Benralizumab is an anti-eosinophilic, anti-interleukin-5 receptor α monoclonal antibody that has been shown to significantly reduce asthma exacerbations and improve lung function for patients with ...severe, uncontrolled asthma. We further explored the efficacy of benralizumab for patients with different baseline blood eosinophil thresholds and exacerbation histories.
This study is a pooled analysis of the results from the randomised, double-blind, placebo-controlled SIROCCO (NCT01928771) and CALIMA (NCT01914757) phase 3 studies. In these studies, patients with severe, uncontrolled asthma were randomly assigned (1:1:1) to receive subcutaneous benralizumab 30 mg, either every 4 weeks or every 8 weeks (with first three doses given every 4 weeks), or placebo every 4 weeks. The primary endpoint was annual exacerbation rate (AER) ratio versus placebo, analysed by baseline eosinophil counts (≥0, ≥150, ≥300, or ≥450 cells per μL) and by number of exacerbations (two vs three or more) during the year before enrolment. The analyses were done in accordance with the intention-to-treat principle.
Of 2295 patients, 756 received benralizumab every 4 weeks, 762 received benralizumab every 8 weeks, and 777 patients received placebo. AER among patients with baseline blood eosinophil counts of at least 0 cells per μL was 1·16 (95% CI 1·05-1·28) in patients who received placebo versus 0·75 (0·66-0·84) in patients who received benralizumab every 8 weeks (rate ratio 0·64, 0·55-0·75; p<0·0001). In patients who received benralizumab every 4 weeks who had eosinophil counts of 0 or more cells per μL, AER was 0·73 (0·65-0·82); rate ratio versus placebo was 0·63 (0·54-0·74; p<0·0001). The extent to which exacerbation rates were reduced increased with increasing blood eosinophil thresholds and with greater exacerbation history in patients in the 4-weekly and 8-weekly benralizumab groups. Greater improvements in AER were seen with benralizumab compared with placebo for patients with a combination of high blood eosinophil thresholds and a history of more frequent exacerbations.
These results will help to guide clinicians when they are deciding whether to use benralizumab to treat patients with severe, uncontrolled, eosinophilic asthma.
AstraZeneca.
Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. We assessed its efficacy and safety in patients with ...uncontrolled asthma.
We randomly assigned 1902 patients 12 years of age or older with uncontrolled asthma in a 2:2:1:1 ratio to receive add-on subcutaneous dupilumab at a dose of 200 or 300 mg every 2 weeks or matched-volume placebos for 52 weeks. The primary end points were the annualized rate of severe asthma exacerbations and the absolute change from baseline to week 12 in the forced expiratory volume in 1 second (FEV
) before bronchodilator use in the overall trial population. Secondary end points included the exacerbation rate and FEV
in patients with a blood eosinophil count of 300 or more per cubic millimeter. Asthma control and dupilumab safety were also assessed.
The annualized rate of severe asthma exacerbations was 0.46 (95% confidence interval CI, 0.39 to 0.53) among patients assigned to 200 mg of dupilumab every 2 weeks and 0.87 (95% CI, 0.72 to 1.05) among those assigned to a matched placebo, for a 47.7% lower rate with dupilumab than with placebo (P<0.001); similar results were seen with the dupilumab dose of 300 mg every 2 weeks. At week 12, the FEV
had increased by 0.32 liters in patients assigned to the lower dose of dupilumab (difference vs. matched placebo, 0.14 liters; P<0.001); similar results were seen with the higher dose. Among patients with a blood eosinophil count of 300 or more per cubic millimeter, the annualized rate of severe asthma exacerbations was 0.37 (95% CI, 0.29 to 0.48) among those receiving lower-dose dupilumab and 1.08 (95% CI, 0.85 to 1.38) among those receiving a matched placebo (65.8% lower rate with dupilumab than with placebo; 95% CI, 52.0 to 75.6); similar results were observed with the higher dose. Blood eosinophilia occurred after the start of the intervention in 52 patients (4.1%) who received dupilumab as compared with 4 patients (0.6%) who received placebo.
In this trial, patients who received dupilumab had significantly lower rates of severe asthma exacerbation than those who received placebo, as well as better lung function and asthma control. Greater benefits were seen in patients with higher baseline levels of eosinophils. Hypereosinophilia was observed in some patients. (Funded by Sanofi and Regeneron Pharmaceuticals; LIBERTY ASTHMA QUEST ClinicalTrials.gov number, NCT02414854 .).
