Multivariate Cluster Analyses to Characterize Asthma Heterogeneity and Benralizumab Responsiveness.

Background: An improved understanding of how severe asthma heterogeneity affects response could inform treatment decisions.

Objectives: Characterize heterogeneity and benralizumab responsiveness in patients grouped by predefined Severe Asthma Research Program clusters using a multivariate approach.

Methods: In post-hoc analyses of the randomized, double-blind, placebo-controlled phase III SIROCCO (NCT01928771) and CALIMA (NCT01914757) studies, patients with severe asthma who received benralizumab or placebo were assigned to clusters using an established discriminant function to analyze 11 clinical characteristics simultaneously.

Benralizumab Prevents Recurrent Exacerbations in Patients with Chronic Obstructive Pulmonary Disease: A Post Hoc Analysis.

Exacerbations in chronic obstructive pulmonary disease (COPD), which tend to occur in clusters and increase with disease severity, come with high societal and economic burdens. Prevention and delay of recurrent exacerbations is an unmet and significant therapeutic need for patients with COPD. GALATHEA (NCT02138916) and TERRANOVA (NCT02155660) were trials assessing efficacy of benralizumab in patients with frequent COPD exacerbations despite treatment.

Psychometric Validation and Meaningful Change Thresholds of the New Nasal Polyposis Symptom Diary.

Objectives: The Nasal Polyposis Symptom Diary (NPSD) is a novel and short patient-reported outcome (PRO) tool specifically developed to assess important and relevant symptoms reported by patients with chronic rhinosinusitis with nasal polyposis (CRSwNP). We evaluated the psychometric properties of 4 predefined NPSD-derived scores intended to support symptom-improvement assessments of investigational therapies for inclusion in product labeling.

Methods: Five hundred eighteen patients with severe CRSwNP from a Phase III clinical trial (NCT03401229) completed the NPSD, comprising 11 items: 8 symptom-specific, 2 symptom-impact, and 1 optional medication-compliance.

Adrenal function recovery after durable oral corticosteroid sparing with benralizumab in the PONENTE study.

Background: Oral corticosteroid (OCS) dependence among patients with severe eosinophilic asthma can cause adverse outcomes, including adrenal insufficiency. PONENTE's OCS reduction phase showed that, following benralizumab initiation, 91.5% of patients eliminated corticosteroids or achieved a final dosage ≤5 mg·day (median (range) 0.

Targeting TSLP in Asthma.

Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine implicated in the initiation and persistence of inflammatory pathways in asthma. Released in response to a range of epithelial insults (eg, allergens, viruses, bacteria, pollutants, and smoke), TSLP initiates multiple downstream innate and adaptive immune responses involved in asthma inflammation. Inhibition of TSLP is postulated to represent a novel approach to treating the diverse phenotypes and endotypes of asthma.

Measuring the patient experience of chronic rhinosinusitis with nasal polyposis: qualitative development of a novel symptom diary.

Background: This qualitative study assessed the experience of patients with chronic rhinosinusitis with nasal polyposis (NP) to inform the development of a novel symptom diary for clinical study use.

Methods: Concept elicitation and cognitive interviews were conducted with patients who had a physician-verified diagnosis of NP and a history of intranasal corticosteroid use. Concepts were identified via open-ended and follow-up questions.

Oral corticosteroid elimination via a personalised reduction algorithm in adults with severe, eosinophilic asthma treated with benralizumab (PONENTE): a multicentre, open-label, single-arm study.

Background: No consensus exists on how to reduce oral corticosteroids after the initiation of biologics in severe asthma. The PONENTE trial evaluated the effectiveness and safety of a rapid, individualised steroid-reduction algorithm, including adrenal insufficiency monitoring, after benralizumab initiation.

Methods: This multicentre, open-label, single-arm study was done at 138 clinical asthma treatment centres across 17 countries.

Efficacy and safety of benralizumab in chronic rhinosinusitis with nasal polyps: A randomized, placebo-controlled trial.

Background: Eosinophilic inflammation has been implicated in the pathogenesis, severity, and treatment responsiveness of chronic rhinosinusitis with nasal polyps (CRSwNP).

Objective: We sought to assess the efficacy and safety of benralizumab-mediated eosinophil depletion for treating CRSwNP.

Methods: The phase 3 OSTRO study enrolled patients with severe CRSwNP who were symptomatic despite treatment with intranasal corticosteroids and who had a history of systemic corticosteroid (SCS) use and/or surgery for nasal polyps (NP).

Benralizumab for adolescent patients with severe, eosinophilic asthma: Safety and efficacy after 3 years of treatment.

Background: Adults and adolescents with severe asthma who completed the 48-week SIROCCO and 56-week CALIMA phase III benralizumab trials entered the safety extension study BORA (NCT02258542). The continued safety and efficacy of benralizumab in the first year of BORA (year 2 of treatment) have been reported.

