Showing papers by "Ian D. Pavord published in 2021"

Efficacy and Safety of Itepekimab in Patients with Moderate-to-Severe Asthma.

Abstract: Background Monoclonal antibodies targeting IgE, interleukin-4 and -13, and interleukin-5 are effective in treating severe type 2 asthma, but new targets are needed. Itepekimab is a new mon...

Derivation of a prototype asthma attack risk scale centred on blood eosinophils and exhaled nitric oxide.

Abstract: Reduction of the risk of asthma attacks is a major goal of current asthma management. We propose to derive a risk scale predicting asthma attacks based on the blood eosinophil count and exhaled nitric oxide (FeNO). Biomarker-stratified trial-level attack rates were extracted and pooled from the control arms of the Novel START, CAPTAIN, QUEST, Benralizumab Phase 2b, PATHWAY, STRATOS 1-2 and DREAM trials (n=3051). These were used to derive rate ratios and the predicted asthma attack rate for different patient groups. The resultant prototype risk scale shows potential to predict asthma attacks, which may be prevented by anti-inflammatory treatment.

Heterogeneity within and between physician-diagnosed asthma and/or COPD: NOVELTY cohort

Abstract: Background Studies of asthma and chronic obstructive pulmonary disease (COPD) typically focus on these diagnoses separately, limiting understanding of disease mechanisms and treatment options NOVELTY is a global, 3-year, prospective observational study of patients with asthma and/or COPD from real-world clinical practice We investigated heterogeneity and overlap by diagnosis and severity in this cohort Methods Patients with physician-assigned asthma, COPD or both (asthma+COPD) were enrolled, stratified by diagnosis and severity Baseline characteristics were reported descriptively by physician-assigned diagnosis and/or severity Factors associated with physician-assessed severity were evaluated using ordinal logistic regression analysis Results Of 11 243 patients, 5940 (528%) had physician-assigned asthma, 1396 (124%) had asthma+COPD and 3907 (348%) had COPD; almost half were from primary care Symptoms, health-related quality of life and spirometry showed substantial heterogeneity and overlap between asthma, asthma+COPD and COPD, with 23%, 62% and 64% of patients, respectively, having post-bronchodilator FEV1/FVC Symptoms and exacerbations increased with greater physician-assessed severity, and were higher in asthma+COPD, but 243% with mild asthma and 204% with mild COPD had experienced ≥1 exacerbation in the past 12 months Medication records suggested both under-treatment and over-treatment relative to severity Blood eosinophil counts varied little across diagnosis/severity groups, but blood neutrophil counts increased with severity across all diagnoses Conclusion This analysis demonstrates marked heterogeneity within, and overlap between, physician-assigned diagnosis and severity groups in patients with asthma and/or COPD Current diagnostic and severity classifications in clinical practice poorly differentiate between clinical phenotypes that may have specific risks and treatment implications

Patient characteristics, biomarkers, and exacerbation risk in severe, uncontrolled asthma.

Abstract: Background: Greater precision in asthma exacerbation risk prediction may improve outcomes. We sought to identify clinical characteristics and biomarkers associated with elevated exacerbation risk in patients with severe, uncontrolled asthma. Methods: Data were pooled from seven similarly designed Phase II and III randomized controlled clinical trials of biologic therapies for the treatment of severe, uncontrolled asthma that enrolled comparable patient populations. Annualized asthma exacerbation rates (AAERs) for patients randomized to placebo were assessed by baseline clinical characteristics and by biomarker concentrations at baseline and over the study duration. Results: The AAER for the 2016 patients in the combined placebo group was 0.91 (95% CI 0.84‒0.98). Baseline characteristics associated with greater AAER were frequent or severe exacerbations within the prior 12 months, nasal polyposis, maintenance oral corticosteroid use, Asian race, and Asian or Western European region. AAER increased with baseline blood eosinophil counts and fractional exhaled nitric oxide (FeNO) concentration, with the greatest AAER occurring for patients with eosinophils ≥300 cells·μL-1 and FeNO ≥50 ppb. No relationship was observed between baseline serum immunoglobulin E concentration and AAER. Combining type 2 inflammation criteria for eosinophils and FeNO had greater prognostic value than either biomarker alone. Persistent eosinophil and FeNO elevations throughout the study period were associated with greater AAER. Conclusions: Exacerbation history, maintenance corticosteroid use, nasal polyposis, Asian race, geographic region, and elevations in blood eosinophil counts and FeNO concentrations (particularly when combined and/or persistently achieving type 2 inflammation criteria) were associated with increased exacerbation risk in patients with severe, uncontrolled asthma.

