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]).

A real-world study of inhaled corticosteroid use in patients with severe eosinophilic asthma treated with mepolizumab.

BACKGROUND: Mepolizumab is a humanized anti-interleukin-5, monoclonal antibody approved for the treatment of patients with severe eosinophilic asthma (SEA). There is limited evidence that mepolizumab can reduce inhaled corticosteroid (ICS) use in these patients. OBJECTIVE: To investigate changes in ICS use and clinical outcomes in patients with SEA who initiated mepolizumab treatment. METHODS: This retrospective cohort study (GlaxoSmithKline identification: 212695/HO-20-19951) used administrative claims data from the IBM Watson Health MarketScan Database (identification period: November 2015 to March 2018). Eligible patients had SEA and were receiving high-dose ICS and mepolizumab. Use of ICS, oral corticosteroid (OCS), and short-acting ß2-agonist and exacerbation frequency were analyzed quarterly during the 12-month follow-up period after mepolizumab initiation. RESULTS: In total, 351 patients were included. The proportion of patients using high-dose ICS decreased in quarters 1 to 4 after mepolizumab initiation (79.8%, 74.6%, 68.9%, 65.5%, respectively); 49.0% of patients reduced or discontinued ICS for one or more quarter. Comparing patients who discontinued ICS vs those who remained on high-dose ICS, a lower proportion had chronic OCS use (3.4%-9.2% vs 13.9%-16.8%) and OCS burst use (15.4%-20.8% vs 19.7%-26.1%) in quarters 1 to 4; similarly in quarters 3 and 4, a lower proportion of patients had exacerbations (16.9% and 20.3% vs 27.2% and 27.7%) and short-acting ß2-agonist claims (35.4% and 39.2% vs 43.3% and 49.0%, respectively). CONCLUSION: In patients with SEA on high-dose ICS, a reduction in both ICS and OCS use was observed after initiating mepolizumab. These findings have important implications for clinical outcomes and follow-up care in this patient population.

Factors leading to discontinuation of biologic therapy in patients with severe asthma.

OBJECTIVE: To assess patient- and physician-reported reasons for discontinuing biologic therapy among patients with severe asthma from a real-world US cohort. METHODS: This retrospective analysis surveyed US physicians and their patients with severe asthma who were receiving/had previously received biologic therapy between August and December 2019. Physicians managing ≥3 patients with asthma per month completed surveys on disease management, demographics, exacerbation history, and biologic adherence for eligible patients. Patients could voluntarily complete a questionnaire, providing perceptions of their disease and treatment. RESULTS: 117 physicians completed case reports for 285 patients; 85 patients had discontinued biologic therapy. Physicians (n = 85) and patients (n = 64) reported patient request (28.2% and 46.9%), shortness of breath (45.9% and 23.4%), other chronic respiratory symptoms (29.4% and 10.9%), cost/reimbursement (17.7%/9.4% and 20.3%/7.8%), and exacerbations (25.9% and 10.9%) among the main reasons for biologic discontinuation. Patients who continued biologic therapy were older (mean age 47.6 years) than those who discontinued (43.8 years), and were more likely to have ≥2 exacerbations in the previous year (52.5% vs 35.3%), allergic rhinitis (70.0% vs 62.4%), or chronic rhinosinusitis (30.0% vs 12.9%). Side effects were cited as reasons by only 15.3% and 7.8% of physicians and patients, respectively. CONCLUSIONS: The most common reasons given for discontinuation of biologic therapy were lack of symptom control, exacerbations, cost, and patient request. These data highlight the complexity of care for this patient group and the need for ongoing, regular assessment of common challenges to biologic continuation and reasons for discontinuation, including both clinical and non-clinical factors.

Real-world effectiveness of mepolizumab in patients with severe asthma and associated comorbidities.

