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Margaret Garin - One of the best experts on this subject based on the ideXlab platform.
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Long-term Safety and Efficacy of Reslizumab in Patients with Eosinophilic Asthma.
The journal of allergy and clinical immunology. In practice, 2020Co-Authors: Kevin Murphy, Leif Bjermer, John M Fahrenholz, Yael Shalit, Margaret Garin, James Zangrilli, Joshua Jacobs, Mario CastroAbstract:In placebo-controlled trials, Reslizumab, an anti-IL-5 monoclonal antibody, significantly reduced asthma exacerbations and improved lung function and asthma control in patients with eosinophilic asthma. This open-label extension study evaluated safety and efficacy of Reslizumab for up to 24 months. After participation in 1 of 3 placebo-controlled, phase III trials in moderate-to-severe eosinophilic asthma, patients received Reslizumab 3.0 mg/kg intravenously every 4 weeks for up to 24 months. Adverse events (AEs), lung function, and patient-reported asthma control were evaluated. In the open-label extension, 1,051 patients received ≥1 Reslizumab dose (480 Reslizumab-naïve, 571 Reslizumab-experienced); median (range) exposure was 319 (36-840) and 343 (36-863) days in Reslizumab-naïve and Reslizumab-experienced patients, respectively. Continuous exposure, including during the placebo-controlled studies, was ≥12 months for 740 patients and ≥24 months for 249 patients. The most common AEs were worsening of asthma and nasopharyngitis. Serious AEs affected 78 of 1,051 (7%) patients; 18 of 1,051 (2%) discontinued treatment because of AEs; and there were 3 deaths (all non-treatment-related). Fifteen adult patients (15 of 1,023; 1%) had malignancies of diverse tissue types. Reslizumab-experienced patients maintained improved lung function and asthma control; Reslizumab-naïve patients had improvements in these measures throughout open-label treatment. Blood eosinophil counts appeared to be returning to baseline after Reslizumab discontinuation. In patients with moderate-to-severe eosinophilic asthma, intravenous Reslizumab 3.0 mg/kg displays favorable long-term safety and sustained long-term efficacy. Initial improvements in lung function and asthma control were maintained for up to 2 years. These findings substantially add to our understanding of the long-term safety and efficacy of anti-IL-5 strategies. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
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population pharmacokinetic and pharmacokinetic pharmacodynamic modeling of weight based intravenous Reslizumab dosing
The Journal of Clinical Pharmacology, 2020Co-Authors: Julie A Passarell, Margaret Garin, David Jaworowicz, Elizabeth A Ludwig, Laura Rabinovichguilatt, Micha Levi, Jill Fiedlerkelly, Mary BondAbstract:Reslizumab 3.0 mg/kg has demonstrated efficacy in clinical studies of patients with eosinophilic asthma and a history of exacerbations. A population pharmacokinetic (PK) model was developed to determine whether 3.0 mg/kg weight-based dosing is appropriate to obtain consistent Reslizumab exposures in all patients. PK data in healthy volunteers and patients >/=12 years with moderate to severe asthma, eosinophilic asthma, or nasal polyposis were analyzed from 4 phase 1, 2 phase 2, and 2 phase 3 studies of intravenous (IV) Reslizumab (N = 804). Covariates evaluated included age, race, sex, baseline weight, renal and liver function, concomitant medications, and antidrug antibody status. Exposure-response models were developed to characterize key efficacy (blood eosinophil levels, forced expiratory volume in 1 second [FEV1 ], Asthma Control Questionnaire [ACQ-7] scores), and safety end points (muscle disorder adverse events [AEs]). Vial-based dosing was evaluated as an alternative to weight-based dosing. IV Reslizumab PK was accurately described by a 2-compartment PK model with 0-order input and first-order elimination. Body weight was the only covariate that significantly influenced PK parameters. However, with weight-based dosing, comparable steady-state exposures were observed across high and low body weights. Greater eosinophil lowering and longer response duration were observed with increasing dose; exposure-related effects on FEV1 and ACQ-7 were also seen, demonstrating the clinical importance of a dosing regimen to optimize Reslizumab exposure. The probability of a muscle disorder AE appeared to increase with increasing exposure. Steady-state exposure measures were similar for both dosing regimens, showing vial-based dosing as an alternative method of achieving the benefits of weight-based dosing.
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Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Modeling of Weight-Based Intravenous Reslizumab Dosing.
