Dupilumab efficacy in subgroups of type 2 asthma with high-dose inhaled corticosteroids at baseline.

This is the final version. Available from Elsevier via the DOI in this record. Data statement: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized, and study documents will be redacted to protect the privacy of our trial participants. Further details on Sanofi’s data sharing criteria, eligible studies, and process for requesting access can be found at: https://www. vivli.org/BACKGROUND AND OBJECTIVE: Dupilumab blocks the shared receptor component for interleukin (IL)-4/IL-13, key and central drivers of type 2 inflammation in multiple diseases. In phase 3 QUEST (NCT02414854), add-on dupilumab 200 and 300 mg every 2 weeks reduced severe exacerbations, improved pre-bronchodilator forced expiratory volume in 1 s (FEV1), and was generally well tolerated in patients with uncontrolled moderate-to-severe asthma. This post hoc analysis assessed dupilumab efficacy in subpopulations of patients with type 2 asthma and high-dose inhaled corticosteroids (ICS). METHODS: Adjusted annualized severe exacerbation rates over the treatment period, least squares (LS) mean change from baseline at Week 12 in pre-bronchodilator FEV1, and LS mean change from baseline at Week 24 in 5-item Asthma Control Questionnaire (ACQ-5) scores were analyzed in subgroups of patients receiving high-dose (>500 μg) ICS with baseline blood eosinophils ≥150 cells/μL and/or fractional exhaled nitric oxide ≥25 ppb. Subgroups included allergic phenotype (with/without), comorbid chronic rhinosinusitis and/or nasal polyposis (with/without), pre-bronchodilator FEV1/forced vital capacity (40 years), median FEV1 reversibility, body mass index (<30/≥30 kg/m2), and sex. RESULTS: Dupilumab vs placebo reduced exacerbations and improved pre-bronchodilator FEV1 at Week 12 and ACQ-5 at Week 24 across subgroups of patients with type 2 asthma and high-dose ICS at baseline. Dupilumab was also effective in patients receiving medium-dose ICS. CONCLUSION: Dupilumab reduced severe exacerbations and improved lung function and asthma control in subgroups of patients with type 2 asthma and high-dose ICS at baseline. CLINICAL TRIAL REGISTRATION NUMBER: NCT02414854.Sanofi and Regeneron Pharmaceuticals, Inc

Modulation of NKp30- and NKp46-Mediated Natural Killer Cell Responses by Poxviral Hemagglutinin

Natural killer (NK) cells are an important element in the immune defense against the orthopox family members vaccinia virus (VV) and ectromelia virus (ECTV). NK cells are regulated through inhibitory and activating signaling receptors, the latter involving NKG2D and the natural cytotoxicity receptors (NCR), NKp46, NKp44 and NKp30. Here we report that VV infection results in an upregulation of ligand structures for NKp30 and NKp46 on infected cells, whereas the binding of NKp44 and NKG2D was not significantly affected. Likewise, infection with ectromelia virus (ECTV), the mousepox agent, enhanced binding of NKp30 and, to a lesser extent, NKp46. The hemagglutinin (HA) molecules from VV and ECTV, which are known virulence factors, were identified as novel ligands for NKp30 and NKp46. Using NK cells with selectively silenced NCR expression and NCR-CD3ζ reporter cells, we observed that HA present on the surface of VV-infected cells, or in the form of recombinant soluble protein, was able to block NKp30-triggered activation, whereas it stimulated the activation through NKp46. The net effect of this complex influence on NK cell activity resulted in a decreased NK lysis susceptibility of infected cells at late time points of VV infection when HA was expression was pronounced. We conclude that poxviral HA represents a conserved ligand of NCR, exerting a novel immune escape mechanism through its blocking effect on NKp30-mediated activation at a late stage of infection

IMP(2)ART systematic review of education for healthcare professionals implementing supported self-management for asthma