Objective: We sought to report outcomes for adolescents during years 2 and 3 of treatment in BORA.

Efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler delivered using co-suspension delivery technology in Japanese patients with moderate-to-very severe chronic obstructive pulmonary disease.

Background: PINNACLE-4 evaluated the efficacy and safety of the long-acting muscarinic antagonist/long-acting β-agonist fixed-dose combination glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI) in patients from Asia, Europe, and the USA with moderate-to-very severe chronic obstructive pulmonary disease (COPD). This pre-specified analysis included Japanese patients in PINNACLE-4.

Methods: In this double-blind randomized study (NCT02343458), patients received GFF MDI (18/9.

Functional respiratory imaging assessment of glycopyrrolate and formoterol fumarate metered dose inhalers formulated using co-suspension delivery technology in patients with COPD.

Background: Functional respiratory imaging (FRI) is a quantitative postprocessing imaging technique used to assess changes in the respiratory system. Using FRI, we characterized the effects of the long-acting muscarinic antagonist (LAMA), glycopyrrolate metered dose inhaler (GP MDI), and the long-acting β-agonist (LABA), formoterol fumarate metered dose inhaler (FF MDI), on airway volume and resistance in patients with moderate-to-severe chronic obstructive pulmonary disease.

Methods: Patients in this phase IIIb, randomized, double-blind crossover study received twice-daily GP MDI (18 μg) and FF MDI (9.

Blood eosinophil count group shifts and kinetics in severe eosinophilic asthma.

Background: Blood eosinophil count (BEC) measurements are a noninvasive, relatively reliable surrogate marker for eosinophilic airway inflammation. Single measurements of peripheral BEC greater than or equal to 150 cells/μL predict the response to anti-eosinophil therapies for patients with characteristics of severe eosinophilic asthma.

Objective: To describe how BECs shift over time for patients with severe, uncontrolled asthma receiving placebo in 2 large, randomized, placebo-controlled clinical trials of benralizumab (SIROCCO and CALIMA).

Safety of Eosinophil-Depleting Therapy for Severe, Eosinophilic Asthma: Focus on Benralizumab.

Eosinophils play a pivotal role in the inflammatory pathology of asthma and have been the target of new biologic treatments for patients with eosinophilic asthma. Given the central role of interleukin (IL)-5 in the eosinophil lifecycle, several therapies directed against the IL-5 pathway have been developed, including the anti-IL-5 antibodies mepolizumab and reslizumab and the IL-5 receptor α (IL-5Rα)-directed cytolytic antibody benralizumab. Eosinophil-depleting therapies represent a relatively new class of asthma treatment, and it is important to understand their long-term efficacy and safety.

Onset of Effect, Changes in Airflow Obstruction and Lung Volume, and Health-Related Quality of Life Improvements with Benralizumab for Patients with Severe Eosinophilic Asthma: Phase IIIb Randomized, Controlled Trial (SOLANA).

Objective: In the SOLANA trial, we sought to physiologically characterize benralizumab's onset of effect and maintenance of that effect for patients with severe eosinophilic asthma.

Methods: SOLANA (NCT02869438) was a multicenter, randomized, double-blind, parallel-group, placebo-controlled, Phase IIIb study conducted at 49 centers in six countries (Chile, Germany, Hungary, the Philippines, South Korea, and the United States). Eligible patients with baseline blood eosinophil counts ≥300 cells/µL were randomized to subcutaneous benralizumab (30 mg) or placebo administered at Days 0, 28, and 56.

Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Improves Lung Function versus Monotherapies in GOLD Category A Patients with COPD: Pooled Data from the Phase III PINNACLE Studies.

Background: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends a short-acting bronchodilator or single long-acting bronchodilator as an initial pharmacological treatment for GOLD category A patients with COPD. We pooled data from the PINNACLE-1, -2, and -4 studies to evaluate the efficacy and safety of the dual bronchodilator fixed-dose combination glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), formulated using co-suspension delivery technology, in GOLD category A patients with moderate-to-very severe COPD.

Materials And Methods: PINNACLE-1, -2, and -4 were Phase III, randomized, double-blind, parallel-group, multicenter studies (NCT01854645, NCT01854658, and NCT02343458).

Efficacy And Safety Of Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler (GFF MDI) Formulated Using Co-Suspension Delivery Technology In Chinese Patients With COPD.

Background: Glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI) is a long-acting muscarinic antagonist/long-acting β-agonist fixed-dose combination therapy delivered by MDI, formulated using innovative co-suspension delivery technology. The PINNACLE-4 study evaluated the efficacy and safety of GFF MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) from Asia, Europe, and the USA. This article presents the results from the China subpopulation of PINNACLE-4.