A significant minority of asthma patients remain uncontrolled despite the use of inhaled corticosteroids (ICS) and long-acting beta-agonists (LABA). A number of add-on therapies, including monoclonal ...antibodies (namely omalizumab) and more recently tiotropium bromide have been recommended for this subgroup of patients. The purpose of this study was to assess the cost-effectiveness of tiotropium versus omalizumab as add-on therapies to ICS + LABA for patients with uncontrolled allergic asthma.
A probabilistic Markov model of asthma was created. Total costs (in 2013 US $) and health outcomes of three interventions including standard therapy (ICS + LABA), add-on therapy with tiotropium, and add-on therapy with omalizumab, were calculated over a 10-year time horizon. Future costs and quality-adjusted life years (QALYs) were discounted at the rate of 3%. Multiple sensitivity analyses were conducted. Cost-effectiveness was evaluated at willingness-to-pay value of $50,000.
The 10-year discounted costs and QALYs for standard therapy were $38,432 and 6.79, respectively. The corresponding values for add-on therapy with tiotropium and with omalizumab were $41,535 and 6.88, and $217,847 and 7.17, respectively. The incremental cost-effectiveness ratios (ICER) of add-on therapy with tiotropium versus standard therapy, and omalizumab versus tiotropium were $34,478/QALY, and $593,643/QALY, respectively. The model outcomes were most sensitive to the costs of omalizumab but were robust against other assumptions.
Although omalizumab had the best health outcomes, add-on therapy with tiotropium was a cost-effective alternative to omalizumab and standard therapy for uncontrolled allergic asthma at willingness-to-pay of $50,000/QALY.
Bronchial thermoplasty is a device-based treatment for subjects ≥ 18 years of age with severe asthma poorly controlled with inhaled corticosteroids and long-acting beta-agonists. The Post-FDA ...Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma (PAS2) study collected data on patients with severe asthma undergoing this procedure.
What are the 5-year efficacy and safety results in patients with severe asthma who have undergone bronchial thermoplasty?
This was a prospective, open-label, observational, multicenter study conducted in the United States and Canada. Subjects 18 to 65 years of age who were taking inhaled corticosteroids ≥ 1,000 μg/d (beclomethasone or equivalent) and long-acting beta-agonists ≥ 80 μg/d (salmeterol or equivalent) were included. Severe exacerbations, hospitalization, ED visits, and medication usage were evaluated for the 12 months prior to and at years 1 through 5 posttreatment. Spirometry was evaluated at baseline and at years 1 through 5 posttreatment.
A total of 284 subjects were enrolled at 27 centers; 227 subjects (80%) completed 5 years of follow-up. By year 5 posttreatment, the proportion of subjects with severe exacerbations, ED visits, and hospitalizations was 42.7%, 7.9%, and 4.8%, respectively, compared with 77.8%, 29.4%, and 16.1% in the 12 months prior to treatment. The proportion of subjects on maintenance oral corticosteroids decreased from 19.4% at baseline to 9.7% at 5 years. Analyses of subgroups based on baseline clinical and biomarker characteristics revealed a statistically significant clinical improvement among all subgroups.
Five years after treatment, subjects experienced decreases in severe exacerbations, hospitalizations, ED visits, and corticosteroid exposure. All subgroups demonstrated clinically significant improvement, suggesting that bronchial thermoplasty improves asthma control in different asthma phenotypes.
ClinicalTrials.gov; No.: NCT01350336; URL: www.
gov.
Phenotypic characteristics of patients with eosinophilic and noneosinophilic asthma are not well characterized in global, real-life severe asthma cohorts.
What is the prevalence of eosinophilic and ...noneosinophilic phenotypes in the population with severe asthma, and can these phenotypes be differentiated by clinical and biomarker variables?
This was an historical registry study. Adult patients with severe asthma and available blood eosinophil count (BEC) from 11 countries enrolled in the International Severe Asthma Registry (January 1, 2015-September 30, 2019) were categorized according to likelihood of eosinophilic phenotype using a predefined gradient eosinophilic algorithm based on highest BEC, long-term oral corticosteroid use, elevated fractional exhaled nitric oxide, nasal polyps, and adult-onset asthma. Demographic and clinical characteristics were defined at baseline (ie, 1 year before or closest to date of BEC).
