Asthma patients' and physicians' perspectives on the burden and management of asthma: post-hoc analysis of APPaRENT 1 and 2 to assess predictors of treatment adherence.

INTRODUCTION: Patient adherence to maintenance medication is critical for improving clinical outcomes in asthma and is a recommended guiding factor for treatment strategy. Previously, the APPaRENT studies assessed patient and physician perspectives on asthma care; here, a post-hoc analysis aimed to identify patient factors associated with good adherence and treatment prescription patterns. METHODS: APPaRENT 1 and 2 were cross-sectional online surveys of 2866 adults with asthma and 1883 physicians across Argentina, Australia, Brazil, Canada, China, France, Italy, Mexico, and the Philippines in 2020-2021. Combined data assessed adherence to maintenance medication, treatment goals, use of asthma action plans, and physician treatment patterns and preferences. Multivariable logistic regression models assessed associations between patient characteristics and both treatment prescription (by physicians) and patient treatment adherence. RESULTS: Patient and physician assessments of treatment goals and adherence differed, as did reporting of short-acting ß2-agonist (SABA) prescriptions alongside maintenance and reliever therapy (MART). Older age and greater patient-reported severity and reliever use were associated with better adherence. Patient-reported prescription of SABA with MART was associated with household smoking, severe or poorly controlled asthma, and living in China or the Philippines. CONCLUSIONS: Results revealed an important disconnect between patient and physician treatment goals and treatment adherence, suggesting that strategies for improving patient adherence to maintenance medication are needed, focusing on younger patients with milder disease. High reliever use despite good adherence may indicate poor disease control. Personalised care considering patient characteristics alongside physician training in motivational communication and shared decision-making could improve patient management and outcomes.

The Incredible Adventure of Omalizumab.

The basis of our current understanding of allergies begins with the discovery of IgE in the mid-1960s. The whole theory of the physiology and pathophysiology of allergic diseases, including rhinitis and asthma, dates from that period. Among the key regions of IgE identified were the FAB (fragment antigen binding) portion that has the ability to capture allergens, and the Cε3 domain, through which IgE binds to its membrane receptor. It was then postulated that blocking IgE at the level of the Cε3 domain would prevent it from binding to its receptor and thus set in motion the allergic cascade. This was the beginning of the development of omalizumab, a monoclonal antibody with an anti-IgE effect. In this article, we review the pathophysiology of allergic disease and trace the clinical development of omalizumab. We also review the benefits of omalizumab treatment that are apparently unrelated to allergies, such as its effect on immunity and bronchial remodeling.

Long-Term Safety of Dupilumab in Patients With Moderate-to-Severe Asthma: TRAVERSE Continuation Study.

BACKGROUND: Previous clinical trials have demonstrated dupilumab efficacy and safety in adults and adolescents with moderate to severe asthma for up to 3 years. OBJECTIVE: The TRAVERSE continuation study (NCT03620747), a single-arm, open-label study, assessed safety and tolerability of dupilumab 300 mg every 2 weeks up to an additional 144 weeks (∼3 years) in patients with moderate to severe asthma who previously completed TRAVERSE (NCT02134028). METHODS: Primary end points were incidence and event rates per 100 patient-years of treatment-emergent adverse events (TEAEs). Secondary end points included adverse events (AEs) of special interest, serious AEs, and AEs leading to study discontinuation. RESULTS: A total of 393 patients participated in the TRAVERSE continuation study (cumulative dupilumab exposure, 431.7 patient-years; median treatment duration, 309 days). A total of 29 patients (7.4%) received more than 958 days of treatment. A total of 214 (54.5%) patients reported at least 1 TEAE (event rate: 171.4); 37 (9.4%) experienced at least 1 treatment-related TEAE, none of which were considered severe; 2 patients reported 6 TEAEs of moderate intensity. A total of 22 (5.6%) patients reported serious AEs (event rate: 6.9). AEs of special interest were reported in 24 patients (6.1%; event rate: 6.0). Five (1.3%) deaths occurred (event rate: 1.2) following serious AEs of coronavirus disease 2019 (COVID-19)-related pneumonia (3 patients), pancreatitis (1 patient), and pulmonary embolism (1 patient). None of the TEAEs leading to death were considered treatment-related. CONCLUSIONS: Dupilumab treatment was well tolerated for up to an additional 3 years. Safety findings were consistent with the known safety profile of dupilumab. These findings further support the long-term use of dupilumab in patients with moderate to severe asthma.