Journal of clinical pharmacology, 2020Co-Authors: Julie A Passarell, Margaret Garin, David Jaworowicz, Micha Levi, Elizabeth Ludwig, Laura Rabinovich-guilatt, Jill Fiedler-kelly, Mary BondAbstract:Reslizumab 3.0 mg/kg has demonstrated efficacy in clinical studies of patients with eosinophilic asthma and a history of exacerbations. A population pharmacokinetic (PK) model was developed to determine whether 3.0 mg/kg weight-based dosing is appropriate to obtain consistent Reslizumab exposures in all patients. PK data in healthy volunteers and patients ≥12 years with moderate to severe asthma, eosinophilic asthma, or nasal polyposis were analyzed from 4 phase 1, 2 phase 2, and 2 phase 3 studies of intravenous (IV) Reslizumab (N = 804). Covariates evaluated included age, race, sex, baseline weight, renal and liver function, concomitant medications, and antidrug antibody status. Exposure-response models were developed to characterize key efficacy (blood eosinophil levels, forced expiratory volume in 1 second [FEV1 ], Asthma Control Questionnaire [ACQ-7] scores), and safety end points (muscle disorder adverse events [AEs]). Vial-based dosing was evaluated as an alternative to weight-based dosing. IV Reslizumab PK was accurately described by a 2-compartment PK model with 0-order input and first-order elimination. Body weight was the only covariate that significantly influenced PK parameters. However, with weight-based dosing, comparable steady-state exposures were observed across high and low body weights. Greater eosinophil lowering and longer response duration were observed with increasing dose; exposure-related effects on FEV1 and ACQ-7 were also seen, demonstrating the clinical importance of a dosing regimen to optimize Reslizumab exposure. The probability of a muscle disorder AE appeared to increase with increasing exposure. Steady-state exposure measures were similar for both dosing regimens, showing vial-based dosing as an alternative method of achieving the benefits of weight-based dosing.
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in patients with severe asthma with eosinophilia in Reslizumab clinical trials high peripheral blood eosinophil levels are associated with low fev1 reversibility
Allergy Asthma & Clinical Immunology, 2020Co-Authors: Christian J Virchow, Lisa Hickey, Evelyn Du, Margaret GarinAbstract:Background: A post hoc analysis of two randomized, placebo-controlled, Phase 3 trials of intravenous Reslizumab, an anti-interleukin-5 (IL-5) biologic for severe eosinophilic asthma. Methods: Relationships between baseline blood eosinophil levels (EOS), forced expiratory volume in 1 s (FEV1) reversibility to beta2-agonists and treatment outcomes were assessed. Results: Mean baseline FEV1 reversibility was numerically lower among patients with high (>/= 400 cells/microL) versus low baseline EOS. Reslizumab produced clinically significant improvement in FEV1, exacerbation rates and patient-reported outcomes after 52 weeks, including in patients with high EOS and low FEV1 reversibility ( /= 12% might exclude patients who would benefit from treatment with anti-IL-5 biologics.
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In patients with severe asthma with eosinophilia in Reslizumab clinical trials, high peripheral blood eosinophil levels are associated with low FEV1 reversibility.
Allergy asthma and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology, 2020Co-Authors: J Christian Virchow, Evelyn Du, Lisa Hickey, Margaret GarinAbstract:A post hoc analysis of two randomized, placebo-controlled, Phase 3 trials of intravenous Reslizumab, an anti-interleukin-5 (IL-5) biologic for severe eosinophilic asthma. Relationships between baseline blood eosinophil levels (EOS), forced expiratory volume in 1 s (FEV1) reversibility to β2-agonists and treatment outcomes were assessed. Mean baseline FEV1 reversibility was numerically lower among patients with high (≥ 400 cells/µL) versus low baseline EOS. Reslizumab produced clinically significant improvement in FEV1, exacerbation rates and patient-reported outcomes after 52 weeks, including in patients with high EOS and low FEV1 reversibility (≤ 14%) to β2-agonists at baseline. Clinical trial eligibility criteria stipulating minimum FEV1 reversibility to β2-agonists of ≥ 12% might exclude patients who would benefit from treatment with anti-IL-5 biologics. © The Author(s) 2020.
Mario Castro - One of the best experts on this subject based on the ideXlab platform.
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Long-term Safety and Efficacy of Reslizumab in Patients with Eosinophilic Asthma.