One thousand seven hundred sixteen patients with prospective data were included; 83.8% were identified as most likely (grade 3), 8.3% were identified as likely (grade 2), and 6.3% identified as least likely (grade 1) to have an eosinophilic phenotype, and 1.6% of patients showed a noneosinophilic phenotype (grade 0). Eosinophilic phenotype patients (ie, grades 2 or 3) showed later asthma onset (29.1 years vs 6.7 years; P < .001) and worse lung function (postbronchodilator % predicted FEV
, 76.1% vs 89.3%; P = .027) than those with a noneosinophilic phenotype. Patients with noneosinophilic phenotypes were more likely to be women (81.5% vs 62.9%; P = .047), to have eczema (20.8% vs 8.5%; P = .003), and to use anti-IgE (32.1% vs 13.4%; P = .004) and leukotriene receptor antagonists (50.0% vs 28.0%; P = .011) add-on therapy.
According to this multicomponent, consensus-driven, and evidence-based eosinophil gradient algorithm (using variables readily accessible in real life), the severe asthma eosinophilic phenotype was more prevalent than previously identified and was phenotypically distinct. This pragmatic gradient algorithm uses variables readily accessible in primary and specialist care, addressing inherent issues of phenotype heterogeneity and phenotype instability. Identification of treatable traits across phenotypes should improve therapeutic precision.
Abstract Purpose The aim of this study was to systematically review the literature on the effect of statins on mortality in patients with infection and/or sepsis. Materials and Methods MEDLINE, ...EMBASE, PapersFirst, and the Cochrane collaboration and the Cochrane Register of controlled trials were searched and were current as of December 2009. Randomized, double-blind or single-blind, placebo-controlled studies; observational cohort studies (retrospective and prospective); and case-controlled studies were included. Types of participants included adult and pediatric subjects with sepsis or various other types of infection. Exposure was defined as the use of a statin for any indication. The primary outcome chosen was mortality from any cause, and secondary outcomes included 30-day mortality, in-hospital mortality, mortality from pneumonia, mortality from bacteremia, mortality from sepsis, and mortality from mixed infection. Results A total of 20 studies were included in the analysis, 18 being cohort studies (12 retrospective, 6 prospective), 1 matched cohort study with 2 case-control studies, and 1 randomized control trial. Meta-analysis for various infection-related outcomes revealed the following pooled odds ratios all in favor of statin use vs non: 0.61 (95% confidence interval CI, 0.48-0.73) for 30-day mortality (n = 7), 0.38 (95% CI, 0.13-0.64) for in-hospital mortality (n = 7), 0.63 (95% CI, 0.55-0.71) for pneumonia-related mortality (n = 7), 0.33 (95% CI, 0.09-0.75) for bacteremia-related mortality (n = 4), 0.40 (95% CI, 0.23-0.57) for sepsis-related mortality (n = 4), and 0.50 (95% CI, 0.18-0.83) for mixed infection-related mortality (n = 4). Conclusions This meta-analysis demonstrated a protective effect for statins in patients with sepsis and/or other infections compared to placebo for various infection-related outcomes. However, our results are limited by the cohort design of the selected studies and the degree of heterogeneity among them, and as a result, further randomized trials are needed to validate the use of statins for sepsis and/or other infections.
Productivity loss is an overlooked aspect of the burden of chronic health conditions. While modern guidelines emphasize achieving clinical control in asthma management, few studies have reported on ...the relationship between asthma control and productivity loss. We calculated the productivity loss that can be avoided by achieving and maintaining clinical control in employed adults with asthma.
We prospectively recruited a population-based random sample of adults with asthma in British Columbia, Canada. We measured productivity loss due to absenteeism and presenteeism using validated instruments, and ascertained asthma control according to the GINA (Global Initiative for Asthma) classification. We estimated the average gain in productivity for each individual if the individual’s asthma was controlled in the past week, by fitting two-part regression models associating asthma control and productivity loss, controlling for potential confounding variables.
The final sample included 300 employed adults (mean age, 47.9 years SD 12.0; 67.3% women). Of these, 49 (16.3%) reported absenteeism, and 137 (45.7%) reported presenteeism. Productivity loss due to presenteeism, but not absenteeism, was associated with asthma control. A person with uncontrolled asthma would avoid $184.80 (Canadian dollars CAD) in productivity loss by achieving clinical control during a week, CAD$167.50 (90.6%) of which would be due to presenteeism. The corresponding value was CAD$34.20 for partially controlled asthma and was not statistically significant.
Our results indicate that substantial gain in productivity can be obtained by achieving asthma control. Presenteeism is more responsive than absenteeism to asthma control, and, thus, is a more important source of preventable burden.