Tezepelumab in patients with allergic and eosinophilic asthma.

Asthma is a heterogeneous disease commonly driven by allergic and/or eosinophilic inflammation, both of which may be present in severe disease. Most approved biologics for severe asthma are indicated for specific phenotypes and target individual downstream type 2 components of the inflammatory cascade. Tezepelumab, a human monoclonal antibody (immunoglobulin G2λ), binds specifically to thymic stromal lymphopoietin (TSLP), an epithelial cytokine that initiates and sustains allergic and eosinophilic inflammation in asthma. By blocking TSLP, tezepelumab has demonstrated efficacy across known asthma phenotypes and acts upstream of all current clinically used biomarkers. In a pooled analysis of the phase 2b PATHWAY (NCT02054130) and phase 3 NAVIGATOR (NCT03347279) studies, compared with placebo, tezepelumab reduced the annualized asthma exacerbation rate over 52 weeks by 62% (95% confidence interval [CI]: 53, 70) in patients with perennial aeroallergen sensitization (allergic asthma); by 71% (95% CI: 62, 78) in patients with a baseline blood eosinophil count ≥300 cells/µL; and by 71% (95% CI: 59, 79) in patients with allergic asthma and a baseline blood eosinophil count ≥300 cells/µL. This review examines the efficacy and mode of action of tezepelumab in patients with allergic asthma, eosinophilic asthma and coexisting allergic and eosinophilic phenotypes.

Impact of dupilumab across seasons in patients with type 2, uncontrolled, moderate-to-severe asthma.

BACKGROUND: Seasonal variability could influence asthma exacerbations. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4/IL-13, key and central drivers of type 2 inflammation. In the 52-week QUEST study (NCT02414854), add-on dupilumab every 2 weeks vs placebo significantly reduced exacerbations and improved prebronchodilator forced expiratory volume in 1 second in patients with uncontrolled, moderate-to-severe asthma. TRAVERSE (NCT02134028), the open-label QUEST extension study, enrolled patients with moderate-to-severe asthma to investigate long-term safety and efficacy of dupilumab, including patients who previously received placebo that initiated dupilumab therapy. OBJECTIVE: To investigate long-term dupilumab efficacy in reducing exacerbations across yearly seasons in patients with type 2 inflammatory asthma with and without clinical evidence of allergic asthma. METHODS: Unadjusted annualized exacerbation rate and proportions of patients experiencing severe asthma exacerbations are reported by month and season and for both hemispheres. RESULTS: The proportion of patients with type 2 asthma experiencing 1 or more severe asthma exacerbations during QUEST was 20.8% vs 10.0% in spring, 18.2% vs 7.3% in summer, 22.2% vs 12.6% in autumn, and 26.4% vs 12.0% in winter, for placebo- vs dupilumab-treated patients, respectively; P was less than .001 for placebo vs dupilumab in all seasons. Reductions in the proportion of patients experiencing severe exacerbations across seasons in subgroups with and without evidence of allergic asthma were similar to the overall type 2 population. Reductions in severe exacerbations observed during QUEST were sustained during TRAVERSE, up to 96 weeks across both hemispheres. CONCLUSION: Dupilumab reduced asthma exacerbations, with no difference in the reduction between seasons, in patients with type 2 inflammation, with and without evidence of allergic asthma. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT02414854, NCT02134028.

Long-term efficacy of dupilumab in severe asthma by baseline oral corticosteroid dose.