The journal of allergy and clinical immunology. In practice, 2020Co-Authors: Kevin Murphy, Leif Bjermer, John M Fahrenholz, Yael Shalit, Margaret Garin, James Zangrilli, Joshua Jacobs, Mario CastroAbstract:In placebo-controlled trials, Reslizumab, an anti-IL-5 monoclonal antibody, significantly reduced asthma exacerbations and improved lung function and asthma control in patients with eosinophilic asthma. This open-label extension study evaluated safety and efficacy of Reslizumab for up to 24 months. After participation in 1 of 3 placebo-controlled, phase III trials in moderate-to-severe eosinophilic asthma, patients received Reslizumab 3.0 mg/kg intravenously every 4 weeks for up to 24 months. Adverse events (AEs), lung function, and patient-reported asthma control were evaluated. In the open-label extension, 1,051 patients received ≥1 Reslizumab dose (480 Reslizumab-naïve, 571 Reslizumab-experienced); median (range) exposure was 319 (36-840) and 343 (36-863) days in Reslizumab-naïve and Reslizumab-experienced patients, respectively. Continuous exposure, including during the placebo-controlled studies, was ≥12 months for 740 patients and ≥24 months for 249 patients. The most common AEs were worsening of asthma and nasopharyngitis. Serious AEs affected 78 of 1,051 (7%) patients; 18 of 1,051 (2%) discontinued treatment because of AEs; and there were 3 deaths (all non-treatment-related). Fifteen adult patients (15 of 1,023; 1%) had malignancies of diverse tissue types. Reslizumab-experienced patients maintained improved lung function and asthma control; Reslizumab-naïve patients had improvements in these measures throughout open-label treatment. Blood eosinophil counts appeared to be returning to baseline after Reslizumab discontinuation. In patients with moderate-to-severe eosinophilic asthma, intravenous Reslizumab 3.0 mg/kg displays favorable long-term safety and sustained long-term efficacy. Initial improvements in lung function and asthma control were maintained for up to 2 years. These findings substantially add to our understanding of the long-term safety and efficacy of anti-IL-5 strategies. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
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effect of fixed dose subcutaneous Reslizumab on asthma exacerbations in patients with severe uncontrolled asthma and corticosteroid sparing in patients with oral corticosteroid dependent asthma results from two phase 3 randomised double blind placebo
The Lancet Respiratory Medicine, 2020Co-Authors: Jonathan A Bernstein, Kevin R Murphy, Joshua J Jacobs, Mario Castro, Christian J Virchow, Jorge Maspero, Yochai Adir, Marc Humbert, Douglas A Marsteller, Jennifer McelhattanAbstract:Summary Background Reslizumab 3 mg/kg administered intravenously is approved for the treatment of severe eosinophilic asthma. We assessed the safety and efficacy of subcutaneous Reslizumab 110 mg in two trials in patients with uncontrolled severe asthma and increased blood eosinophils. The aim was to establish whether subcutaneous Reslizumab 110 mg can reduce exacerbation rates in these patients (study 1) or reduce maintenance oral corticosteroid dose in patients with corticosteroid-dependent asthma (study 2). Methods Both studies were randomised, double-blind, placebo-controlled, phase 3 studies. Entry criteria for study 1 were uncontrolled severe asthma, two or more asthma exacerbations in the previous year, a blood eosinophil count of 300 cells per μL or more (including no more than 30% patients with an eosinophil count ClinicalTrials.gov , NCT02452190 (study 1) and NCT02501629 (study 2). Findings Between Aug 12, 2015, and Jan 31, 2018, 468 patients in study 1 were randomly assigned to placebo (n=232) or subcutaneous Reslizumab (n=236), and 177 in study 2 to placebo (n=89) or subcutaneous Reslizumab (n=88). In study 1, we found no significant difference in the exacerbation rate between Reslizumab and placebo in the intention-to-treat population (rate ratio 0·79, 95% CI 0·56–1·12; p=0·19). Subcutaneous Reslizumab reduced exacerbation frequency compared with placebo in the subgroup of patients with blood eosinophil counts of 400 cells per μL or more (0·64, 95% CI 0·43–0·95). Greater reductions in annual exacerbation risk (p=0·0035) and longer time to first exacerbation were observed for patients with higher trough serum Reslizumab concentrations. In study 2, we found no difference between placebo and fixed-dose subcutaneous Reslizumab in categorised percentage reduction in daily oral corticosteroid dose (odds ratio for a lower category of oral corticosteroid use in the Reslizumab group vs the placebo group, 1·23, 95% CI 0·70–2·16; p=0·47). The frequency of adverse events and serious adverse events with Reslizumab were similar to those with placebo in both studies. Interpretation Fixed-dose (110 mg) subcutaneous Reslizumab was not effective in reducing exacerbation frequency in patients with uncontrolled asthma and increased blood eosinophils (≥300 cells/μL), or in reducing the daily maintenance oral corticosteroid dose in patients with oral corticosteroid-dependent severe eosinophilic asthma. Higher exposures than those observed with 110 mg subcutaneous Reslizumab are required to achieve maximal efficacy. Funding Teva Branded Pharmaceutical Products R&D.
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safety of Reslizumab in uncontrolled asthma with eosinophilia a pooled analysis from 6 trials
The Journal of Allergy and Clinical Immunology: In Practice, 2020Co-Authors: Christian J Virchow, Yael Shalit, Margaret Garin, Rohit K Katial, Guy Brusselle, Mirna Mcdonald, Mario CastroAbstract:Abstract Background Intravenous Reslizumab, a monoclonal interleukin-5 antibody, is approved for treating severe asthma with eosinophilia. Limited structured information is available on the safety of Reslizumab in larger populations. Objective The aim of this study was to investigate the safety profile of intravenous Reslizumab 3.0 mg/kg by analyzing data from six asthma clinical trials: five placebo-controlled (duration ≤52 weeks) and one open-label extension (up to 2 years of treatment). Methods Patients were aged 12–75 years with inadequately controlled asthma with eosinophilia. In the placebo-controlled trials, 730 patients received placebo and 1028 Reslizumab 3.0 mg/kg. Results Adverse events (AEs) and serious AEs occurred in higher percentages of patients in the placebo group (81% and 9%) than with Reslizumab (67% and 6%). Asthma, nasopharyngitis and upper respiratory tract infection were the most common AEs with placebo and Reslizumab. Three cases of anaphylaxis, related to Reslizumab, were successfully managed with standard therapies. No significant difference in the incidence of malignancies was seen when compared with placebo or the general population. Among 756 patients with >12 months of Reslizumab exposure, the AE rate was lower than in the placebo-controlled trials (367.3 vs 433.9 events/100 patient-years). The incidence of AEs in patients on treatment for >12 months was no higher than in patients with shorter treatment durations. Conclusions This analysis confirms that treatment with intravenous Reslizumab for >12 months is well tolerated in patients with asthma, with no evidence of rare safety events that were not detected in individual trials.
