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

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

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

Severe Asthma Standard-of-Care Background Medication Reduction With Benralizumab: ANDHI in Practice Substudy

Background: The phase IIIb, randomized, parallel-group, placebo-controlled ANDHI double-blind (DB) study extended understanding of the efficacy of benralizumab for patients with severe eosinophilic asthma. Patients from ANDHI DB could join the 56-week ANDHI in Practice (IP) single-arm, open-label extension substudy. Objective: Assess potential for standard-of-care background medication reductions while maintaining asthma control with benralizumab. Methods: Following ANDHI DB completion, eligible adults were enrolled in ANDHI IP. After an 8-week run-in with benralizumab, there were 5 visits to potentially reduce background asthma medications for patients achieving and maintaining protocol-defined asthma control with benralizumab. Main outcome measures for non-oral corticosteroid (OCS)-dependent patients were the proportions with at least 1 background medication reduction (ie, lower inhaled corticosteroid dose, background medication discontinuation) and the number of adapted Global Initiative for Asthma (GINA) step reductions at end of treatment (EOT). Main outcomes for OCS-dependent patients were reductions in daily OCS dosage and proportion achieving OCS dosage of 5 mg or lower at EOT. Results: For non-OCS-dependent patients, 53.3% (n = 208 of 390) achieved at least 1 background medication reduction, increasing to 72.6% (n = 130 of 179) for patients who maintained protocol-defined asthma control at EOT. A total of 41.9% (n = 163 of 389) achieved at least 1 adapted GINA step reduction, increasing to 61.8% (n = 110 of 178) for patients with protocol-defined EOT asthma control. At ANDHI IP baseline, OCS dosages were 5 mg or lower for 40.4% (n = 40 of 99) of OCS-dependent patients. Of OCS-dependent patients, 50.5% (n = 50 of 99) eliminated OCS and 74.7% (n = 74 of 99) achieved dosages of 5 mg or lower at EOT. Conclusions: These findings demonstrate benralizumab's ability to improve asthma control, thereby allowing background medication reduction

Does obesity produce a distinct asthma phenotype?

Obesity and asthma prevalence have been increasing over the past decade. Epidemiological evidence demonstrates that obesity results in an increased risk of developing incident asthma. Even modest levels of increased weight increase asthma risk. Recently published data suggest that obese asthma patients may represent a distinct phenotype of asthma. Obese asthma patients demonstrate increased asthma severity, as indicated by increased exacerbations and decreased asthma control; however, they do not appear to have increased airway cellular inflammation. It seems likely that obesity does not contribute to asthma through conventional Th type 2-mediated inflammatory pathways but, rather, through separate mechanisms that are specific to the obese state. This may explain the variable responses of obese asthma patients to conventional asthma therapies, specifically, relative corticosteroid resistance. Small studies suggest improvements in the disease with weight loss in obese asthma patients, and other interventions to target asthma in obese individuals need to be investigated. Several postulated mechanisms for the occurrence of this distinct phenotype have been postulated: 1) the presence of comorbidities, such as gastroesophageal reflux disease and sleep disordered breathing, 2) systemic inflammation associated with obesity (with elevated levels of circulating cytokines, such as IL-6 and TNF-α), 3) increased oxidative stress, and 4) hormones of obesity, such as adiponectin, leptin, and resistin. Although the mechanisms underlying obesity in asthma require further investigation, obesity plays a major role in the asthma epidemic and likely results in a distinct phenotype of the disease

SARS-CoV-2 vaccines: a triumph of science and collaboration

Roughly 1 year after the first case of COVID-19 was identified and less than 1 year after the sequencing of SARS-CoV-2, multiple SARS-CoV-2 vaccines with demonstrated safety and efficacy in phase III clinical trials are available. The most promising vaccines have targeted the surface glycoprotein (S-protein) of SARS-CoV-2 and achieved an approximate 85%–95% reduction in the risk of symptomatic COVID-19, while retaining excellent safety profiles and modest side effects in the phase III clinical trials. The mRNA, replication-incompetent viral vector, and protein subunit vaccine technologies have all been successfully employed. Some novel SARS-CoV-2 variants evade but do not appear to fully overcome the potent immunity induced by these vaccines. Emerging real-world effectiveness data add evidence for protection from severe COVID-19. This is an impressive first demonstration of the effectiveness of the mRNA vaccine and vector vaccine platforms. The success of SARS-CoV-2 vaccine development should be credited to open science, industry partnerships, harmonization of clinical trials, and the altruism of study participants. The manufacturing and distribution of the emergency use–authorized SARS-CoV-2 vaccines are ongoing challenges. What remains now is to ensure broad and equitable global vaccination against COVID-19

S-Nitrosoglutathione Reductase: An Important Regulator in Human Asthma

Rationale: Nitric oxide bioactivity, mediated through the formation of S-nitrosothiols (SNOs), has a significant effect on bronchomotor tone. S-Nitrosoglutathione is an endogenous bronchodilator that is decreased in children with asthmatic respiratory failure and in adults with asthma undergoing segmental airway challenge. Recently we showed that S-nitrosoglutathione reductase (GSNOR) regulates endogenous SNOs. Mice with genetic deletion of GSNOR are protected from airway hyperresponsivity in an allergic asthma model