Background: Dupilumab has been shown to improve clinical outcomes long term while reducing oral corticosteroid (OCS) dose in patients with severe OCS-dependent asthma. This post hoc analysis assesses the impact of OCS dose at baseline (≤10 or >10 mg·day-1) on long-term outcomes of dupilumab treatment. Methods: Annualised severe asthma exacerbation rates, forced expiratory volume in 1 s (FEV1), measures of asthma control and quality of life, and OCS dose were evaluated in patients from the phase 3 VENTURE trial with severe OCS-dependent asthma, further categorised by OCS dose ≤10 or >10 mg·day-1 at parent study baseline (PSBL), who enrolled in TRAVERSE. Results: Dupilumab reduced the annualised exacerbation rate in VENTURE, and it remained low throughout TRAVERSE (0.202-0.265 (OCS ≤10 mg·day-1 at PSBL) and 0.221-0.366 (OCS >10 mg·day-1 at PSBL)). Improvements in pre-bronchodilator FEV1, asthma control and quality of life observed in VENTURE dupilumab patients were sustained throughout TRAVERSE. Patients on placebo during VENTURE showed rapid improvements in FEV1 upon initiating dupilumab in TRAVERSE, which were sustained to the end of TRAVERSE. Reductions in OCS dose observed in VENTURE were maintained throughout TRAVERSE, with more than two-thirds of patients achieving reductions in OCS doses to ≤5 mg·day-1 by TRAVERSE week 48. Conclusions: Improvements in clinical outcomes and reductions in OCS dose with dupilumab observed in VENTURE were maintained throughout TRAVERSE, regardless of baseline disease severity. Patients who switched from placebo in VENTURE to dupilumab in TRAVERSE had improved clinical outcomes and reductions in OCS dose comparable to those given dupilumab in VENTURE.

Burden of refractory and unexplained chronic cough on patients' lives: a cohort study.

Background: Chronic cough (cough lasting for ≥8 weeks) can lead to significant impairment in quality of life (QoL). Using patient-reported outcomes, this cohort study assessed the perceived impact of chronic cough on QoL and everyday life in patients from outpatient hospital clinics with refractory chronic cough (RCC) or unexplained chronic cough (UCC). Methods: This was a multicentre, non-interventional survey study. Cough severity was assessed on a 0-100 mm Visual Analogue Scale (VAS). Frequency, intensity and disruptiveness of cough were assessed using an adaptation of the Cough Severity Diary. The impact of cough on QoL was assessed using the Leicester Cough Questionnaire (LCQ). The physical impact of cough and associated impact on everyday life activities were explored using purpose-designed questions. Results: 191 patients responded to the survey; 121 (63.4%) had RCC and 149 were women (78.0%). Mean score on the cough severity VAS was 62.9 mm. Mean LCQ total score of 11.9 indicated reduced QoL. Cough impaired patients' everyday life, including the inability to speak fluently (58.0% of patients) and feeling tired/drained (46.6%). Women perceived poorer chronic cough-related QoL than men, as reflected by lower LCQ scores, and greater impairment of physical health, including cough-related stress urinary incontinence, and psychological health. Conclusions: Patients with RCC/UCC experience a significant burden in their everyday life, including impaired QoL, and perceive a negative impact on physical and psychological health and everyday activities, affecting work, relationships and leisure activities. The impact appears to be greater in women than men for several of the aspects studied.

Efficacy and Potential Positioning of Tezepelumab in the Treatment of Severe Asthma.

The excellent results for monoclonal antibodies in the treatment of severe uncontrolled asthma (SUCA) represent a milestone in current treatment of asthmatic disorders. Remaining, however, are several subsidiary areas for improvement in which new biologics are expected to make a decisive contribution. These biologics include tezepelumab, a monoclonal antibody that blocks thymic stromal lymphopoietin (TSLP). TSLP is an epithelial-release cytokine (alarmin) that plays a key role in initiating both the innate (group 2 innate lymphoid cell (ILC) pathway) and the acquired (T helper 2 (Th2) pathway) immune responses by activating the type 2 (T2) asthma inflammatory pathway through both. It is also thought that it may additionally intervene in the neutrophilic non-T2 inflammatory pathway (via interaction with ILC3 and interleukin-17). Six clinical trials that included 2187 patients with uncontrolled asthma, with 2 or more exacerbations in the previous year, on medium/high-dose inhaled corticosteroids and at least 1 other controller, have demonstrated - irrespective of T2 endotype (and possibly also non-T2 endotype) - the efficacy and safety of tezepelumab, as it significantly reduces exacerbations (61.7%-66%) and bronchial hyperresponsiveness, and improves lung function, disease control, and quality of life. Tezepelumab could be indicated for the treatment of patients with, independently of the T2 phenotype (eosinophilic and non-eosinophilic), and may even be the only biologic available for treatment of non-T2 SUCA.

