Results of a Phase 2b Trial With GB001, a Prostaglandin D2 Receptor 2 Antagonist, in Moderate to Severe Eosinophilic Asthma

Asthma; Asthma worsening; Eosinophilic asthmaAsma; Empitjorament de l'asma; Asma eosinofílicaAsma; Empeoramiento del asma; Asma eosinofílicaBackground Prostaglandin D2 receptor 2 (DP2) antagonists inhibit prostaglandin D2-induced effects, including recruitment and activation of cells driving asthma pathogenesis. However, challenges identifying target population and end points persist. Research Question What is the effect of the DP2 antagonist GB001 on asthma worsening in patients with moderate to severe eosinophilic asthma? Study Design and Methods In this phase IIb, randomized, double-blind, placebo-controlled, dose-ranging, parallel-group, multicenter study, GB001 or placebo was added to standard-of-care treatment in patients with moderate to severe asthma with a blood eosinophil count ≥ 250 cells/μL. Patients aged ≥ 18 years to < 75 years received one of four once-daily treatments (GB001 20 mg, 40 mg, or 60 mg or placebo). The primary end point was the proportion of patients who experienced asthma worsening by 24 weeks. Efficacy analyses were performed for the intention-to-treat population and safety analyses for patients who received at least one dose of study treatment. Results A total of 480 patients were treated. The ORs for asthma worsening for GB001 20 mg, 40 mg, and 60 mg vs placebo were 0.674 (95% CI, 0.398-1.142), 0.677 (95% CI, 0.399-1.149), and 0.651 (95% CI, 0.385-1.100), respectively. Analysis according to baseline blood eosinophil levels and/or fractional exhaled nitric oxide did not show greater treatment effects with higher values. Elevated liver aminotransferase levels and adverse events leading to discontinuation were more frequent for GB001 60 mg than with placebo, GB001 20 mg, and GB001 40 mg. Interpretation Although GB001 did not significantly reduce the odds of asthma worsening, reductions favoring GB001 were observed. Treatment effects were consistent regardless of high/low type 2 phenotype. The overall safety profile was acceptable, although GB001 60 mg was associated with risk of liver injury.This work was supported by GB001, Inc., a wholly owned subsidiary of Gossamer Bio, Inc

Resident alveolar macrophageâ derived vesicular SOCS3 dampens allergic airway inflammation

Resident alveolar macrophages (AMs) suppress allergic inflammation in murine asthma models. Previously we reported that resident AMs can blunt inflammatory signaling in alveolar epithelial cells (ECs) by transcellular delivery of suppressor of cytokine signaling 3 (SOCS3) within extracellular vesicles (EVs). Here we examined the role of vesicular SOCS3 secretion as a mechanism by which AMs restrain allergic inflammatory responses in airway ECs. Bronchoalveolar lavage fluid (BALF) levels of SOCS3 were reduced in asthmatics and in allergenâ challenged mice. Ex vivo SOCS3 secretion was reduced in AMs from challenged mice and this defect was mimicked by exposing normal AMs to cytokines associated with allergic inflammation. Both AMâ derived EVs and synthetic SOCS3 liposomes inhibited the activation of STAT3 and STAT6 as well as cytokine gene expression in ECs challenged with ILâ 4/ILâ 13 and house dust mite (HDM) extract. This suppressive effect of EVs was lost when they were obtained from AMs exposed to allergic inflammationâ associated cytokines. Finally, inflammatory cell recruitment and cytokine generation in the lungs of OVAâ challenged mice were attenuated by intrapulmonary pretreatment with SOCS3 liposomes. Overall, AM secretion of SOCS3 within EVs serves as a brake on airway EC responses during allergic inflammation, but is impaired in asthma. Synthetic liposomes encapsulating SOCS3 can rescue this defect and may serve as a framework for novel therapeutic approaches targeting airway inflammation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154378/1/fsb220322-sup-0001-FigS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154378/2/fsb220322.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154378/3/fsb220322_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154378/4/fsb220322-sup-0005-TableS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154378/5/fsb220322-sup-0003-FigS3.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154378/6/fsb220322-sup-0004-FigS4.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154378/7/fsb220322-sup-0002-FigS2.pd

Use of a Cross-Sectional Survey in the Adult Population to Characterize Persons at High-Risk for Chronic Obstructive Pulmonary Disease