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predicting responders to Reslizumab after 16 weeks of treatment using an algorithm derived from clinical studies of patients with severe eosinophilic asthma
American Journal of Respiratory and Critical Care Medicine, 2019Co-Authors: Eric D Bateman, Margaret Garin, Mario Castro, Matthew Germinaro, Janice Canvin, Ratko Djukanovic, Robert Noble, R BuhlAbstract:Rationale: Reslizumab is a humanized anti–IL-5 monoclonal antibody used as add-on maintenance treatment for patients with uncontrolled eosinophilic asthma.Objectives: To predict response and nonres...
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Reslizumab compared with benralizumab in patients with eosinophilic asthma a systematic literature review and network meta analysis
The Journal of Allergy and Clinical Immunology: In Practice, 2019Co-Authors: Thomas B Casale, Maud Pacou, Laura Mesana, Gaelle Farge, Mario CastroAbstract:Background The interaction of IL-5 with its receptor on eosinophils increases the activation and maintenance of eosinophils; blocking this interaction reduces asthma symptoms in patients with the eosinophilic phenotype. Reslizumab, which binds to IL-5, and benralizumab, which targets the IL-5 receptor α subunit, have not been compared in head-to-head trials. Objective To indirectly compare Reslizumab with benralizumab in similar patient populations using a network meta-analysis. Methods A systematic literature review was conducted and a network meta-analysis was performed on eligible studies using the Markov Chain Monte-Carlo simulation method and a Bayesian statistical framework. Results Eleven studies were identified, 4 of which evaluated clinically relevant doses and had outcomes at similar time points. To control for population differences, subgroups were selected for the base-case efficacy analysis: a benralizumab subgroup with blood eosinophil levels of greater than or equal to 300 cells/μL (n = 1537) and a Reslizumab subgroup in Global Initiative for Asthma step 4/5 with 2 or more previous exacerbations and greater than or equal to 400 eosinophils/μL (n = 318). Safety was analyzed in the full population (N = 3462). Reslizumab significantly improved Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ) scores compared with benralizumab once every 4 weeks and there were reasonably high posterior probabilities that Reslizumab is superior to benralizumab once every 4 weeks and once every 8 weeks for ACQ score, AQLQ score, FEV1, and clinical asthma exacerbations. Conclusions This indirect comparison suggests that Reslizumab may be more efficacious than benralizumab in patients with eosinophilic asthma in Global Initiative for Asthma step 4/5 with elevated blood eosinophil levels (benralizumab, ≥300/μL; Reslizumab, ≥400/μL) and 2 or more exacerbations in the previous year.
James Zangrilli - One of the best experts on this subject based on the ideXlab platform.
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Long-term Safety and Efficacy of Reslizumab in Patients with Eosinophilic Asthma.
The journal of allergy and clinical immunology. In practice, 2020Co-Authors: Kevin Murphy, Leif Bjermer, John M Fahrenholz, Yael Shalit, Margaret Garin, James Zangrilli, Joshua Jacobs, Mario CastroAbstract:In placebo-controlled trials, Reslizumab, an anti-IL-5 monoclonal antibody, significantly reduced asthma exacerbations and improved lung function and asthma control in patients with eosinophilic asthma. This open-label extension study evaluated safety and efficacy of Reslizumab for up to 24 months. After participation in 1 of 3 placebo-controlled, phase III trials in moderate-to-severe eosinophilic asthma, patients received Reslizumab 3.0 mg/kg intravenously every 4 weeks for up to 24 months. Adverse events (AEs), lung function, and patient-reported asthma control were evaluated. In the open-label extension, 1,051 patients received ≥1 Reslizumab dose (480 Reslizumab-naïve, 571 Reslizumab-experienced); median (range) exposure was 319 (36-840) and 343 (36-863) days in Reslizumab-naïve and Reslizumab-experienced patients, respectively. Continuous exposure, including during the placebo-controlled studies, was ≥12 months for 740 patients and ≥24 months for 249 patients. The most common AEs were worsening of asthma and nasopharyngitis. Serious AEs affected 78 of 1,051 (7%) patients; 18 of 1,051 (2%) discontinued treatment because of AEs; and there were 3 deaths (all non-treatment-related). Fifteen adult patients (15 of 1,023; 1%) had malignancies of diverse tissue types. Reslizumab-experienced patients maintained improved lung function and asthma control; Reslizumab-naïve patients had improvements in these measures throughout open-label treatment. Blood eosinophil counts appeared to be returning to baseline after Reslizumab discontinuation. In patients with moderate-to-severe eosinophilic asthma, intravenous Reslizumab 3.0 mg/kg displays favorable long-term safety and sustained long-term efficacy. Initial improvements in lung function and asthma control were maintained for up to 2 years. These findings substantially add to our understanding of the long-term safety and efficacy of anti-IL-5 strategies. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