Los excelentes resultados de los anticuerpos monoclonales en el tratamiento del asma grave no controlada (AGNC) constituyen un hito en el tratamiento actual de los trastornos asmáticos. Sin embargo, aún quedan varios aspectos complementarios susceptibles de mejorar para los que se esperan contribuciones decisivas de los nuevos biofármacos, entre los cuales se encuentra el tezepelumab, un anticuerpo monoclonal que bloquea la linfopoyetina estromal tímica (TSLP). La TSLP es una citocina de liberación epitelial (alarmina) que desempeña una función clave en el inicio de las respuestas inmunitarias tanto innata (vía de las células linfocíticas innatas [ILC] del grupo 2) como adaptativa (vía de los linfocitos T cooperadores 2 [Th2]), activando la vía inflamatoria del asma del tipo 2 (T2) mediante ambas. También se cree que puede intervenir en la vía inflamatoria neutrofílica con T2 baja (mediante la interacción con los ILC3 y la interleucina 17). En seis ensayos clínicos que incluyeron a 2.187 pacientes con asma no controlada, dos o más exacerbaciones en el año anterior, a tratamiento con corticosteroides inhalados en dosis medias o altas y con un mínimo de un tratamiento preventivo adicional, se ha demostrado la eficacia y seguridad del tezepelumab sin importar el endotipo T2 (y posiblemente tampoco el endotipo no T2), ya que reduce significativamente las exacerbaciones (61,7-66%) y la hiperreactividad bronquial y mejora la función pulmonar, el control de la enfermedad y la calidad de vida. El tezepelumab puede estar indicado para tratar a pacientes con asma grave, independientemente del fenotipo T2 (eosinofílico y no eosinofílico), y tal vez sea incluso el único biofármaco existente para el tratamiento del AGNC no T2.

Dupilumab sustains efficacy in patients with moderate-to-severe type 2 asthma regardless of inhaled corticosteroids dose.

BACKGROUND: Dupilumab, a human monoclonal antibody, blocks the shared receptor component for interleukins-4/13, key and central drivers of type 2 inflammation. The TRAVERSE (NCT02134028) open-label extension study demonstrated the long-term safety and efficacy of dupilumab in patients ≥12 years who completed a previous dupilumab asthma study. The safety profile was consistent with that observed in the parent studies. Here, we assess whether dupilumab sustains long-term efficacy in patients regardless of inhaled corticosteroid (ICS) dose at parent study baseline (PSBL). METHODS: Patients from phase 2b (NCT01854047) or phase 3 (QUEST; NCT02414854) studies receiving high- or medium-dose ICS at PSBL and enrolled in TRAVERSE were included. We analyzed unadjusted annualized severe exacerbation rates, change from PSBL in pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV1 ), 5-item asthma control questionnaire, and type 2 biomarkers in patients with type 2 asthma at baseline (blood eosinophils ≥150 cells/µL or fractional exhaled nitric oxide [FeNO] ≥25 ppb), and subgroups defined by baseline blood eosinophils or FeNO. RESULTS: Of patients with type 2 asthma (n = 1666), 891 (53.5%) were receiving high-dose ICS at PSBL. In this subgroup, unadjusted exacerbation rates for dupilumab versus placebo were 0.517 versus 1.883 (phase 2b) and 0.571 versus 1.300 (QUEST) over the parent study (52 weeks) and remained low throughout TRAVERSE (0.313-0.494). Improvements in pre-BD FEV1 were sustained throughout TRAVERSE. Similar clinical efficacy was observed among patients receiving medium-dose ICS at PSBL and biomarker subgroups. CONCLUSIONS: Dupilumab showed sustained efficacy for up to 3 years in patients with uncontrolled, moderate-to-severe type 2 asthma on high- or medium-dose ICS.

Omalizumab in Severe Asthma: Effect on Oral Corticosteroid Exposure and Remodeling. A Randomized Open-Label Parallel Study.