BACKGROUND: Patients with severe asthma frequently have associated comorbidities, which can compound existing symptoms, complicating asthma management. OBJECTIVE: To describe the real-world effectiveness of mepolizumab in patients with severe asthma stratified by common overlapping comorbidities. METHODS: This was a retrospective analysis of patients with asthma from the MarketScan Commercial and Medicare Supplemental Database initiating mepolizumab treatment (index date). Eligible patients had more than or equal to 1 claim (excluding claims for diagnostic tests) with a diagnosis code for more than or equal to 1 of 7 comorbidities (atopic disease, nasal polyps, chronic sinusitis, obesity, respiratory infections, chronic obstructive pulmonary disease, and depression/anxiety) during the 12-month preindex baseline period; these were used to stratify patients into 7 nonmutually exclusive subgroups. Outcomes included asthma exacerbations and exacerbation-related health care resource utilization during the 12-month baseline and follow-up periods. Each patient acted as their own control. RESULTS: Of the 639 patients included, the most common comorbidities were atopic diseases (73.2%), respiratory infections (55.6%), and chronic sinusitis (45.1%). Across all 7 comorbidity subgroups, there were significant (P < .05) reductions of 38% to 55% and 57% to 83% in exacerbations and exacerbations requiring hospitalization, respectively, during the follow-up vs baseline period, except for exacerbations requiring hospitalization in the nasal polyp subgroup, owing to the small subgroup sample size. During the follow-up vs baseline periods, mean number of oral corticosteroids claims was significantly (P < .001) reduced by 29% to 38%; 39% to 47% of patients achieved greater than or equal to 50% oral corticosteroids dose reduction. Significant reductions in exacerbation-related health care resource utilization were also observed. CONCLUSION: Mepolizumab treatment provided real-world clinical benefits in patients.

Real-world evidence: Patient views on asthma in respiratory specialist clinics in America.

BACKGROUND: Approximately 30% to 50% of patients with moderate/severe asthma have inadequately controlled disease despite adherence to inhaled corticosteroid (ICS)/long-acting ß2-agonist (LABA) therapy. Data on prevalence and burden of uncontrolled asthma in specialty settings are lacking. OBJECTIVE: To evaluate the prevalence and burden of uncontrolled asthma in respiratory specialist clinics in the United States. METHODS: Adults with physician-diagnosed asthma attending pulmonary and allergy clinics with self-reported ICS use in the previous 4 weeks completed an electronic questionnaire including the Asthma Control Test and St George's Respiratory Questionnaire. Additional information was collected using an electronic case report form. RESULTS: Of 774 patients attending 12 pulmonary and 12 allergy clinics, 53% were not well controlled (mean [SD] Asthma Control Test, 14.3 [3.6] vs 22.4 [1.6] in well-controlled patients). Among ICS/LABA users, 56% were not well controlled, which increased with increasing ICS dose (low-dose 45.7%; high-dose 59.7%). The not well-controlled group reported more respiratory illnesses, more comorbidities, and poorer health-related quality of life (mean [SD] St George's Respiratory Questionnaire, 46.1 [18.9] vs 19.8 [12.9] in the well-controlled group). These patients also had more asthma exacerbations (≥1 exacerbation, 68.9% vs 43.1%) and increased health care resource utilization (≥1 asthma-related hospitalization, 10.7% vs 2.7%); 27.3% were also receiving systemic corticosteroids. Approximately 40% of the population were eligible for step-up to ICS/LABA/long-acting muscarinic antagonist triple therapy, and 20% were eligible for biologic therapy. CONCLUSION: Substantial unmet needs exist among patients with inadequately controlled asthma managed in United States specialist settings, which may be addressed by improved patient and physician education, better guideline implementation, and improved adherence.

A randomized trial of benralizumab, an antiinterleukin 5 receptor α monoclonal antibody, after acute asthma.

BACKGROUND: Patients with frequent asthma exacerbations resulting in emergency department (ED) visits are at increased risk for future exacerbations. We examined the ability of 1 dose of benralizumab, an investigational antiinterleukin 5 receptor α monoclonal antibody, to reduce recurrence after acute asthma exacerbations. METHODS: In this randomized, double-blind, placebo-controlled study, eligible subjects presented to the ED with an asthma exacerbation, had partial response to treatment, and greater than or equal to 1 additional exacerbation within the previous year. Subjects received 1 intravenous infusion of placebo (n = 38) or benralizumab (0.3 mg/kg, n = 36 or 1.0 mg/kg, n = 36) added to outpatient management. The primary outcome was the proportion of subjects with greater than or equal to 1 exacerbation at 12 weeks in placebo vs the combined benralizumab groups. Other outcomes included the time-weighted rate of exacerbations at week 12, adverse events, blood eosinophil counts, asthma symptom changes, and health care resource utilization. RESULTS: The proportion of subjects with greater than or equal to 1 asthma exacerbation at 12 weeks was not different between placebo and the combined benralizumab groups (38.9% vs 33.3%; P = .67). However, compared with placebo, benralizumab reduced asthma exacerbation rates by 49% (3.59 vs 1.82; P = .01) and exacerbations resulting in hospitalization by 60% (1.62 vs 0.65; P = .02) in the combined groups. Benralizumab reduced blood eosinophil counts but did not affect other outcomes, while demonstrating an acceptable safety profile. CONCLUSIONS: When added to usual care, 1 dose of benralizumab reduced the rate and severity of exacerbations experienced over 12 weeks by subjects who presented to the ED with acute asthma.

Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia.

BACKGROUND: Many asthmatic patients exhibit sputum eosinophilia associated with exacerbations. Benralizumab targets eosinophils by binding IL-5 receptor α, inducing apoptosis through antibody-dependent cell-mediated cytotoxicity. OBJECTIVES: We sought to evaluate the safety of benralizumab in adults with eosinophilic asthma and its effects on eosinophil counts in airway mucosal/submucosal biopsy specimens, sputum, bone marrow, and peripheral blood. METHODS: In this multicenter, double-blind, placebo-controlled phase I study, 13 subjects were randomized to single-dose intravenous placebo or 1 mg/kg benralizumab (day 0; cohort 1), and 14 subjects were randomized to 3 monthly subcutaneous doses of placebo or 100 or 200 mg of benralizumab (days 0, 28, and 56; cohort 2). Cohorts 1 and 2 were consecutive. RESULTS: The incidence of adverse events was similar between groups. No serious adverse events related to benralizumab occurred. In cohort 1 intravenous benralizumab produced a median decrease from baseline of 61.9% in airway mucosal eosinophil counts (day 28; placebo: +19.6%; P = .28), as well as an 18.7% decrease (day 21) in sputum and a 100% decrease (day 28) in blood counts. Eosinophils were not detectable in bone marrow of benralizumab-treated subjects (day 28, n = 4). In cohort 2 subcutaneous benralizumab demonstrated a combined (100 + 200 mg) median reduction of 95.8% in airway eosinophil counts (day 84; placebo, 46.7%; P = .06), as well as an 89.9% decrease (day 28) in sputum and a 100% decrease (day 84) in blood counts. CONCLUSION: Single-dose intravenous and multiple-dose subcutaneous benralizumab reduced eosinophil counts in airway mucosa/submucosa and sputum and suppressed eosinophil counts in bone marrow and peripheral blood. The safety profile supports further development. Additional studies are needed to assess the clinical benefit in asthmatic patients.

Machine Learning Approaches to Predict Asthma Exacerbations: A Narrative Review.

The implementation of artificial intelligence (AI) and machine learning (ML) techniques in healthcare has garnered significant attention in recent years, especially as a result of their potential to revolutionize personalized medicine. Despite advances in the treatment and management of asthma, a significant proportion of patients continue to suffer acute exacerbations, irrespective of disease severity and therapeutic regimen. The situation is further complicated by the constellation of factors that influence disease activity in a patient with asthma, such as medical history, biomarker phenotype, pulmonary function, level of healthcare access, treatment compliance, comorbidities, personal habits, and environmental conditions. A growing body of work has demonstrated the potential for AI and ML to accurately predict asthma exacerbations while also capturing the entirety of the patient experience. However, application in the clinical setting remains mostly unexplored, and important questions on the strengths and limitations of this technology remain. This review presents an overview of the rapidly evolving landscape of AI and ML integration into asthma management by providing a snapshot of the existing scientific evidence and proposing potential avenues for future applications.

A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma.

Pre-clinical data demonstrate a pivotal role for interleukin (IL)-13 in the development and maintenance of asthma. This study assessed the effects of tralokinumab, an investigational human IL-13-neutralising immunoglobulin G4 monoclonal antibody, in adults with moderate-to-severe uncontrolled asthma despite controller therapies. 194 subjects were randomised to receive tralokinumab (150, 300 or 600 mg) or placebo subcutaneously every 2 weeks. Primary end-point was change from baseline in mean Asthma Control Questionnaire score (ACQ-6; ACQ mean of six individual item scores) at week 13 comparing placebo and combined tralokinumab dose groups. Secondary end-points included pre-bronchodilator lung function, rescue ß(2)-agonist use and safety. Numerical end-points are reported as mean±sd. At week 13, change from baseline in ACQ-6 was -0.76±1.04 for tralokinumab versus -0.61±0.90 for placebo (p=0.375). Increases from baseline in forced expiratory volume in 1 s (FEV(1)) were 0.21±0.38 L versus 0.06±0.48 L (p=0.072), with a dose-response observed across the tralokinumab doses tested. ß(2)-agonist use (puffs per day) was decreased for tralokinumab -0.68±1.45 versus placebo -0.10±1.49 (p=0.020). The increase in FEV(1) following tralokinumab treatment remained evident 12 weeks after the final dose. Safety profile was acceptable with no serious adverse events related to tralokinumab. No improvement in ACQ-6 was observed, although tralokinumab treatment was associated with improved lung function.