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long term safety and efficacy of Reslizumab in patients with eosinophilic asthma
The Journal of Allergy and Clinical Immunology: In Practice, 2017Co-Authors: Kevin R Murphy, Joshua J Jacobs, Leif Bjermer, John M Fahrenholz, Yael Shalit, Margaret Garin, James Zangrilli, Mario CastroAbstract:Background In placebo-controlled trials, Reslizumab, an anti-IL-5 monoclonal antibody, significantly reduced asthma exacerbations and improved lung function and asthma control in patients with eosinophilic asthma. Objective This open-label extension study evaluated safety and efficacy of Reslizumab for up to 24 months. Methods After participation in 1 of 3 placebo-controlled, phase III trials in moderate-to-severe eosinophilic asthma, patients received Reslizumab 3.0 mg/kg intravenously every 4 weeks for up to 24 months. Adverse events (AEs), lung function, and patient-reported asthma control were evaluated. Results In the open-label extension, 1,051 patients received ≥1 Reslizumab dose (480 Reslizumab-naive, 571 Reslizumab-experienced); median (range) exposure was 319 (36-840) and 343 (36-863) days in Reslizumab-naive and Reslizumab-experienced patients, respectively. Continuous exposure, including during the placebo-controlled studies, was ≥12 months for 740 patients and ≥24 months for 249 patients. The most common AEs were worsening of asthma and nasopharyngitis. Serious AEs affected 78 of 1,051 (7%) patients; 18 of 1,051 (2%) discontinued treatment because of AEs; and there were 3 deaths (all non-treatment-related). Fifteen adult patients (15 of 1,023; 1%) had malignancies of diverse tissue types. Reslizumab-experienced patients maintained improved lung function and asthma control; Reslizumab-naive patients had improvements in these measures throughout open-label treatment. Blood eosinophil counts appeared to be returning to baseline after Reslizumab discontinuation. Conclusions In patients with moderate-to-severe eosinophilic asthma, intravenous Reslizumab 3.0 mg/kg displays favorable long-term safety and sustained long-term efficacy. Initial improvements in lung function and asthma control were maintained for up to 2 years. These findings substantially add to our understanding of the long-term safety and efficacy of anti-IL-5 strategies.
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Reslizumab in patients with inadequately controlled late onset asthma and elevated blood eosinophils
Pulmonary Pharmacology & Therapeutics, 2017Co-Authors: Guy Brusselle, Matthew Germinaro, Sivan Weiss, James ZangrilliAbstract:Abstract Introduction Asthma with adult onset and elevated blood eosinophils is a difficult-to-treat subgroup. This post hoc analysis evaluated Reslizumab, an anti-interleukin-5 monoclonal antibody, in patients with late-onset eosinophilic asthma. Methods Data from two 52-week placebo-controlled trials of Reslizumab IV 3 mg/kg every 4 weeks in patients aged 12–75 years with inadequately controlled asthma, ≥1 asthma exacerbation within 12 months, and screening blood eosinophils ≥400/μL (NCT01287039/NCT01285323) were stratified by age of asthma onset ( Results 273 patients with late-onset asthma (placebo, n = 130; Reslizumab, n = 143) and 658 with early-onset asthma (placebo, n = 336; Reslizumab, n = 322) were included. Baseline demographics were similar between groups. The interaction between age at onset of asthma and effect of Reslizumab on asthma exacerbations was statistically significant (p = 0.0083). Compared with placebo, Reslizumab produced a 75% relative reduction in asthma exacerbations in patients with late-onset asthma (rate ratio [RR] 0.25; 95% confidence interval [CI], 0.16, 0.40), substantially larger than the reduction in earlier onset patients (RR 0.58; 95% CI, 0.44, 0.76). Similar findings were observed for other measures of asthma, including forced expiratory volume in 1 s (FEV 1 ). The adverse event profile of Reslizumab was similar in patients with early- or late-onset asthma. Conclusions Compared with placebo, Reslizumab produced larger reductions in asthma exacerbations and larger improvements in lung function in patients with late versus early-onset asthma.