INTRODUCTION: Data on the clinical efficacy and remodeling of omalizumab therapy in patients on oral corticosteroids (OC) are limited. OBJECTIVE: The purpose of the study is to show that in patients with corticosteroid-dependent asthma, omalizumab is a corticosteroid-sparing therapy able to inhibit airway remodeling and to reduce disease burden (lung function impairment, exacerbations). METHODS: This study is a randomised open-label study evaluating the addition of omalizumab to the standard of care in patients with severe asthma receiving oral corticosteroids. The primary endpoint was represented by the change in OC monthly dose by the end of treatment and secondary endpoints included spirometry changes, airway inflammation (FeNO), number of exacerbations and airways remodelling assessed by bronchial biopsies studied by transmission electron microscopy. As a safety variable, adverse effects were recorded. RESULTS: Efficacy was assessed for 16 patients in the omalizumab group and 13 in the control group. The final cumulative mean monthly OC doses were 34.7 mg and 217 mg for the omalizumab and control group, respectively; the mean difference between groups adjusted for baseline was -148.1 [95% confidence interval (CI) -243.6, -52.5; p = 0.004]. OC withdrawal of 75% versus 7.7% (p = 0.001) was observed in the omalizumab and control group, respectively. Omalizumab provided a slowing of forced expiratory volume in one second (FEV1) loss (70 mL versus 260 mL), a significant decrease in FeNO values and a reduction in the annual relative risk of clinically significant exacerbations of 54%. The treatment was well tolerated. The morphological study showed a significant decrease in basement membrane thickness in the omalizumab group (6.7 µm versus 4.6 µm) compared with controls (6.9 µm versus 7 µm) [mean difference between groups adjusted for baseline was -2.4 (95% CI -3.7, -1.2; p < 0.001], as well as a decrease in intercellular spaces (1.18 µm versus 0.62 µm and 1.21 µm versus 1.20 µm, p = 0.011, respectively). A qualitative improvement was also observed in the treated group. CONCLUSIONS: Omalizumab showed a marked OC-sparing capacity and was associated with an improvement in clinical management that correlated with bronchial epithelial repair. In OC-dependent asthma, reversibility of remodelling is possible; the concepts that basement membrane enlargement is detrimental and that chronic airway obstruction is systematically irreversible are outdated (EudraCT: 2009-010914-31).

Basic assessment of chronic cough in primary care and referral pathways of patients to different specialists.

BACKGROUND: Chronic cough (CC; cough that lasts 8 weeks or longer) poses major effective assessment challenges. Assessment of CC may vary considerably among medical specialists. OBJECTIVES: The aim was to evaluate similarities and consistency of responses across different specialists when performing a basic assessment of CC patients in primary care, and referring patients based on clinical findings or test results. METHODS: A modified Delphi approach was used. A survey with 74 statements on initial assessment of CC and referral pathways was addressed to a panel of different specialists, who voted the statements in two rounds. RESULTS: Seventy-seven physicians [18 primary care physicians (PCPs), 24 pulmonologists, 22 allergists, and 13 ear, nose, and throat specialists] from the National Healthcare System of Spain answered the questionnaire. After two rounds, the panel reached a consensus on 63 out of the 74 proposed items (85.1%). Consensus was not reached among the panelists of at least one specialty on 15 out of these 63 agreed items. The panel agreed on those clinical aspects that should be evaluated by PCPs in all patients with CC including the impact of CC on quality of life. Agreement was reached on initial actions to be taken in primary care, including substitution of drugs that may induce cough, performing a chest X-ray, introduction of anti-reflux measures, initiation of empirical anti-reflux pharmacological therapy in some cases, and performing a spirometry with bronchodilator test and hemogram if an etiological diagnosis was not reached. The panelists agreed on a list of diseases that PCPs should assess before referring CC patients. Algorithms were developed for initial assessment and targeted referral of patients with CC from primary care. CONCLUSION: This study provides the perspective of different medical specialists on how to perform a basic assessment of CC patients in primary care and how and when to refer patients to other specialists.

Remission outcomes in severe eosinophilic asthma with mepolizumab therapy: Analysis of the REDES study.

