncontrolled asthma. We evaluated the effects of tezepelumab in reducing type 2 (T2) inflammatory biomarker levels in the PATHWAY population, and the relationship between baseline T2 biomarker levels and AAER. METHODS: Adults with severe, uncontrolled asthma (n = 550) were randomized to tezepelumab (70 mg or 210 mg every 4 weeks, or 280 mg every 2 weeks) or placebo for 52 weeks. Blood eosinophil count, fractional exhaled nitric oxide (FeNO), and serum total immunoglobulin (Ig)E, interleukin (IL)-5, IL-13, periostin, thymus and activation-regulated chemokine (TARC), and TSLP were measured at baseline and over 52 weeks. AAERs were analyzed by baseline threshold (high/low) biomarker levels. RESULTS: Positive correlations were observed between T2 inflammatory biomarkers (blood eosinophil count, FeNO, IL-5, IL-13 and periostin) at baseline. At Week 52, treatment with tezepelumab 210 mg reduced all biomarker levels measured from baseline versus placebo. Exacerbations were reduced by 55-83% in the pooled tezepelumab cohort versus placebo, irrespective of baseline blood eosinophil count, FeNO, or serum total IgE, IL-5, IL-13, periostin, TARC, or TSLP, when these biomarkers were assessed individually. CONCLUSION: At baseline, positive correlations between specific T2 inflammatory biomarkers were observed. Tezepelumab reduced multiple T2 inflammatory biomarkers, which indicates decreased airway inflammation, and reduced exacerbations irrespective of baseline T2 biomarker profiles in patients with severe asthma.

Efficacy of Tezepelumab in Patients with Severe, Uncontrolled Asthma and Perennial Allergy.

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 FEV1 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 FEV1 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.

Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma.

BACKGROUND: Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, an epithelial-cell-derived cytokine implicated in the pathogenesis of asthma. The efficacy and safety of tezepelumab in patients with severe, uncontrolled asthma require further assessment. METHODS: We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Patients (12 to 80 years of age) were randomly assigned to receive tezepelumab (210 mg) or placebo subcutaneously every 4 weeks for 52 weeks. The primary end point was the annualized rate of asthma exacerbations over a period of 52 weeks. This end point was also assessed in patients with baseline blood eosinophil counts of less than 300 cells per microliter. Secondary end points included the forced expiratory volume in 1 second (FEV1) and scores on the Asthma Control Questionnaire-6 (ACQ-6; range, 0 [no impairment] to 6 [maximum impairment]), Asthma Quality of Life Questionnaire (AQLQ; range, 1 [maximum impairment] to 7 [no impairment]), and Asthma Symptom Diary (ASD; range, 0 [no symptoms] to 4 [worst possible symptoms]). RESULTS: Overall, 1061 patients underwent randomization (529 were assigned to receive tezepelumab and 532 to receive placebo). The annualized rate of asthma exacerbations was 0.93 (95% confidence interval [CI], 0.80 to 1.07) with tezepelumab and 2.10 (95% CI, 1.84 to 2.39) with placebo (rate ratio, 0.44; 95% CI, 0.37 to 0.53; P<0.001). In patients with a blood eosinophil count of less than 300 cells per microliter, the annualized rate was 1.02 (95% CI, 0.84 to 1.23) with tezepelumab and 1.73 (95% CI, 1.46 to 2.05) with placebo (rate ratio, 0.59; 95% CI, 0.46 to 0.75; P<0.001). At week 52, improvements were greater with tezepelumab than with placebo with respect to the prebronchodilator FEV1 (0.23 vs. 0.09 liters; difference, 0.13 liters; 95% CI, 0.08 to 0.18; P<0.001) and scores on the ACQ-6 (-1.55 vs. -1.22; difference, -0.33; 95% CI, -0.46 to -0.20; P<0.001), AQLQ (1.49 vs. 1.15; difference, 0.34; 95% CI, 0.20 to 0.47; P<0.001), and ASD (-0.71 vs. -0.59; difference, -0.12; 95% CI, -0.19 to -0.04; P = 0.002). The frequencies and types of adverse events did not differ meaningfully between the two groups. CONCLUSIONS: Patients with severe, uncontrolled asthma who received tezepelumab had fewer exacerbations and better lung function, asthma control, and health-related quality of life than those who received placebo. (Funded by AstraZeneca and Amgen; NAVIGATOR ClinicalTrials.gov number, NCT03347279.).