A blood atlas of COVID-19 defines hallmarks of disease severity and specificity

Abstract: SummaryTreatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete understanding of potentially druggable immune mediators of disease. To advance this, we present a comprehensive multi-omic blood atlas in patients with varying COVID-19 severity and compare with influenza, sepsis and healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity revealed cells, their inflammatory mediators and networks as potential therapeutic targets, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Tensor and matrix decomposition of the overall dataset revealed feature groupings linked with disease severity and specificity. Our systems-based integrative approach and blood atlas will inform future drug development, clinical trial design and personalised medicine approaches for COVID-19.

Dupilumab efficacy in adolescents with uncontrolled, moderate-to-severe asthma: LIBERTY ASTHMA QUEST.

Abstract: To the Editor, Asthma prevalence has increased globally among adolescents in recent years, yet this population remains understudied.1 Dupilumab, a fully human VelocImmune®derived monoclonal antibody,2,3 blocks the shared receptor component for interleukin (IL)4 and IL13, key and central drivers of type 2 inflammation in multiple diseases.4,5 In the phase 3 LIBERTY ASTHMA QUEST study (NCT02414854), addon dupilumab 200/300 mg every 2 weeks vs placebo significantly reduced severe asthma exacerbations and improved prebronchodilator forced expiratory volume in 1 second (FEV1) in patients with uncontrolled, moderatetosevere asthma. Treatment effects were greater in patients with elevated type 2 biomarkers at baseline.6 This post hoc analysis of QUEST assessed the efficacy of dupilumab in adolescent patients aged 12– 17 years compared with adults aged ≥18 years. The study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice guideline and approved by local institutional review boards or ethics committees. All patients provided written informed consent before participating in the trial. Prespecified endpoints were changed from baseline in prebronchodilator FEV1 and annualized severe exacerbation rate (AER). Changes from baseline were assessed post hoc for postbronchodilator FEV1, percentage predicted FEV1 (ppFEV1), Asthma Control Questionnaire (ACQ5) response, fractional exhaled nitric oxide (FeNO) levels, blood eosinophil counts, and serum total immunoglobulin E (IgE). Subgroups of adolescent and adult patients with elevated type 2 biomarkers (blood eosinophils ≥150 cells/μL or FeNO ≥20 ppb) at baseline were also examined post hoc. 107 adolescents aged 12– 17 years (5.6% of total population) and 1795 (94.4%) adults were randomized. Due to the small proportion of adolescents in the overall population, differences in baseline characteristics between patients receiving dupilumab and placebo were observed (Table S1); results should be interpreted within the context of these limitations. Dupilumab significantly improved lung function and exacerbation rates in adults, as previously observed in the overall QUEST population (Figures S1 and S2).6 In the adolescent population, dupilumab (200 and 300 mg) vs matched placebo significantly improved prebronchodilator FEV1 at Week 12 by 0.37L (95% CI, 0.13– 0.61; p=.003) and 0.27L (95% CI, 0.02– 0.52; p=.037) (Figure 1A). In the 80% of adolescent patients with elevated baseline type 2 biomarker levels treated with dupilumab 200 mg, the magnitude of this improvement was greater (0.43L; 95% CI, 0.17– 0.69; p=.002) than in the corresponding intentiontotreat (ITT) adolescent subgroup (Figure 1B). At almost all visits during the treatment period, numerically or statistically significant improvements were observed in postbronchodilator FEV1 (Figure 1C) and ppFEV1 (Figure 1D) in both dupilumab groups vs placebo in the adolescent population. Improvements in ppFEV1 with dupilumab vs placebo were also observed for adolescents with elevated baseline type 2 biomarkers (Figure 1E). In adolescents, a 46% numerical reduction in adjusted AER (95% CI, 0.24– 1.21) was observed with dupilumab 200 mg vs placebo. Adjusted AER in the dupilumab 300 mg group was 13% (95% CI, 0.48– 2.69) higher vs matched placebo (Figure 2A). Similar results were seen in adolescents with elevated baseline type 2 biomarkers (Figure 2B). The increased AER seen in adolescents treated with dupilumab 300 mg is in marked contrast to the AER in adults as well as adolescents exposed to 200 mg q2w, and also contrasts with the improvement in FEV1 observed for adolescents in both the 200 and 300 mg groups. This may be due to the imbalance observed in the number of severe exacerbations in the previous year between the dupilumab 300 mg group and the matched placebo group (mean 1.53 and 2.22, respectively) that would affect the adjusted exacerbation rate. Unadjusted AER was numerically lower with both dupilumab doses vs matched placebo in the overall adolescent population and patients with elevated baseline type 2 biomarkers (Figure 2C,D). Dupilumab treatment numerically reduced median FeNO levels and serum total IgE vs placebo in adolescents and adults; median eosinophil concentrations remained constant over time in adolescent patients (Figure S3). Dupilumab treatment numerically improved ACQ5 scores vs placebo by Week 52 (Table S2). Healthrelated qualityoflife improvements (measured by AQLQ scores) mirrored those seen in ACQ5 scores (Table S2). Dupilumab was generally well tolerated, with safety consistent with the known dupilumab safety profile (Table S3). In conclusion, dupilumab improved lung function and reduced levels of type 2 biomarkers in the subpopulation of adolescents with uncontrolled, moderatetosevere asthma, supporting the use of dupilumab in this population.