Introduction: Clinical remission as a multicomponent treatment goal in severe asthma is being explored in clinical practice. This post hoc analysis used data from the REDES study to assess the proportion of patients with severe eosinophilic asthma achieving our multicomponent definitions of clinical remission after 1 year of mepolizumab treatment. Methods: The real-world, retrospective observational REDES study enrolled patients with severe eosinophilic asthma who were newly prescribed mepolizumab and with ≥12 months of medical records pre-enrolment. Multicomponent clinical remission was defined as: oral corticosteroid (OCS)-free; exacerbation-free; asthma control test (ACT) score ≥20; and with or without post-bronchodilator forced expiratory volume in 1 second ≥80%. Baseline characteristics were also assessed in those who did/did not achieve clinical remission. Results: 37% and 30% of patients with severe eosinophilic asthma met our proposed three- and four-component on-treatment clinical remission definitions; an increase from 2% and 3% at baseline. Most frequently achieved individual components of clinical remission were: OCS-free; ACT score ≥20. For patients fulfilling the multicomponent clinical remission definitions, at baseline we observed higher blood eosinophil counts, better ACT scores and lung function, lower maintenance OCS use, and a slightly lower rate of prior exacerbations versus those who did not. Discussion: Clinical remission is a realistic target in clinical practice for a subset of patients with severe eosinophilic asthma receiving mepolizumab. Further studies are required to elucidate whether features linked to the underlying endotype can help predict treatment outcomes, increase rates of clinical remission, and potentially modify disease progression.

Characteristics and Management of Patients with Refractory or Unexplained Chronic Cough in Outpatient Hospital Clinics in Spain: A Retrospective Multicenter Study.

PURPOSE: Chronic cough (cough that persists for ≥ 8 weeks) can cause a range of physical symptoms and psychosocial effects that significantly impair patients' quality of life. Refractory chronic cough (RCC) and unexplained chronic cough (UCC) are challenging to diagnose and manage, with substantial economic implications for healthcare systems. METHODS: This retrospective multicenter non-interventional study aimed to characterize the profile and health resource consumption of patients with RCC or UCC who attended outpatient clinics at Spanish hospitals. Data were collected from medical records of patients with RCC or UCC for up to 3 years before study inclusion. RESULTS: The patient cohort (n = 196) was representative of the chronic cough population (77.6% female, mean age 58.5 years). Two-thirds of patients (n = 126) had RCC. The most frequently visited doctors were pulmonologists (93.4% of patients) and primary care physicians (78.6%), with a mean of 5 visits per patient over three years' observation. The most common diagnostic tests were chest x-ray (83.7%) and spirometry with bronchodilation (77.0%). The most commonly prescribed treatments were proton pump inhibitors (79.6%) and respiratory medications (87.8%). Antibiotics were prescribed empirically to 56 (28.6%) patients. Differences between RCC or UCC groups related mainly to approaches used to manage cough-associated conditions (gastroesophageal reflux disease, asthma) in patients with RCC. CONCLUSION: RCC and UCC are responsible for high health resource utilization in Spanish hospitals. Specific treatments targeting the pathological processes driving chronic cough may provide opportunities to reduce the associated burden for patients and healthcare systems.

Potential impact of mepolizumab in stepping down anti-osteporotic treatment in corticosteroid-dependent asthma.

Oral corticosteroids (OCS) are commonly used for the acute management of severe asthma exacerbations or as maintenance therapy; however, chronic use is associated with significant toxicities, e.g., osteoporosis. In the REal worlD Effectiveness and Safety (REDES) study of mepolizumab in a multicentric Spanish cohort of asthma patients, mepolizumab effectively reduced clinically severe asthma exacerbations and decreased OCS dependence. This post-hoc analysis further evaluates mepolizumab's de-escalation effect on OCS dose. Patients enrolled in REDES who had OCS consumption data available for 12 months pre- and post-mepolizumab treatment were included in this analysis. Primary outcomes were to determine the change in the proportion of patients eligible for anti-osteoporotic treatment due to the changes in OCS consumption before and after 1 year of mepolizumab treatment. All analyses are descriptive. Approximately one-third (98/318; 30.8%) of patients in REDES were on maintenance OCS at the time of mepolizumab treatment initiation. In REDES, mean cumulative OCS exposure decreased by 54.3% after 1 year of treatment. The proportion of patients on high-dose OCS (≥7.5 mg/day) fell from 57.1% at baseline to 28.9% after 12 months of mepolizumab treatment. Thus, 53.6% of OCS-dependent asthma patients treated with mepolizumab would cease to be candidates for anti-osteoporotic treatment according to guidelines thresholds.