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Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels a randomized phase 3 study
Chest, 2016Co-Authors: Leif Bjermer, James Zangrilli, Jorge Maspero, Sivan Weiss, Catherine Lemiere, Matthew GerminaroAbstract:Background This phase 3 study further characterizes the efficacy and safety of Reslizumab (a humanized anti-IL-5 monoclonal antibody) in patients aged 12 to 75 years with asthma inadequately controlled by at least a medium-dose inhaled corticosteroid and with a blood eosinophil count ≥ 400 cells/μL. Methods Patients were randomized to receive Reslizumab 0.3 or 3.0 mg/kg or placebo administered once every 4 weeks for 16 weeks (total four doses). The primary end point was change from baseline in pre-bronchodilator FEV 1 over 16 weeks. Secondary end points included FVC, forced expiratory flow at 25% to 75% of FVC (FEF 25%-75% ), patient-reported control of asthma symptoms, short-acting β-agonist (SABA) use, blood eosinophil levels, and safety. Results Reslizumab significantly improved FEV 1 (difference vs placebo [Reslizumab 0.3 and 3.0 mg/kg], 115 mL [95% CI, 16-215; P = .0237] and 160 mL [95% CI, 60-259; P = .0018]). Clinically meaningful increases in FVC (130 mL) and FEF 25%-75% (233 mL/s) were observed with Reslizumab 3.0 mg/kg. Reslizumab improved scores on the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ) vs placebo (greater effects seen with 3.0 mg/kg; P Conclusions Reslizumab improved lung function, asthma control and symptoms, and quality of life. It was well tolerated in patients with inadequately controlled asthma (despite standard therapy) and elevated blood eosinophil levels. Overall, the 3.0-mg/kg dose of Reslizumab provided greater improvements in asthma outcomes vs the 0.3-mg/kg dose, with comparable safety. Trial Registry ClinicalTrials.gov; No.: NCT01270464; URL: www.clinicaltrials.gov.
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phase 3 study of Reslizumab in patients with poorly controlled asthma effects across a broad range of eosinophil counts
Chest, 2016Co-Authors: Jonathan Corren, James Zangrilli, Steven Weinstein, Lindsay Janka, Margaret GarinAbstract:Background IL-5, a mediator of eosinophil activity, is an important potential treatment target in patients with uncontrolled asthma. The efficacy of Reslizumab, a humanized anti-human IL-5 monoclonal antibody, has been characterized in patients with blood eosinophils ≥ 400 cells/μL. This study further characterizes the efficacy and safety of Reslizumab in patients with poorly-controlled asthma, particularly those with eosinophils Methods Patients were randomly assigned to intravenous Reslizumab 3.0 mg/kg or placebo once every 4 weeks for 16 weeks. The primary end point was the change in FEV 1 from baseline to week 16. Secondary measures included Asthma Control Questionnaire-7 (ACQ-7) scores, use of short-acting β-agonists (SABAs), and FVC. Results Four hundred ninety-two patients received ≥ 1 dose of placebo (n = 97) or Reslizumab (n = 395). In the overall population, mean FEV 1 change from baseline to week 16 was not significantly different between Reslizumab and placebo, and no significant relationship was detected between treatment, baseline blood eosinophils and change in FEV 1 . In the subgroup of patients with baseline eosinophils 1 compared with those receiving placebo. In the subgroup with eosinophils ≥ 400 cells/μL, however, treatment with Reslizumab was associated with much larger improvements in FEV 1 , ACQ-7, rescue SABA use, and FVC compared with the placebo group. Reslizumab was well tolerated, with fewer overall adverse events compared with placebo (55% vs 73%). Conclusions Reslizumab was well tolerated in patients with inadequately controlled asthma. Clinically meaningful effects on lung function and symptom control were not seen in patients unselected for baseline eosinophils. Trial Registry ClinicalTrials.gov; No.: NCT01508936; URL: www.clinicaltrials.gov
Guy Brusselle - One of the best experts on this subject based on the ideXlab platform.
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safety of Reslizumab in uncontrolled asthma with eosinophilia a pooled analysis from 6 trials
The Journal of Allergy and Clinical Immunology: In Practice, 2020Co-Authors: Christian J Virchow, Yael Shalit, Margaret Garin, Rohit K Katial, Guy Brusselle, Mirna Mcdonald, Mario CastroAbstract:Abstract Background Intravenous Reslizumab, a monoclonal interleukin-5 antibody, is approved for treating severe asthma with eosinophilia. Limited structured information is available on the safety of Reslizumab in larger populations. Objective The aim of this study was to investigate the safety profile of intravenous Reslizumab 3.0 mg/kg by analyzing data from six asthma clinical trials: five placebo-controlled (duration ≤52 weeks) and one open-label extension (up to 2 years of treatment). Methods Patients were aged 12–75 years with inadequately controlled asthma with eosinophilia. In the placebo-controlled trials, 730 patients received placebo and 1028 Reslizumab 3.0 mg/kg. Results Adverse events (AEs) and serious AEs occurred in higher percentages of patients in the placebo group (81% and 9%) than with Reslizumab (67% and 6%). Asthma, nasopharyngitis and upper respiratory tract infection were the most common AEs with placebo and Reslizumab. Three cases of anaphylaxis, related to Reslizumab, were successfully managed with standard therapies. No significant difference in the incidence of malignancies was seen when compared with placebo or the general population. Among 756 patients with >12 months of Reslizumab exposure, the AE rate was lower than in the placebo-controlled trials (367.3 vs 433.9 events/100 patient-years). The incidence of AEs in patients on treatment for >12 months was no higher than in patients with shorter treatment durations. Conclusions This analysis confirms that treatment with intravenous Reslizumab for >12 months is well tolerated in patients with asthma, with no evidence of rare safety events that were not detected in individual trials.