The economic impact of multimorbidity in severe or difficult-to-treat asthma has not been comprehensively investigated.
To estimate the incremental healthcare costs of coexisting chronic conditions ...(comorbidities) in patients with severe asthma, compared with non-severe asthma and no asthma.
Using health administrative data in British Columbia, Canada (1996-2016), we identified, based on the intensity of drug use and occurrence of exacerbations, individuals who experienced severe asthma in an incident year. We also constructed matched cohorts of individuals without an asthma diagnosis and those who had mild/dormant or moderate asthma (non-severe asthma) throughout their follow-up. Health service use records during follow-up were categorised into 16 major disease categories based on the International Classification of Diseases. Incremental costs (in 2016 Canadian Dollars, CAD$1=US$0.75=₤0.56=€0.68) were estimated as the adjusted difference in healthcare costs between individuals with severe asthma compared with those with non-severe asthma and non-asthma.
Relative to no asthma, incremental costs of severe asthma were $2779 per person-year (95% CI 2514 to 3045), with 54% ($1508) being attributed to comorbidities. Relative to non-severe asthma, severe asthma was associated with incremental costs of $1922 per person-year (95% CI 1670 to 2174), with 52% ($1003) being attributed to comorbidities. In both cases, the most costly comorbidity was respiratory conditions other than asthma ($468 (17%) and $451 (23%), respectively).
Comorbidities accounted for more than half of the incremental medical costs in patients with severe asthma. This highlights the importance of considering the burden of multimorbidity in evidence-informed decision making for patients with severe asthma.
Individualized prediction of treatment response may improve the value proposition of advanced treatment options in severe asthma. This study aimed to investigate the combined capacity of patient ...characteristics in predicting treatment response to mepolizumab in patients with severe asthma.
Patient-level data were pooled from two multinational phase 3 trials of mepolizumab in severe eosinophilic asthma. We fitted penalized regression models to quantify reductions in the rate of severe exacerbations and the 5-item Asthma Control Questionnaire (ACQ5) score. The capacity of 15 covariates towards predicting treatment response was quantified by the Gini index (measuring disparities in treatment benefit) as well as observed treatment benefit within the quintiles of predicted treatment benefit.
There was marked variability in the ability of patient characteristics to predict treatment response; covariates explained greater heterogeneity in predicting treatment response to asthma control than to exacerbation frequency (Gini index 0.35 v. 0.24). Key predictors for treatment benefit for severe exacerbations included exacerbation history, blood eosinophil count, baseline ACQ5 score and age, and those for symptom control included blood eosinophil count and presence of nasal polyps. Overall, the average reduction in exacerbations was 0.90/year (95%CI, 0.87‒0.92) and average reduction in ACQ5 score was 0.18 (95% CI, 0.02‒0.35). Among the top 20% of patients for predicted treatment benefit, exacerbations were reduced by 2.23/year (95% CI, 2.03‒2.43) and ACQ5 score were reduced by 0.59 (95% CI, 0.19‒0.98). Among the bottom 20% of patients for predicted treatment benefit, exacerbations were reduced by 0.25/year (95% CI, 0.16‒0.34) and ACQ5 by -0.20 (95% CI, -0.51 to 0.11).
A precision medicine approach based on multiple patient characteristics can guide biologic therapy in severe asthma, especially in identifying patients who will not benefit as much from therapy. Patient characteristics had a greater capacity to predict treatment response to asthma control than to exacerbation.
ClinicalTrials.gov number, NCT01691521 (registered September 24, 2012) and NCT01000506 (registered October 23, 2009).
Drug-tolerant persister cells (persisters) evade apoptosis upon targeted and conventional cancer therapies and represent a major non-genetic barrier to effective cancer treatment. Here, we show that ...cells that survive treatment with pro-apoptotic BH3 mimetics display a persister phenotype that includes colonization and metastasis in vivo and increased sensitivity toward ferroptosis by GPX4 inhibition. We found that sublethal mitochondrial outer membrane permeabilization (MOMP) and holocytochrome c release are key requirements for the generation of the persister phenotype. The generation of persisters is independent of apoptosome formation and caspase activation, but instead, cytosolic cytochrome c induces the activation of heme-regulated inhibitor (HRI) kinase and engagement of the integrated stress response (ISR) with the consequent synthesis of ATF4, all of which are required for the persister phenotype. Our results reveal that sublethal cytochrome c release couples sublethal MOMP to caspase-independent initiation of an ATF4-dependent, drug-tolerant persister phenotype.
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