Related or not? Development of spontaneous Creutzfeldt–Jakob disease in a patient with chronic, well-controlled HIV: A case report and review of the literature

Background: We report a novel case of a rare disease: spontaneous Creutzfeldt–Jakob disease in a patient with well-controlled HIV. We explore the relationship between spontaneous Creutzfeldt–Jakob disease and HIV. Case report: A 66-year-old man with long-standing, well-controlled HIV infection presented with 3 months of progressive, subacute neurocognitive decline. His symptoms included conceptual apraxia, apathy, memory impairment, and gait disturbance, and were initially attributed to depressive “pseudo-dementia.” Unfortunately, the patient’s symptoms rapidly progressed and he ultimately succumbed to his illness. Autopsy confirmed the clinical diagnosis of spontaneous Creutzfeldt–Jakob disease. Discussion: This case highlights spontaneous Creutzfeldt–Jakob disease as a rare terminal illness in the setting of well-controlled chronic HIV. To our knowledge, this is the first report of a patient with chronic and previously well-controlled HIV infection dying from a prion disease. Despite the very different epidemiology and pathophysiology of HIV and spontaneous Creutzfeldt–Jakob disease, this case does raise questions of whether certain host genetic factors could predispose to both conditions, albeit currently, there is no clear causal link between HIV and spontaneous Creutzfeldt–Jakob disease

Benralizumab improves symptoms of patients with severe, eosinophilic asthma with a diagnosis of nasal polyposis

BackgroundClinically meaningful improvement in the Sino‐Nasal Outcome Test‐22 (SNOT‐22) was observed in patients with severe, eosinophilic asthma, and nasal polyposis (NP) treated with benralizumab in the ANDHI trial. A post hoc assessment of the effects of benralizumab on SNOT‐22 response and asthma efficacy measures in these patients was conducted for further characterization of the efficacy and safety of benralizumab for patients with severe asthma and NP.MethodsAdults with severe, eosinophilic asthma who had experienced ≥2 prior‐year exacerbations despite high‐dosage inhaled corticosteroid plus additional controller[s] were randomized to 24 weeks of benralizumab or placebo. Patients with physician‐diagnosed chronic rhinosinusitis with NP of any severity ongoing at baseline who consented to participate were included in the current ANDHI NP substudy population. Effect on NP symptoms was assessed by the SNOT‐22, with an improvement of at least 8.9 defined as clinically significant (responder). Effects on chronic asthma outcomes were assessed by means of annualized asthma exacerbation rate (AER), St. George’s Respiratory Questionnaire (SGRQ) total score, forced expiratory volume in one second (FEV1), and Asthma Control Questionnaire‐6 (ACQ‐6). All p‐values were nominal.ResultsOf the ANDHI population (n = 656), 23% (n = 153) participated in the NP substudy (n = 96 benralizumab; n = 57 placebo). Patients were 50% female, with mean age of 53 years, had prior‐year AER = 3.3; mean pre‐bronchodilator FEV1 = 55% predicted; and median blood eosinophil count ​= 510 cells/µl. For patients with high baseline SNOT‐22 scores (>30), benralizumab treatment improved symptoms of NP as measured by SNOT‐22 from baseline to Week 24 compared with placebo (Week 24: −10.44 [p = .0176]). Percentage of responders to SNOT‐22 was greater for benralizumab vs. placebo (71.3% vs. 45.5%; p = .0036), and effect was enhanced for patients with high baseline SNOT‐22 scores (>30). A 69% reduction vs. placebo in annualized AER (0.77 vs. 2.47; p < .0001) and greater clinically meaningful improvements from baseline in SGRQ total score (−16.7), FEV1 (+0.32 L), and ACQ‐6 (–0.88) were observed (p < .0001). Benralizumab was well‐tolerated. Frequency of adverse events (AEs) was similar for benralizumab (76.0%) and placebo (73.7%) groups. Most common AEs (frequency ≥5%) reported at a greater frequency in benralizumab vs. placebo included headache, sinusitis, pyrexia, and influenza.ConclusionsThese substudy data from ANDHI demonstrated the efficacy profile of benralizumab for patients with severe, eosinophilic asthma and NP, with improvement in SNOT‐22 and asthma outcomes.The combination of asthma and nasal polyposis provides significant treatment challenges and substantial disease burden, including a greater number of asthma exacerbations annually, which negatively impacts quality of life. Clinically meaningful improvement in the SNOT‐22 was observed early and maintained over time for patients with severe, eosinophilic asthma and nasal polyposis treated with benralizumab in the ANDHI trial. This ANDHI substudy demonstrated that benralizumab is safe and efficacious for patients with severe, eosinophilic asthma and nasal polyposis, with improvement in SNOT‐22 total scores and asthma outcomes. Abbreviation: ACQ‐6, Asthma Control Questionnaire‐6; AER, asthma exacerbation rate; CRSwNP, chronic rhinosinusitis with nasal polyposis; FEV1, forced expiratory volume in 1 second; SGRQ, St. George’s Respiratory Questionnaire; SNOT‐22, Sino‐Nasal Outcome TestPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/171162/1/all14902_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/171162/2/all14902.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 &ge;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 &ge;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&ndash;34 years-old met high-risk criteria. Longer tobacco duration was associated with an increased prevalence of COPD, particularly &gt;20 years. Seventy-nine percent of persons &ge;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