Two-year integrated steroid-sparing analysis and safety of benralizumab for severe asthma.

Objective: Treatment with benralizumab significantly reduces exacerbations and improves lung function after 1 year and decreases oral corticosteroid (OCS) use after 28 weeks for patients with severe, uncontrolled eosinophilic asthma. We assessed whether these effects on OCS reduction are sustained for up to an additional year of treatment while maintaining an acceptable safety profile.

Methods: Data on OCS maintenance dosage were collected for adult patients with baseline blood eosinophil counts ≥150 cells/μL treated with add-on benralizumab 30 mg (every 4 [Q4W] or 8 weeks [Q8W; first three doses Q4W]) from the 28-week ZONDA study and were integrated with results from the predefined 56-week adult completion phase of the BORA extension study.

Two-Year Integrated Efficacy And Safety Analysis Of Benralizumab In Severe Asthma.

Background: Benralizumab is an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody. Treatment with benralizumab significantly reduces exacerbations and improves lung function after 1 year for patients with severe, uncontrolled eosinophilic asthma.

Objective: We explored whether benralizumab efficacy was sustained after an additional year of treatment while maintaining an acceptable safety profile.

Single-Use Autoinjector Functionality And Reliability For At-Home Administration Of Benralizumab For Patients With Severe Asthma: GRECO Trial Results.

Purpose: Accessorized prefilled syringes (APFS) have demonstrated functionality and reliability for subcutaneous (SC) delivery, including self-administration, of benralizumab 30 mg in the clinic or at home. The multicenter, open-label GRECO study (NCT02918071) assessed functionality and reliability of a single-use autoinjector (AI) for at-home benralizumab administration by patients or their caregivers.

Patients And Methods: Adults with severe asthma received benralizumab SC injections at the study site at Weeks 0, 4, and 8.

Corticosteroid tapering with benralizumab treatment for eosinophilic asthma: PONENTE Trial.

Benralizumab is an interleukin-5 receptor α-directed cytolytic monoclonal antibody approved in several countries for the add-on maintenance treatment of patients with severe eosinophilic asthma aged 12 years and older. In the 28-week Phase III ZONDA trial (ClinicalTrials.gov identifier: NCT02075255), benralizumab produced a median 75% reduction from baseline in oral corticosteroid (OCS) dosage ( 25% for placebo) while maintaining asthma control for patients with OCS-dependent severe asthma.

Predicting response to benralizumab in chronic obstructive pulmonary disease: analyses of GALATHEA and TERRANOVA studies.

Background: Benralizumab did not significantly reduce exacerbations compared with placebo in the phase 3 GALATHEA and TERRANOVA trials of benralizumab for patients with chronic obstructive pulmonary disease (COPD). We aimed to identify clinical and physiological characteristics of patients with COPD that could help to identify people who are likely to have the greatest treatment effect with benralizumab.

Methods: We analysed individual study and pooled results from GALATHEA and TERRANOVA.

Comparison of autoinjector with accessorized prefilled syringe for benralizumab pharmacokinetic exposure: AMES trial results.

Objective: We compared the pharmacokinetic exposure following a single subcutaneous dose of benralizumab 30 mg using either autoinjectors (AI) or accessorized prefilled syringes (APFS). APFS and AI functionality and reliability for at-home benralizumab delivery have been demonstrated in the GREGALE and GRECO studies, respectively.

Methods: In the open-label AMES study (NCT02968914), 180 healthy adult men and women were randomized to one of two device (AI or APFS) and three injection site (upper arm, abdomen, or thigh) combinations.

A Randomized, Double-Blind, Double-Dummy Study of Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Relative to Umeclidinium/Vilanterol Dry Powder Inhaler in COPD.

Introduction: Glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI), formulated using co-suspension delivery technology, is the only approved fixed-dose combination long-acting muscarinic antagonist/long-acting β-agonist (LAMA/LABA) delivered via MDI. Direct comparisons of GFF MDI versus other LAMA/LABAs have not previously been performed. We assessed the efficacy and safety of GFF MDI relative to umeclidinium/vilanterol dry powder inhaler (UV DPI) in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD).

Sputum is reduced in COPD following treatment with benralizumab.

We hypothesized whether the reduction in eosinophilic airway inflammation in patients with chronic obstructive pulmonary disease (COPD) following treatment with benralizumab, a humanized, afucosylated, monoclonal antibody that binds to interleukin-5 receptor α, increases the airway bacterial load. Analysis of sputum samples of COPD patients participating in a Phase II trial of benralizumab indicated that sputum 16S rDNA load and were reduced following treatment with benralizumab. However, in vitro, eosinophils did not affect the killing of the common airway pathogens or .