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Care pathways for the selection of a biologic in severe asthma
European Respiratory Journal, 2017Co-Authors: Jean Bousquet, Guy Brusselle, Roland Buhl, William W. Busse, Alvaro A. Cruz, Ratko Djukanovic, Christian Domingo, Nicola A. Hanania, Marc HumbertAbstract:Physicians need care pathways to select a biologic in type 2 severe asthma (omalizumab, mepolizumab, Reslizumab) http://ow.ly/pygw30gB7Bv
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stratification of eosinophilic asthma patients treated with Reslizumab and gina step 4 or 5 therapy
ERJ Open Research, 2017Co-Authors: Guy Brusselle, Sivan Weiss, Janice Canvin, R BuhlAbstract:Reslizumab, an anti-interleukin-5 monoclonal antibody, significantly reduces exacerbation frequency and improves lung function, asthma control and quality of life in adults with severe eosinophilic asthma, as demonstrated in Phase III studies. This secondary analysis assessed Reslizumab's efficacy in patients receiving baseline treatment per Global Initiative for Asthma (GINA) Step 4 and Step 5 guidelines. Pooled data from duplicate, Phase III, Reslizumab versus placebo studies in patients with severe eosinophilic asthma (blood eosinophils ≥400 cells·µL-1) were stratified by baseline therapy. Efficacy assessments were exacerbation rates and changes from baseline forced expiratory volume in 1 s (FEV1) and patient-reported outcomes. Of 953 patients, 69% (n=657) and 11% (n=106) were receiving Step 4 and Step 5 therapy, respectively. Compared with placebo, Reslizumab reduced exacerbation rates by 53% (95% CI 0.36-0.62) and 72% (95% CI 0.15-0.52), in Step 4 and Step 5 groups respectively. By study end, Reslizumab increased FEV1 in Step 4 and Step 5 groups by 103 mL (95% CI 52-154 mL) and 237 mL (95% CI 68-407 mL), respectively. Reslizumab also improved patient-reported outcomes compared with placebo in both groups. Reslizumab reduces exacerbation rates and improves lung function and patient-reported outcomes in patients with eosinophilic asthma receiving therapy per Steps 4 and 5 of the GINA guidelines.
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Reslizumab in eosinophilic asthma a review
Drugs, 2017Co-Authors: Emma D Deeks, Guy BrusselleAbstract:Reslizumab (Cinqaero®; Cinqair®) is a humanized monoclonal antibody against interleukin-5 (IL-5), a cytokine mediator of eosinophilic airway inflammation. Reslizumab is indicated as an add-on treatment for severe eosinophilic asthma in adults, on the basis of data from the BREATH phase III clinical trial programme. In three double-blind BREATH studies of up to 52 weeks’ duration, adding intravenous Reslizumab (3 mg/kg, once every 4 weeks) to the current asthma therapy of patients (aged 12–75 years) with eosinophilic asthma inadequately controlled with inhaled corticosteroids resulted in significant reductions in clinical asthma exacerbation frequency and significant improvements in lung function, asthma control and health-related quality of life relative to adding placebo. Pooled data from the two trials of 52 weeks’ duration indicated similar benefits with Reslizumab across various patient subgroups, including patients with severe eosinophilic asthma. Reslizumab was generally well tolerated, with very few recipients experiencing severe or serious treatment-related adverse events. Moreover, in an open-label extension study, continued use of Reslizumab for up to 2 years was associated with durable lung function benefit, without any new tolerability concerns. Thus, intravenous Reslizumab extends the valuable add-on treatment options for adults with severe eosinophilic asthma inadequately controlled with standard therapies.
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Reslizumab in patients with inadequately controlled late onset asthma and elevated blood eosinophils
Pulmonary Pharmacology & Therapeutics, 2017Co-Authors: Guy Brusselle, Matthew Germinaro, Sivan Weiss, James ZangrilliAbstract:Abstract Introduction Asthma with adult onset and elevated blood eosinophils is a difficult-to-treat subgroup. This post hoc analysis evaluated Reslizumab, an anti-interleukin-5 monoclonal antibody, in patients with late-onset eosinophilic asthma. Methods Data from two 52-week placebo-controlled trials of Reslizumab IV 3 mg/kg every 4 weeks in patients aged 12–75 years with inadequately controlled asthma, ≥1 asthma exacerbation within 12 months, and screening blood eosinophils ≥400/μL (NCT01287039/NCT01285323) were stratified by age of asthma onset ( Results 273 patients with late-onset asthma (placebo, n = 130; Reslizumab, n = 143) and 658 with early-onset asthma (placebo, n = 336; Reslizumab, n = 322) were included. Baseline demographics were similar between groups. The interaction between age at onset of asthma and effect of Reslizumab on asthma exacerbations was statistically significant (p = 0.0083). Compared with placebo, Reslizumab produced a 75% relative reduction in asthma exacerbations in patients with late-onset asthma (rate ratio [RR] 0.25; 95% confidence interval [CI], 0.16, 0.40), substantially larger than the reduction in earlier onset patients (RR 0.58; 95% CI, 0.44, 0.76). Similar findings were observed for other measures of asthma, including forced expiratory volume in 1 s (FEV 1 ). The adverse event profile of Reslizumab was similar in patients with early- or late-onset asthma. Conclusions Compared with placebo, Reslizumab produced larger reductions in asthma exacerbations and larger improvements in lung function in patients with late versus early-onset asthma.