Pharmacokinetic and Pharmacodynamic Modeling of Tezepelumab to Guide Phase 3 Dose Selection for Patients With Severe Asthma.

Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, an epithelial cytokine involved in asthma pathogenesis. In the phase 2b PATHWAY study (ClinicalTrials.gov identifier: NCT02054130), tezepelumab significantly reduced exacerbations in adults with severe, uncontrolled asthma. We used pharmacokinetic (PK) and pharmacodynamic (PD) modeling to guide tezepelumab dose selection for phase 3 trials in patients with severe asthma. PK data from 7 clinical studies were used to develop a population PK model. Population PK-PD models were developed to characterize the relationship between tezepelumab PK and asthma exacerbation rate (AER) and fractional exhaled nitric oxide (FeNO) levels (using phase 2b PD data only). Tezepelumab PK were well described by a 2-compartment model with first-order absorption; PK parameter estimates were consistent with those of other immunoglobulin G2 antibodies. PK-PD models predicted that subcutaneous dosing at 210 mg every 4 weeks was associated with ≈90% of the maximum drug effect of tezepelumab on AER and FeNO; further dose increases were not expected to result in additional, clinically meaningful treatment benefit. No clinically significant covariates of treatment effects on AER and FeNO were identified. Population PK simulations, exposure-response relationships and safety profiles of tezepelumab at doses up to 280 mg every 2 weeks suggested that no dose adjustment based on body weight or for adolescents was required. These results support the selection of 210 mg every 4 weeks subcutaneously as the dose for phase 3 studies of tezepelumab in adults and adolescents with severe asthma.

Tezepelumab improves patient-reported outcomes in patients with severe, uncontrolled asthma in PATHWAY.

BACKGROUND: Patients with severe, uncontrolled asthma experience frequent exacerbations and hospitalization, leading to poor health-related quality of life. In the phase 2b PATHWAY study (NCT02054130), tezepelumab reduced exacerbations by up to 71% and improved lung function, asthma control, and health-related quality of life vs placebo. OBJECTIVE: This analysis further assessed the impact of tezepelumab on patient-reported outcomes (PROs) in PATHWAY. METHODS: Adults with severe, uncontrolled asthma were randomized to subcutaneous tezepelumab (70 mg every 4 weeks, 210 mg every 4 weeks, or 280 mg every 2 weeks) or placebo for 52 weeks. PROs were assessed using the asthma control questionnaire-6 (ACQ-6) and the asthma quality of life questionnaire (standardized) for patients aged 12 years or older (AQLQ[S]+12). The proportions of responders (defined by improvements of ≥0.5 in ACQ-6 or AQLQ(S)+12 scores) and patients whose asthma was well-controlled, partially-controlled, or uncontrolled in the tezepelumab and placebo groups were identified. The Asthma Daily Diary questionnaire was used to assess changes in overall symptom severity. RESULTS: Overall, 550 patients were randomized. Up to 82% and 77% of tezepelumab-treated patients were ACQ-6 and AQLQ(S)+12 responders, respectively, compared with 70% and 64% of placebo-treated patients, respectively. The proportions of patients with well-controlled or partially-controlled asthma were higher in the tezepelumab-treated group than in the placebo group. In addition, tezepelumab improved the overall symptom severity. CONCLUSION: Tezepelumab treatment improved PROs vs placebo, as indicated by the higher proportion of ACQ-6 and AQLQ(S)+12 responders and improvements in symptom severity in the tezepelumab dose groups. These data further support the benefits of tezepelumab in patients with severe, uncontrolled asthma.