Abstract Despite a robust evidence base for its effectiveness, implementation of supported self-management for asthma is suboptimal. Professional education is an implementation strategy with proven effectiveness, though the specific features linked with effectiveness are often unclear. We performed a systematic review of randomised controlled trials and controlled clinical trials (published from 1990 and updated to May 2017 using forward citation searching) to determine the effectiveness of professional education on asthma self-management support and identify features of effective initiatives. Primary outcomes reflected professional behaviour change (provision of asthma action plans) and patient outcomes (asthma control; unscheduled care). Data were coded using the Effective Practice and Organisation of Care Taxonomy, the Theoretical Domains Framework (TDF), and Bloom’s Taxonomy and synthesised narratively. Of 15,637 articles identified, 18 (reporting 15 studies including 21 educational initiatives) met inclusion criteria. Risk of bias was high for five studies, and unclear for 10. Three of 6 initiatives improved action plan provision; 1/2 improved asthma control; and 2/7 reduced unscheduled care. Compared to ineffective initiatives, effective initiatives were more often coded as being guideline-based; involving local opinion leaders; including inter-professional education; and addressing the TDF domains ‘social influences’; ‘environmental context and resources’; ‘behavioural regulation’; ‘beliefs about consequences’; and ‘social/professional role and identity’. Findings should be interpreted cautiously as many strategies were specified infrequently. However, identified features warrant further investigation as part of implementation strategies aiming to improve the provision of supported self-management for asthma

Real-life effectiveness of indacaterol&ndash;glycopyrronium after switching from tiotropium or salmeterol/fluticasone therapy in patients with symptomatic COPD: the POWER study

Alan Kaplan,1 Kenneth R Chapman,2 Syed M Anees,3 Irvin Mayers,4 Driss Rochdi,5 Michel Djandji,5 David Pr&eacute;fontaine,5 Andrew McIvor6 1Family Physician Airways Group of Canada, University of Toronto, Toronto, ON, Canada; 2Division of Respiratory Medicine, Department of Medicine, University of Toronto, Toronto, ON, Canada; 3Schulich School of Medicine &amp; Dentistry &ndash; Western University, University of Windsor, ON, Canada; 4Division of Pulmonary Medicine, Department of Medicine, University of Alberta, Edmonton, AB, Canada; 5Novartis Pharmaceuticals Canada Inc., Montreal, QC, Canada; 6Department of Medicine, McMaster University, Firestone Institute for Respiratory Health, Hamilton, ON, Canada Purpose: In contrast to randomized controlled trials (RCTs), changes in maintenance pharmacotherapy in clinical practice occur without a washout period. The Prospective cohort study for the real-life effectiveness evaluation of glycOpyrronium With indacatERol combination in the management of COPD in Canada (POWER) study evaluated the real-life effectiveness of indacaterol/glycopyrronium (IND/GLY) following a direct switch from a long-acting muscarinic antagonist (LAMA, tiotropium) or long-acting &beta;2-agonist (LABA)/inhaled corticosteroid (ICS) maintenance treatment (salmeterol/fluticasone [SFC]).Methods: POWER was a single-cohort, prospective, multicenter, interventional study in which patients with moderate-to-severe COPD, who remained symptomatic on their current treatment of once-daily (od) tiotropium 18&nbsp;&micro;g or twice-daily (bid) SFC (any dose), were switched to treatment with open-label IND/GLY 110/50&nbsp;&micro;g od for 16&nbsp;weeks. Effectiveness end points were change from baseline in trough FEV1, transition dyspnea index (TDI) total scores, and COPD assessment test (CAT) scores at 16&nbsp;weeks.Results: Trough FEV1 improved by 175&nbsp;mL at Week 16 in patients who switched to IND/GLY. The change was 176&nbsp;mL (95% CI: 135&ndash;217) when switched from tiotropium and 172&nbsp;mL (95% CI: 85&ndash;258) when switched from SFC fixed-dose combination (FDC). At Week 16, significant improvements were observed in the mean TDI total scores (&Delta;=2.5) and CAT scores (&Delta;=-6.5) after the switch to IND/GLY treatment (both P&lt;0.0001). Additionally, IND/GLY was well tolerated in patients with moderate-to-severe COPD, and no safety signal was observed.Conclusion: In clinical practice settings, a direct switch from previous treatment with either tiotropium or SFC to IND/GLY was safe and provided superior clinically significant improvements in lung function and patient-related outcomes in patients with moderate-to-severe COPD.Clinical trial registration: NCT02202616. Keywords: COPD assessment test, dyspnea, FEV1, indacaterol/glycopyrronium, lung function, TD