Assessment of dupilumab in children with moderate-to-severe type 2 asthma with or without evidence of allergic asthma.

BACKGROUND: Cytokines, such as interleukins (IL)-4/5/13, play a key role in multiple type 2 inflammatory diseases, including allergic asthma. Dupilumab, a human monoclonal antibody, blocks the shared receptor component for IL-4/IL-13, inhibiting signaling. In this post hoc analysis of VOYAGE (NCT02948959), dupilumab efficacy was evaluated in patients aged 6-11 years with type 2 asthma with or without evidence of allergic asthma (baseline serum total IgE ≥30 IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L). METHODS: Annualized severe exacerbation rates (AER) and changes in pre-bronchodilator (Pre-BD) forced expiratory volume in one second (FEV1 ), percent-predicted pre-BD FEV1 (ppFEV1 ), and Asthma Control Score (ACQ)-7 were assessed during the treatment period. RESULTS: 350 children (261 with and 89 without evidence of allergic asthma) were included. Dupilumab versus placebo significantly reduced AER in patients with (0.24 vs. 0.62, relative risk reduction [RRR]: 62% [95% CI, 39-76], P < .0001) and without (0.39 vs. 0.80, RRR: 51% [95% CI, 0-76], P < .05) evidence of allergic asthma. Significant improvements in ppFEV1 , pre-bronchodilator FEV1 , and ACQ-7 scores were observed in dupilumab versus placebo throughout the treatment period in patients with evidence of allergic asthma. In patients without evidence of allergic asthma, numerical improvements in pre-bronchodilator FEV1 and asthma control were observed by Week 52. CONCLUSION: Dupilumab versus placebo reduced asthma exacerbations in children with type 2 asthma irrespective of evidence of allergic asthma; similar trends were observed in changes in lung function. Significant improvement in asthma control was observed in patients with evidence of allergic asthma, but not in those without.

Dupilumab pharmacokinetics and effect on type 2 biomarkers in children with moderate-to-severe asthma.

BACKGROUND: Type 2 inflammation is common in children with asthma. Dupilumab, a human antibody, blocks the signaling of interleukin -4 and -13, key and central drivers of type 2 inflammation. In the LIBERTY ASTHMA VOYAGE (NCT02948959) study, dupilumab reduced severe asthma exacerbations and improved lung function in children aged 6 to 11 years with uncontrolled, moderate-to-severe asthma. OBJECTIVE: To assess the pharmacokinetics of dupilumab and type 2 biomarker changes in children with type 2 asthma in VOYAGE. METHODS: Patients were randomized to dupilumab 100 mg (≤30 kg) or 200 mg (>30 kg) or placebo every 2 weeks for 52 weeks. Dupilumab concentrations and changes in type 2 biomarkers were assessed at each visit. RESULTS: Dupilumab concentrations in serum reached a steady state by week 12, with mean concentrations of 51.2 mg/L and 79.4 mg/L in children receiving dupilumab 100 mg every 2 weeks and 200 mg every 2 weeks, respectively (therapeutic range in adults and adolescents: 29-80 mg/L). Reductions in type 2 biomarkers were comparable between regimens, and greater in patients treated with dupilumab vs placebo. In children treated with dupilumab 100 mg and 200 mg every 2 weeks, the median percent changes (Q1-Q3) from baseline at week 52 were, respectively, -78.6% (-86.3 to -69.80) and -78.6% (-84.9 to -70.1) for serum total immunoglobulin E, -53.6% (-66.4 to -34.6) and -43.7% (-58.6 to -28.5) for thymus and activation-regulated chemokine; -25.7% (-60.0 to 27.6) and -33.3% (-60.6 to 16.6) for blood eosinophils, and -47.7% (-73.8 to 18.9) and -55.6% (-73.6 to -20.0) for fractional exhaled nitric oxide. CONCLUSION: Weight-tiered dose regimens achieved mean concentrations within the dupilumab therapeutic range. The median decreases in type 2 biomarker levels were similar between dose regimens. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02948959.

From the Allergic Cascade to the Epithelium-Driven Disease: The Long Road of Bronchial Asthma.

In medicine, much of the progress made is due to the emergence of new drugs [...].

The Changing Asthma Management Landscape and Need for Appropriate SABA Prescription.

