Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma

Juan Carlos Ivancevich Monday, 21 May 2018 21:35

Mario Castro, M.D., Jonathan Corren, M.D., Ian D. Pavord, M.D., Jorge Maspero, M.D., Sally Wenzel, M.D., Klaus F. Rabe, M.D., William W. Busse, M.D., Linda Ford, M.D., Lawrence Sher, M.D., J. Mark FitzGerald, M.D., Constance Katelaris, M.D., Yuji Tohda, M.D., et al.

NEJM May 21, 2018
DOI: 10.1056/NEJMoa1804092

Abstract
BACKGROUND
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.

METHODS
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 (FEV1) before bronchodilator use in the overall trial population. Secondary end points included the exacerbation rate and FEV1 in patients with a blood eosinophil count of 300 or more per cubic millimeter. Asthma control and dupilumab safety were also assessed.

RESULTS
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 FEV1 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.

CONCLUSIONS
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.)

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Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma

Juan Carlos Ivancevich Monday, 21 May 2018 20:16

N Eng J Med. May 21, 2018

DOI: 10.1056/NEJMoa1804093

Klaus F. Rabe, M.D., Ph.D., Parameswaran Nair, M.D., Ph.D., Guy Brusselle, M.D., Ph.D., Jorge F. Maspero, M.D., Mario Castro, M.D., Lawrence Sher, M.D., Hongjie Zhu, Ph.D., Jennifer D. Hamilton, Ph.D., Brian N. Swanson, Ph.D., Asif Khan, M.B., B.S., M.P.H., Jingdong Chao, Ph.D., Heribert Staudinger, M.D., Ph.D., et al.

Abstract

BACKGROUND

Dupilumab is a fully human anti–interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. Its effectiveness in reducing oral glucocorticoid use in patients with severe asthma while maintaining asthma control is unknown.

METHODS

We randomly assigned 210 patients with oral glucocorticoid–treated asthma to receive add-on dupilumab (at a dose of 300 mg) or placebo every 2 weeks for 24 weeks. After a glucocorticoid dose-adjustment period before randomization, glucocorticoid doses were adjusted in a downward trend from week 4 to week 20 and then maintained at a stable dose for 4 weeks. The primary end point was the percentage reduction in the glucocorticoid dose at week 24. Key secondary end points were the proportion of patients at week 24 with a reduction of at least 50% in the glucocorticoid dose and the proportion of patients with a reduction to a glucocorticoid dose of less than 5 mg per day. Severe exacerbation rates and the forced expiratory volume in 1 second (FEV1) before bronchodilator use were also assessed.

RESULTS

The percentage change in the glucocorticoid dose was −70.1% in the dupilumab group, as compared with −41.9% in the placebo group (P<0.001); 80% versus 50% of the patients had a dose reduction of at least 50%, 69% versus 33% had a dose reduction to less than 5 mg per day, and 48% versus 25% completely discontinued oral glucocorticoid use. Despite reductions in the glucocorticoid dose, in the overall population, dupilumab treatment resulted in a severe exacerbation rate that was 59% (95% confidence interval [CI], 37 to 74) lower than that in the placebo group and resulted in an FEV1 that was 0.22 liters (95% CI, 0.09 to 0.34) higher. Injection-site reactions were more common with dupilumab than with placebo (9% vs. 4%). Transient blood eosinophilia was observed in more patients in the dupilumab group than in the placebo group (14% vs. 1%).

CONCLUSIONS

In patients with glucocorticoid-dependent severe asthma, dupilumab treatment reduced oral glucocorticoid use while decreasing the rate of severe exacerbations and increasing the FEV1. Transient eosinophilia was observed in approximately 1 in 7 dupilumab-treated patients. (Funded by Sanofi and Regeneron Pharmaceuticals; LIBERTY ASTHMA VENTURE ClinicalTrials.gov number, NCT02528214.)

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Nerve ablation after bronchial thermoplasty and sustained improvement in severe asthma

Juan Carlos Ivancevich Thursday, 17 May 2018 11:56
N. FacciolongoA. DiStefanoV. PietriniC. GaleoneF. BellanovaF. MenzellaN. ScichiloneR. PiroG. L. BajocchiB. BalbiL. AgostiniP. P. SalsiD. Formisano and M. Lusuardi

Abstract

Background

Bronchial thermoplasty (BT) is a non-pharmacological intervention for severe asthma whose mechanism of action is not completely explained by a reduction of airway smooth muscle (ASM). In this study we analyzed the effect of BT on nerve fibers and inflammatory components in the bronchial mucosa at 1 year.

Methods

Endobronchial biopsies were obtained from 12 subjects (mean age 47 ± 11.3 years, 50% male) with severe asthma. Biopsies were performed at baseline (T0) and after 1 (T1), 2 (T2) and 12 (T12) months post-BT, and studied with immunocytochemistry and microscopy methods. Clinical data including Asthma Quality of Life Questionnaire (AQLQ) and Asthma Control Questionnaire (ACQ) scores, exacerbations, hospitalizations, oral corticosteroids use were also collected at the same time points.

Results

A statistically significant reduction at T1, T2 and T12 of nerve fibers was observed in the submucosa and in ASM compared to T0. Among inflammatory cells, only CD68 showed significant changes at all time points. Improvement of all clinical outcomes was documented and persisted at the end of follow up.

Conclusions

A reduction of nerve fibers in epithelium and in ASM occurs earlier and persists at one year after BT. We propose that nerve ablation may contribute to mediate the beneficial effects of BT in severe asthma.

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Clinical and Economic Impact of a One-Year Treatment With Omalizumab in Patients With Severe Allergic Asthma Within a Drug Programme in Poland

Juan Carlos Ivancevich Thursday, 17 May 2018 12:02

Karina Jahnz-Różyk; Joanna Lis; Marta Warchoł; Aleksandra Kucharczyk

BMC Pulm Med. 2018;18(48) 

Abstract and Introduction

Abstract

Background Allergic asthma is the most prevalent phenotype of severe asthma where treatment with omalizumab (OMB) has been proven to be particularly beneficial. In Poland, OMB therapy is available and reimbursed within a drug programme where strict inclusion and exclusion criteria are defined.

The objective of this study was to present a descriptive analysis regarding the trends in outcomes (clinical, quality of life, costs) among a cohort of patients who satisfy inclusion criteria for the initiation of OMB treatment and who successfully responded to OMB according to a set of objective criteria.

Methods A retrospective analysis of data collected during the 52 weeks of OMB treatment was carried out. The study population was adolescents and adults with severe allergic asthma that was uncontrolled despite a combination of high-dose inhaled corticosteroids (ICS)/long-acting beta-agonists (LABA) and/or other controllers (leukotriene receptor antagonists (LTRA), sustained-release theophylline, and short- or long-acting muscarinic antagonists (SAMA/LAMA), who were the first to finish the one-year treatment. A clinical and cost analysis for patients included in the programme was conducted comparing the one-year pre-treatment period to the one-year treatment period outcomes.

Results Data of 85 patients who completed the first year of therapy were reviewed and analysed. Add-on OMB treatment resulted in a median decrease in exacerbation rate of 66% relative to the baseline and a reduction in oral steroid (OCS) dose by an average of 7.7 mg. At the end of the 52 weeks of therapy the changes in the quality of life questionnaire (AQLQ) and the asthma control questionnaire (ACQ) scores were 1.86 and 1.45 points, respectively. The mean cost of asthma treatment increased by an average of 15,979 EUR per patient per year (baseline period – 802 EUR/patient/year; OMB treatment – 16,781 EUR/patient/year). The cost to avoid one exacerbation was 17721 EUR.

Conclusion The clinical outcomes for the observed subset of patients were highly improved. At the same time, costs of the treatment increased, mainly due to the high OMB costs. Other costs associated with a lower number of hospitalizations and ED and office visits and a reduction in OCS dose decreased. These descriptive data can be used for further investigation in defining patients who benefit the most from OMB treatment in clinical practice.

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Prevalence of asthma among the adult general population of five Middle Eastern countries: results of the SNAPSHOT program

Juan Carlos Ivancevich Monday, 14 May 2018 20:59
Hesham TarrafOmur AydinDilsad MunganMohammad AlbaderBassam MahboubAdam DobleAaicha LahlouLuqman TariqFayaz Aziz and Abdelkader El Hasnaoui

Abstract

Background

Asthma is a common chronic respiratory disease leading to morbidity, mortality and impaired quality of life worldwide. Information on asthma prevalence in the Middle East is fragmented and relatively out-dated. The SNAPSHOT program was conducted to obtain updated information.

Methods

SNAPSHOT is a cross-sectional epidemiological program carried out in five Middle Eastern countries (Egypt, Turkey, Kuwait, Saudi Arabia, and the United Arab Emirates, the latter three grouped into a Gulf cluster) to collect data on asthma, allergic rhinitis, benign prostatic hyperplasia and bipolar disorder. The survey was carried out by telephone in a random sample of the adult general population with quotas defined according to country demographics. The analysis presented in this paper focuses on asthma. Subjects were screened for asthma based on criteria from the global Asthma Insights and Reality studies. Current prevalence (last 12 months) was estimated. Multivariate logistic regression analyses were used to investigate risk factors related to asthma and the association with allergic rhinitis and other co-morbidities. Quality of life was assessed using the three-level EQ-5D questionnaire.

Results

2124 out of the 33,486 subjects enrolled in the SNAPSHOT program fulfilled the criteria for asthma. The adjusted prevalence of asthma ranged from 4.4% [95% CI: 4.0–4.8%] in Turkey, to 6.7% [95% CI: 6.2–7.2%] in Egypt and 7.6% [95% CI: 7.1–8.0%] in the Gulf cluster. Prevalence was higher (p < 0.0001) in women than men and increased with age (p < 0.0001). Co-morbidities occurred more frequently in asthma subjects compared to the non-asthma population (38% vs. 15% p < 0.0001). Subjects with asthma reported a lower (p < 0.0001) EQ-VAS score (68.2 ± 22.9) compared to the general population (78.1 ± 17.5). The risk factors associated with asthma were age, gender, country, and certain co-morbidities, namely respiratory, cardiovascular, gastrointestinal, nervous, and neurological diseases.

Conclusion

The observed adjusted prevalence of asthma in the Middle East ranges from 4.4% to 7.6%, which is comparatively lower than the reported prevalence in Europe and North America. Asthma has a negative impact on quality of life, and is associated with high levels of co-morbid diseases, indicating a need for physicians to check for co-morbidities and ensure they are managed correctly in all asthma patients.

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Editor: Juan C. Ivancevich, MD

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