Rationale/Objective: The Behavioral Risk Factor Surveillance System (BRFSS) health survey has been used to describe the epidemiology of chronic obstructive pulmonary disease (COPD) in the US. Through addressing respiratory symptoms and tobacco use, it could also be used to characterize COPD risk. Methods: Four US states added questions to the 2015 BRFSS regarding productive cough, shortness of breath, dyspnea on exertion, and tobacco duration. We determined COPD risk categories: provider-diagnosed COPD as self-report, high-risk for COPD as ≥ 10 years tobacco smoking and at least one significant respiratory symptom, and low risk was neither diagnosed COPD nor high risk. Disease burden was defined by respiratory symptoms and health impairments. Data were analyzed using multiple logistic regression models with age as a covariate. Results: Among 35,722 adults ≥ 18 years, the overall prevalence of COPD and high-risk for COPD were 6.6% and 5.1%. Differences among COPD risk groups were evident based on gender, race, age, geography, tobacco use, health impairments, and respiratory symptoms. Risk for disease was seen early where 3.75% of 25–34 years-old met high-risk criteria. Longer tobacco duration was associated with an increased prevalence of COPD, particularly \u3e 20 years. Seventy-nine percent of persons ≥ 45 years-old with frequent shortness of breath (SOB) reported having or being at risk of COPD, reflecting disease burden. Conclusion: These data, representing nearly 18% of US adults, indicates those at high risk for COPD share many, but not all of the characteristics of persons diagnosed with the disease and demonstrates the value of the BRFSS as a tool to define lung health at a population level

Adrenal Insufficiency is Not a Barrier to OCS Elimination in the PONENTE Study

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OCS Reduction According to the Presence of Nasal Polyps or Atopic Status in the PONENTE Study

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Asthma Exacerbations are Associated with a decline in Lung Function : A Longitudinal Population-Based Study

Funding This study was conducted by the Observational and Pragmatic Research Institute (OPRI) Pte Ltd and was partially funded by Optimum Patient Care Global and AstraZeneca Ltd. No funding was received by the Observational & Pragmatic Research Institute Pte Ltd (OPRI) for its contribution. Acknowledgements The authors thank the UK primary care sites that contributed anonymised patient data to this study; Drs Jaco Voorham and Marjan Kerkhof for their contributions to the preparation and analysis of the data; and Audrey Ang and Andrea Teh Xin Yi for coordinating logistical and administrative support for the development of this manuscript. We also thank our Thorax peer reviewers for their in-depth comments and suggestions which greatly improved the quality of this article.Peer reviewedPostprin

The burden of severe asthma in sub-Saharan Africa : findings from the African Severe Asthma Project

Funding: Funded by a project grant from the GSK Africa Non-communicable Disease Open Lab (project 8019).Background Severe asthma is associated with high morbidity, mortality and health care utilization but its burden in Africa is unknown. Objective To determine the burden (prevalence, mortality and activity and work impairment) of severe asthma in three Easter Africa countries (Uganda, Kenya and Ethiopia). Methods Using the American Thoracic Society/European Respiratory Society (ATS/ERS) case definition of severe asthma we analyzed for the prevalence of severe asthma (requiring GINA steps 4–5 asthma medications for the previous year to achieve control) and severe refractory asthma (remains uncontrolled despite treatment with GINA steps 4–5 asthma medications) in a cohort of 1086 asthma patients who had been in care for 12 months and had received all GINA recommended medications. Asthma control was assessed using the asthma control questionnaire (ACQ). Results Overall, the prevalence of severe asthma and severe refractory asthma was 25.6% (95% CI 23.1–28.3) and 4.6% (95% CI 3.5–6.0) respectively. Patients with severe asthma were (non- severe vs. severe vs. severe refractory) older (39, 42, 45 years, p=0.011), had high skin prick test reactivity (67.1%, 76.0%, 76.0%, p=0.004), had lower FEV1% (81%, 61%, 55.5%, p=<0.001), lower quality of life score (129, 127 vs 121, p=<0.001) and higher activity impairment (10%, 30%, 50%, p=<0.001). Conclusion The prevalence of severe asthma in Africa is high and is associated with high morbidity and poor quality of life.Publisher PDFPeer reviewe

Cluster analysis of inflammatory biomarker expression in the International Severe Asthma Registry (ISAR)

Funding: ISAR is conducted by Optimum Patient Care Global Ltd, and co-funded by OPC Global Ltd and AstraZeneca.Peer reviewedPublisher PD