SOURCE: a phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel group trial to evaluate the efficacy and safety of tezepelumab in reducing oral corticosteroid use in adults with oral corticosteroid dependent asthma.

BACKGROUND: Many patients with severe asthma continue to experience asthma symptoms and exacerbations despite standard-of-care treatment. A substantial proportion of these patients require long-term treatment with oral corticosteroids (OCS), often at high doses, which are associated with considerable multiorgan adverse effects, including metabolic disorders, osteoporosis and adrenal insufficiency. Tezepelumab is a human monoclonal antibody that blocks the activity of the epithelial cytokine thymic stromal lymphopoietin. In the PATHWAY phase 2b study (NCT02054130), tezepelumab significantly reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma. Several ongoing phase 3 trials (SOURCE, NCT03406078; NAVIGATOR, NCT03347279; DESTINATION, NCT03706079) are assessing the efficacy and safety of tezepelumab in patients with severe, uncontrolled asthma. Here, we describe the design and objectives of SOURCE, a phase 3 OCS-sparing study. METHODS: SOURCE is an ongoing phase 3, multicentre, randomized, double-blind, placebo-controlled study to evaluate the effect of tezepelumab 210 mg administered subcutaneously every 4 weeks on OCS dose reduction in adults with OCS-dependent asthma. The study comprises a 2-week screening and enrolment period, followed by an OCS optimization phase of up to 8 weeks and a 48-week treatment period, which consists of a 4-week induction phase, followed by a 36-week OCS reduction phase and an 8-week maintenance phase. The primary objective is to assess the effect of tezepelumab compared with placebo in reducing the prescribed OCS maintenance dose. The key secondary objective is to assess the effect of tezepelumab on asthma exacerbation rates. Other secondary objectives include the proportion of patients with a reduction in OCS dose (100% or 50% reduction or those receiving < 5 mg) and the effect of tezepelumab on lung function and patient-reported outcomes. CONCLUSIONS: SOURCE is evaluating the OCS-sparing potential of tezepelumab in patients with OCS-dependent asthma. SOURCE also aims to demonstrate that treatment with tezepelumab in patients with severe asthma is associated with reductions in exacerbation rates and improvements in lung function, asthma control and health-related quality of life, while reducing OCS dose. TRIAL REGISTRATION: NCT03406078 ( ClinicalTrials.gov ). Registered 23 January 2018. https://clinicaltrials.gov/ct2/show/NCT03406078.

NAVIGATOR: a phase 3 multicentre, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of tezepelumab in adults and adolescents with severe, uncontrolled asthma.

BACKGROUND: Patients with severe, uncontrolled asthma have a significant unmet need for new treatments that have broader effects on airway inflammation, and that provide greater improvements in asthma outcomes than currently approved biologics and standard-of-care therapies. Tezepelumab is a human monoclonal antibody that blocks the activity of the epithelial cytokine thymic stromal lymphopoietin. In the PATHWAY phase 2b study (NCT02054130), tezepelumab significantly reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma, irrespective of baseline disease phenotype. This article reports the design and objectives of the pivotal phase 3 NAVIGATOR study. METHODS: NAVIGATOR (NCT03347279) is an ongoing randomized, double-blind, placebo-controlled trial in adults (18-80 years old) and adolescents (12-17 years old) with severe, uncontrolled asthma, who are receiving treatment with medium- or high-dose inhaled corticosteroids plus at least one additional controller medication with or without oral corticosteroids (N = 1061). The study population includes approximately equal proportions of patients with high (≥ 300 cells/µL) and low (< 300 cells/µL) blood eosinophil counts. The study comprises a 5-6-week screening period, a 52-week treatment period and a 12-week post-treatment follow-up period. All patients will receive their prescribed controller medications without change throughout the study. The primary efficacy endpoint is the annualized asthma exacerbation rate during the 52-week treatment period. Key secondary endpoints include the effect of tezepelumab on lung function, asthma control and health-related quality of life. DISCUSSION: NAVIGATOR is evaluating the effect of tezepelumab in patients with a broad range of severe asthma phenotypes at baseline, including those with low blood eosinophil counts. The target sample size for NAVIGATOR (N = 1060) was achieved, and it is the largest clinical study of tezepelumab in severe, uncontrolled asthma to date. NAVIGATOR aims to further investigate the effect of tezepelumab on exacerbations and build on observations from the phase 2b PATHWAY study, and to demonstrate further the potential of tezepelumab to provide patients with severe, uncontrolled asthma with improvements in lung function, asthma control and health-related quality of life. TRIAL REGISTRATION: NCT03347279 (ClinicalTrials.gov). Registered 20 November 2017.