Short-acting ß2 agonists (SABAs) have been a mainstay of asthma treatment since the 1950s, and have been mainly recommended as-needed for symptom relief alongside daily inhaled corticosteroid (ICS)-based maintenance treatment for the past 30 years. However, patient adherence to regular ICS-based anti-inflammatory maintenance therapy is frequently poor, leading to SABA overuse for symptom relief and associated poor outcomes. At present, there is a lack of consensus between treatment guidelines on how SABA should be used, and as-needed ICS-formoterol is suggested by some as an alternative reliever therapy. Here, we examine the pharmacology and current use of inhaled SABAs, identify that regular dosing of ICS can encourage appropriate SABA use, and appraise the evidence used to support the changing reliever treatment recommendations. We conclude that SABA continues to play an important role in the asthma management landscape, and give our views on how it should be used in patients with mild-moderate asthma, to complement regular ICS-based maintenance treatment.

Consensus on mild asthma management: results of a modified Delphi study.

OBJECTIVE: In order to understand the role of regular controller inhaled corticosteroids (ICS) versus as-needed ICS-formoterol in managing mild asthma, we performed a modified Delphi procedure. METHODS: Opinions from 16 respiratory experts to three surveys and during a virtual scientific workshop helped to develop final consensus statements (pre-defined as 70% agreement). RESULTS: Thirteen participants completed all rounds (response rate 81%). At the end of the procedure, there was final consensus on: regular daily ICS being the recommended treatment approach in mild persistent asthma, with better symptom control and robust long-term clinical data compared with as-needed ICS-formoterol (85%); to avoid noncompliance, frequently seen in mild asthma patients, regular ICS dosing should be accompanied by ongoing education on treatment adherence (100%); treatment aims should be targeting asthma control (92%) and reduction of exacerbation risk (85%). No consensus was reached on whether GINA or national guidelines most influence prescribing decisions. CONCLUSIONS: It is important to encourage patients to be adherent and to target both asthma control and exacerbation risk reduction. There is robust clinical evidence to support proactive regular dosing with ICS controller therapy plus as-needed short-acting beta-agonists for the management of patients with mild asthma.

Dupilumab reduced impact of severe exacerbations on lung function in patients with moderate-to-severe type 2 asthma.

BACKGROUND: Severe asthma exacerbations increase the risk of accelerated lung function decline. This analysis examined the effect of dupilumab on forced expiratory volume in 1 s (FEV1 ) in patients with moderate-to-severe asthma and elevated type 2 biomarkers from phase 3 LIBERTY ASTHMA QUEST (NCT02414854). METHODS: Changes from baseline in pre- and post-bronchodilator (BD) FEV1 and 5-item Asthma Control Questionnaire (ACQ-5) scores were assessed in patients with elevated type 2 biomarkers at baseline (type 2-150/25: eosinophils ≥150 cells/µl and/or fractional exhaled nitric oxide [FeNO] ≥25 ppb; type 2-300/25: eosinophils ≥300 cells/µl and/or FeNO ≥25 ppb), stratified as exacerbators (≥1 severe exacerbation during the study) or non-exacerbators. RESULTS: In exacerbators and non-exacerbators, dupilumab increased pre-BD FEV1 by Week 2 vs placebo; differences were maintained to Week 52 (type 2-150/25: LS mean difference (LSMD) vs placebo: 0.17 L (95% CI: 0.10-0.24) and 0.17 L (0.12-0.23); type 2-300/25: 0.22 L (0.13-0.30) and 0.21 L (0.15-0.28)), in exacerbators and non-exacerbators, respectively (p < .0001). Similar trends were seen for post-BD FEV1 . Dupilumab vs placebo also showed significantly greater improvements in post-BD FEV1 0-42 days after first severe exacerbation in type 2-150/25 (LSMD vs placebo: 0.13 L [0.06-0.20]; p = .006) and type 2-300/25 (0.14 L [0.06-0.22]; p = .001) patients. ACQ-5 improvements were greater with dupilumab vs placebo in both groups. CONCLUSION: Dupilumab treatment led to improvements in lung function independent of exacerbations and appeared to reduce the impact of exacerbations on lung function in patients who experienced a severe exacerbation during the study.