Rhinology Future Debates, an EUFOREA Report

The first Rhinology Future Debates was held in Brussels in December 2016, organized by EUFOREA (European Forum for Research and Education in Allergy and Airways diseases). The purpose of these debates is to bring novel developments in the field of Rhinology to the attention of the medical, paramedical and patient community, in a highly credible and balanced context. For the first time in Rhinology, a peer to peer scientific exchange with key experts in the field of rhinology and key medical colleagues from leading industries let to a brainstorming and discussion event on a number of hot issues in Rhinology. Novel developments are presented by key experts from industry and/or key thought leaders in Rhinology, and then followed by a lively debate on the potential positioning of new developments in care pathways, the strengths and weaknesses of the novel development(s), and comparisons with existing and/or competing products, devices, and/or molecules. As all debates are recorded and distributed on-line with limited editing (www.rhinology-future.com), EUFOREA aims at maximizing the education of the target groups on novel developments, allowing a critical appraisal of the future and a more rapid implementation of promising novel tools, techniques and/or molecules in clinical practise in Europe. The next Rhinology Future debate will be held in Brussels in December 201

Dupilumab Efficacy in Steroid-Dependent Severe Asthma by Baseline Oral Corticosteroid Dose

Background: Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4/-13, key and central drivers of type 2 inflammation in multiple diseases. In the phase 3 LIBERTY ASTHMA VENTURE (VENTURE) study (NCT02528214), dupilumab versus placebo reduced oral corticosteroid (OCS) dose and improved clinical outcomes in patients with OCS-dependent severe asthma. Dupilumab efficacy in patients with varying disease burden (defined by baseline OCS dose) has not been assessed. Objective: This post hoc analysis of VENTURE evaluated dupilumab efficacy across subgroups defined by baseline OCS dose. Methods: The OCS dose, proportion no longer needing OCS at week 24, annualized severe exacerbation rate, and least squares mean change from baseline in pre- and post-bronchodilator forced expiratory volume in 1 second at week 24 were evaluated in VENTURE patients with OCS-dependent severe asthma receiving dupilumab 300 mg every 2 weeks versus placebo, categorized by a baseline OCS dose of less than 10 mg/d or 10 or more mg/d. Results: Dupilumab reduced daily OCS dose from baseline at week 24 in both dose groups. In dupilumab-/placebo-treated patients with a baseline OCS dose of less than 10 mg/d and 10 or more mg/d, 72%/42% and 37%/23% stopped OCS by week 24 (P < .01/P < .05), respectively. Dupilumab significantly reduced the annualized severe exacerbation rate by 71% and 48% (P < .01/P < .05). At week 24, dupilumab improved pre- and post-bronchodilator forced expiratory volume in 1 second in patients in both dose groups. Conclusions: In patients with OCS-dependent severe asthma receiving lower or higher baseline OCS doses, dupilumab significantly reduced the OCS dose and improved the likelihood of no longer requiring OCS while also reducing exacerbations and improving lung function

Characteristics and treatment regimens across ERS SHARP severe asthma registries

Little is known about the characteristics and treatments of patients with severe asthma across Europe, but both are likely to vary. This is the first study in the European Respiratory Society Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) Clinical Research Collaboration and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals. This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases. Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6 kg\ub7m 122 (the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1 s % predicted was 20.9% (the Netherlands versus Hungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335 \ub5g\ub7day 121 between those from Slovenia versus Poland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344 \ub5g\ub7day 121 in those starting anti-IgE (Slovenia versus Spain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively. The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries