The emergence of new biologics for severe asthma

Patients with severe asthma experience severe symptoms and frequent exacerbations despite intensive treatment with inhaled and oral glucocorticoids. Biologics for severe asthma aim to reduce asthma-related and glucocorticoid-induced morbidity. Recently, new biologics targeting interleukin (IL)-5, IL-5 receptor and IL-4/IL-13, which are all cytokines involved in so-called type 2 airway inflammation, were approved for severe asthma. They show a reduction in exacerbation rate and an oral glucocorticoid-sparing effect. Studies with upstream biologics targeting alarmin cytokines such as thymic stromal lymphopoietin (TSLP) and IL-33 are underway, and newly designed bispecific antibodies targeting more than one pathway are in early phases of development. Such pathway-targeted add-on treatments will soon become standard of care for all patients with severe asthma

Real-World Effectiveness of Reslizumab in Patients with Severe Eosinophilic Asthma - "First Initiators" and "Switchers"

BACKGROUND: Reslizumab, a biologic targeting interleukin-5 has been shown to reduce asthma exacerbations and maintenance oral corticosteroid (OCS) use in randomized controlled trials and pre-post studies in patients with severe eosinophilic asthma. However, real-world effectiveness data of reslizumab are scarce, and it is unknown whether reslizumab has added value after switching from another type-2 biologic. OBJECTIVE: To evaluate (1) real-world effectiveness of reslizumab on severe asthma exacerbations, maintenance OCS-use and overall treatment response, both in biologic naïve patients who initiated reslizumab, and in patients who switched from another type-2 biologic. (2) physicians experience with reslizumab treatment. METHODS: This observational real-world study evaluated data from 134 adults with severe eosinophilic asthma included in the Dutch severe asthma registry (RAPSODI) who initiated reslizumab treatment (4-weekly infusions, 0.3 mg/kg) before April 2020 and had follow-up data ≥6 months. Clinical asthma experts completed surveys on their experience with reslizumab treatment. RESULTS: Overall, reslizumab reduced exacerbation rate (OR(95%CI): 0.10(0.05-0.21), p<0.001), oral corticosteroid use (OR(95%CI) 0.2(0.0-0.5), p<0.001) and maintenance dose, median(CI): 5.0(0.0-10.0) to 0.0(0.0-5.0), p<0.001), with comparable results in biologic-naïve reslizumab initiators and switchers. The overall response to reslizumab was graded 'good' or 'excellent' in 59.2% of patients. The additive effectiveness of reslizumab after switching from another biologic was reflected in physicians' surveys. CONCLUSION: Real-world data show that reslizumab reduces severe asthma exacerbations and oral corticosteroid use in patients with severe eosinophilic asthma, both in biologic-naïve reslizumab initiators and in those who switched from another type-2 biologic. This additional value of reslizumab was recognized by clinical asthma experts

Real-World Effectiveness of Reslizumab in Patients with Severe Eosinophilic Asthma - "First Initiators" and "Switchers"

BACKGROUND: Reslizumab, a biologic targeting interleukin-5 has been shown to reduce asthma exacerbations and maintenance oral corticosteroid (OCS) use in randomized controlled trials and pre-post studies in patients with severe eosinophilic asthma. However, real-world effectiveness data of reslizumab are scarce, and it is unknown whether reslizumab has added value after switching from another type-2 biologic. OBJECTIVE: To evaluate (1) real-world effectiveness of reslizumab on severe asthma exacerbations, maintenance OCS-use and overall treatment response, both in biologic naïve patients who initiated reslizumab, and in patients who switched from another type-2 biologic. (2) physicians experience with reslizumab treatment. METHODS: This observational real-world study evaluated data from 134 adults with severe eosinophilic asthma included in the Dutch severe asthma registry (RAPSODI) who initiated reslizumab treatment (4-weekly infusions, 0.3 mg/kg) before April 2020 and had follow-up data ≥6 months. Clinical asthma experts completed surveys on their experience with reslizumab treatment. RESULTS: Overall, reslizumab reduced exacerbation rate (OR(95%CI): 0.10(0.05-0.21), p<0.001), oral corticosteroid use (OR(95%CI) 0.2(0.0-0.5), p<0.001) and maintenance dose, median(CI): 5.0(0.0-10.0) to 0.0(0.0-5.0), p<0.001), with comparable results in biologic-naïve reslizumab initiators and switchers. The overall response to reslizumab was graded 'good' or 'excellent' in 59.2% of patients. The additive effectiveness of reslizumab after switching from another biologic was reflected in physicians' surveys. CONCLUSION: Real-world data show that reslizumab reduces severe asthma exacerbations and oral corticosteroid use in patients with severe eosinophilic asthma, both in biologic-naïve reslizumab initiators and in those who switched from another type-2 biologic. This additional value of reslizumab was recognized by clinical asthma experts

Evaluation of real-world mepolizumab use in severe asthma across Europe: the SHARP experience with privacy-preserving federated analysis

Background An objective of the Severe Heterogeneous Asthma Registry, Patient-centered (SHARP) is to produce real-world evidence on a pan-European scale by linking nonstandardised, patient-level registry data. Mepolizumab has shown clinical efficacy in randomised controlled trials and prospective real-world studies and could therefore serve as a proof of principle for this novel approach. The aim of the present study was to harmonise data from 10 national severe asthma registries and characterise patients receiving mepolizumab, assess its effectiveness on annual exacerbations and maintenance oral glucocorticoid (OCS) use, and evaluate treatment patterns. Methods In this observational cohort study, registry data (5871 patients) were extracted for harmonisation. Where harmonisation was possible, patients who initiated mepolizumab between 1 January 2016 and 31 December 2021 were examined. Changes of a 12-month (range 11–18 months) period in frequent (two or more) exacerbations, maintenance OCS use and dose were analysed in a privacy-preserving manner using meta-analysis of generalised estimating equation parameters. Periods before and during the coronavirus disease 2019 pandemic were analysed separately. Results In 912 patients who fulfilled selection criteria, mepolizumab significantly reduced frequent exacerbations (OR 0.18, 95% CI 0.13–0.25), maintenance OCS use (OR 0.75, 95% CI 0.61–0.92) and dose (mean −3.93 mg·day−1, 95% CI −5.24–2.62 mg·day−1) in the pre-pandemic group, with similar trends in the pandemic group. Marked heterogeneity was observed between registries in patient characteristics and mepolizumab treatment patterns. Conclusions By harmonising patient-level registry data and applying federated analysis, SHARP demonstrated the real-world effectiveness of mepolizumab on asthma exacerbations and maintenance OCS use in severe asthma patients across Europe, consistent with previous evidence. This paves the way for future pan-European real-world severe asthma studies using patient-level data in a privacy-proof manner

Correction to Lancet Respir Med 2021; published online June 17, https://doi.org/10.1016/S2213-2600(21)00237-X (The Lancet Respiratory Medicine, (S221326002100237X), (10.1016/S2213-2600(21)00237-X))

Aman J, Duijvelaar E, Botros L, et al. Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial. Lancet Respir Med 2021; published online June 17. https://doi.org/10.1016/S2213-2600(21)00237-X—In this Article, the authors Elisabeth C W Neefjes', Jeroen N Wessel's, Carolina C Pamplona's, and Elise M A Slob's names were incorrect. Rianne J A Hoek's affiliation should have been “Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, VUMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands”. These corrections have been made to the online version as of June 25, 2021, and will be made to the printed version

Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial

BACKGROUND: The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak. METHODS: This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged ≥18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1-9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020-001236-10). FINDINGS: Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56-73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0·95 [95% CI 0·76-1·20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0·51 [0·27-0·95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0·52 (95% CI 0·26-1·05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1·07 (0·63-1·80; p=0·81). The median duration of invasive mechanical ventilation was 7 days (IQR 3-13) in the imatinib group compared with 12 days (6-20) in the placebo group (p=0·0080). 91 (46%) of 197 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events. INTERPRETATION: The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings. FUNDING: Amsterdam Medical Center Foundation, Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ZonMW, and the European Union Innovative Medicines Initiative 2

Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial

BACKGROUND: The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak. METHODS: This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged ≥18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1-9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020-001236-10). FINDINGS: Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56-73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0·95 [95% CI 0·76-1·20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0·51 [0·27-0·95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0·52 (95% CI 0·26-1·05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1·07 (0·63-1·80; p=0·81). The median duration of invasive mechanical ventilation was 7 days (IQR 3-13) in the imatinib group compared with 12 days (6-20) in the placebo group (p=0·0080). 91 (46%) of 197 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events. INTERPRETATION: The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings. FUNDING: Amsterdam Medical Center Foundation, Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ZonMW, and the European Union Innovative Medicines Initiative 2