Asthma in pregnancy: An update.

Abstract: AimTo update obstetric care providers about asthma management.SummaryAsthma is the most frequent comorbid chronic illness in pregnancy. Convincing evidence shows that uncontrolled asthma magnifies ...

Challenging the paradigm: moving from umbrella labels to treatable traits in airway disease

Abstract: Airway diseases were initially described by nonspecific patterns of symptoms, for example “dry and wheezy” and “wet and crackly”. The model airway disease is cystic fibrosis, which has progressed from nonspecific reactive treatments such as antibiotics for airway infection to molecular sub-endotype, proactive therapies with an unequivocal evidence base, early diagnosis, and biomarkers of treatment efficacy. Unfortunately, other airway diseases lag behind, not least because nonspecific umbrella labels such as “asthma” are considered to be diagnoses not mere descriptions. Pending the delineation of molecular sub-endotypes in other airway disease the concept of treatable traits, and consideration of airway disease in a wider context is preferable. A treatable trait is a characteristic amenable to therapy, with measurable benefits of treatment. This approach determines what pathology is actually present and treatable, rather than using umbrella labels. We determine if airway inflammation is present, and whether there is airway eosinophilia which will likely respond to inhaled corticosteroids; whether there is variable airflow obstruction due to bronchoconstriction which will respond to β2-agonists; and whether there is unsuspected underlying airway infection which should be treated with antibiotics unless there is an underlying endotype which can be addressed, as for example an immunodeficiency. The context of airway disease should also be extrapulmonary comorbidities, social and environmental factors, and a developmental perspective, particularly this last aspect if preventive strategies are being contemplated. This approach allows targeted treatment for maximal patient benefit, as well as preventing the discarding of therapies which are useful for appropriate subgroups of patients. Failure to appreciate this almost led to the discarding of valuable treatments such as prednisolone. Educational aims To use cystic fibrosis as a paradigm to show the benefits of the journey from nonspecific umbrella terms to specific endotypes and sub-endotypes, as a road map for other airway diseases to follow. Demonstrate that nonspecific labels to describe airway disease can and should be abandoned in favour of treatable traits to ensure diagnostic and therapeutic precision. Begin to learn to see airway disease in the context of extrapulmonary comorbidities, and social and environmental factors, as well as with a developmental perspective.

Biological therapies for asthma

Abstract: Five to 10% of asthma patients remain symptomatic and/or have asthma attacks despite adequate inhaled and systemic therapy. Eosinophilic, type 2 airway inflammation is seen in half of these patients with severe asthma. There is now convincing evidence that type 2 inflammation drives susceptibility to asthma attacks and is associated with a good response to biological therapies. Monoclonal antibodies targeting immunoglobulin E, interleukin (IL)-5 and IL-4/13 now have established efficacy in severe type 2 asthma. Novel alarmin-blocking and crystal-dissolving therapies are promising. Prescribing biologics, weaning steroids and treating subsequent exacerbations are rapidly evolving clinical challenges.

Pre-existing asthma as a comorbidity does not modify cytokine responses and severity of COVID-19

Abstract: A significant portion of COVID-19 sufferers have asthma. The impacts of asthma on COVID-19 progression are still unclear but a modifying effect is plausible as respiratory viruses are acknowledged to be an important trigger for asthma exacerbations and a different, potentially type-2 biased, immune response might occur. In this study, we compared the blood circulating cytokine response to COVID-19 infection in patients with and without asthma. Plasma samples and clinical information were collected from 80 patients with mild (25), severe (36) or critical (19) COVID-19 and 29 healthy subjects at the John Radcliffe Hospital, Oxford, UK. The concentrations of 51 circulating proteins in the plasma samples were measured with Luminex and compared between groups. Total 16 pre-existing asthma patients were found (3 in mild, 10 in severe, and 3 in critical COVID-19). The prevalence of asthma in COVID-19 severity groups did not suggest a clear correlation between asthma and COVID-19 severity. Within the same COVID-19 severity group, no differences were observed between patients with or without asthma on oxygen saturation, CRP, neutrophil counts, and length of hospital stay. The mortality in the COVID-19 patients with asthma (12.5%) was not higher than that in patients without asthma (17.2%). No significant difference was found between asthmatic and non-asthmatic in circulating cytokine response in different COVID-19 severity groups, including the cytokines strongly implicated in COVID-19 such as CXCL10, IL-6, CCL2, and IL-8. Pre-existing asthma was not associated with an enhanced cytokine response after COVID-19 infection, disease severity or mortality.