Thymic stromal lymphopoietin: its role and potential as a therapeutic target in asthma.

INTRODUCTION: Thymic stromal lymphopoietin (TSLP), an epithelial cytokine (alarmin), is a central regulator of the immune response to inhaled environmental insults such as allergens, viruses and pollutants, initiating a cascade of downstream inflammation. There is compelling evidence that TSLP plays a major role in the pathology of asthma, and therapies that aim to block its activity are in development. AREAS COVERED: We review studies conducted in humans and human cells, largely published in PubMed January 2010-October 2019, that investigated the innate and adaptive immune mechanisms of TSLP in asthma relevant to type 2-driven (eosinophilic/allergic) inflammation and non-type 2-driven (non-eosinophilic/non-allergic) inflammation, and the role of TSLP as a mediator between immune cells and structural cells in the airway. Clinical data from studies evaluating TSLP blockade are also discussed. EXPERT OPINION: The position of TSLP at the top of the inflammatory cascade makes it a promising therapeutic target in asthma. Systemic anti-TSLP monoclonal antibody therapy with tezepelumab has yielded positive results in clinical trials to date, reducing exacerbations and biomarkers of inflammation in patients across the spectrum of inflammatory endotypes. Inhaled anti-TSLP is an alternative route currently under evaluation. The long-term safety and efficacy of TSLP blockade need to be evaluated.

Tezepelumab in Adults with Uncontrolled Asthma.

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 .).

Colonic manometry in children with defecatory disorders. role in diagnosis and management.

OBJECTIVE: The aim of this study was to evaluate the role of colonic manometry in clarifying pathophysiology of childhood defecatory disorders and to evaluate its impact on management. METHODS: We conducted a retrospective review of medical records of children referred to undergo colonic manometry to a tertiary care Motility Center from 1996 to 2001. Families were followed up a median of 20 months after evaluation (range 3-60 months). RESULTS: A total of 150 colonic manometries were performed in 146 children (74 male, median age 79 months, range 4-225 months). Colonic manometry had been requested to clarify the pathophysiology of lower GI symptoms in 68%; as part of diagnostic workup for chronic intestinal pseudo-obstruction in 11%; to decide about reanastomosis of a diverted colon in 7%; and to clarify the pathophysiology of persisting symptoms after surgery for Hirschsprung's disease in 14%. Normal motility was found in the entire colon in 38% of children. In 17%, there was normal motility in the proximal colon with abnormality limited to the dilated distal colon. Abnormal motility was found in 45% of children. After colonic manometry, treatment changes were recommended in 93% of patients. We were able to follow up 65% of the families. When recommendations were followed (96% of the contacted patients), the symptoms improved in 78%, were unchanged in 18%, and were worse in 4% of patients. Among the parents, 88% believed that the suggestions given after colonic manometry had been helpful in improving their children's health. CONCLUSIONS: Colonic manometry may provide information useful in guiding therapy in a subgroup of patients with defecatory disorders.