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effect of fixed dose subcutaneous Reslizumab on asthma exacerbations in patients with severe uncontrolled asthma and corticosteroid sparing in patients with oral corticosteroid dependent asthma results from two phase 3 randomised double blind placebo
The Lancet Respiratory Medicine, 2020Co-Authors: Jonathan A Bernstein, Kevin R Murphy, Joshua J Jacobs, Mario Castro, Christian J Virchow, Jorge Maspero, Yochai Adir, Marc Humbert, Douglas A Marsteller, Jennifer McelhattanAbstract:Summary Background Reslizumab 3 mg/kg administered intravenously is approved for the treatment of severe eosinophilic asthma. We assessed the safety and efficacy of subcutaneous Reslizumab 110 mg in two trials in patients with uncontrolled severe asthma and increased blood eosinophils. The aim was to establish whether subcutaneous Reslizumab 110 mg can reduce exacerbation rates in these patients (study 1) or reduce maintenance oral corticosteroid dose in patients with corticosteroid-dependent asthma (study 2). Methods Both studies were randomised, double-blind, placebo-controlled, phase 3 studies. Entry criteria for study 1 were uncontrolled severe asthma, two or more asthma exacerbations in the previous year, a blood eosinophil count of 300 cells per μL or more (including no more than 30% patients with an eosinophil count ClinicalTrials.gov , NCT02452190 (study 1) and NCT02501629 (study 2). Findings Between Aug 12, 2015, and Jan 31, 2018, 468 patients in study 1 were randomly assigned to placebo (n=232) or subcutaneous Reslizumab (n=236), and 177 in study 2 to placebo (n=89) or subcutaneous Reslizumab (n=88). In study 1, we found no significant difference in the exacerbation rate between Reslizumab and placebo in the intention-to-treat population (rate ratio 0·79, 95% CI 0·56–1·12; p=0·19). Subcutaneous Reslizumab reduced exacerbation frequency compared with placebo in the subgroup of patients with blood eosinophil counts of 400 cells per μL or more (0·64, 95% CI 0·43–0·95). Greater reductions in annual exacerbation risk (p=0·0035) and longer time to first exacerbation were observed for patients with higher trough serum Reslizumab concentrations. In study 2, we found no difference between placebo and fixed-dose subcutaneous Reslizumab in categorised percentage reduction in daily oral corticosteroid dose (odds ratio for a lower category of oral corticosteroid use in the Reslizumab group vs the placebo group, 1·23, 95% CI 0·70–2·16; p=0·47). The frequency of adverse events and serious adverse events with Reslizumab were similar to those with placebo in both studies. Interpretation Fixed-dose (110 mg) subcutaneous Reslizumab was not effective in reducing exacerbation frequency in patients with uncontrolled asthma and increased blood eosinophils (≥300 cells/μL), or in reducing the daily maintenance oral corticosteroid dose in patients with oral corticosteroid-dependent severe eosinophilic asthma. Higher exposures than those observed with 110 mg subcutaneous Reslizumab are required to achieve maximal efficacy. Funding Teva Branded Pharmaceutical Products R&D.
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Reslizumab in the treatment of inadequately controlled asthma in adults and adolescents with elevated blood eosinophils clinical trial evidence and future prospects
Therapeutic Advances in Respiratory Disease, 2017Co-Authors: Jorge MasperoAbstract:Eosinophils have long been implicated as playing a central role in the pathophysiology of asthma in many patients, and eosinophilic asthma is now recognized as an important asthma endotype. Eosinophil differentiation, maturation, migration, and survival are primarily under the control of interleukin-5 (IL-5). Reslizumab is a humanized monoclonal (immunoglobulin G4/κ) antibody that binds with high affinity to circulating human IL-5 and downregulates the IL-5 signaling pathway, potentially disrupting the maturation and survival of eosinophils. In 2016, an intravenous formulation of Reslizumab was approved in the USA, Canada, and Europe as add-on maintenance treatment for patients aged ⩾18 years with severe asthma and with an eosinophilic phenotype. The efficacy of Reslizumab as add-on intravenous therapy has been reported in several phase III studies in patients with inadequately controlled moderate-to-severe asthma and elevated blood eosinophil counts (⩾400 cells/µl). Compared with placebo, Reslizumab was ...
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Reslizumab for inadequately controlled asthma with elevated blood eosinophil levels a randomized phase 3 study
Chest, 2016Co-Authors: Leif Bjermer, James Zangrilli, Jorge Maspero, Sivan Weiss, Catherine Lemiere, Matthew GerminaroAbstract:Background This phase 3 study further characterizes the efficacy and safety of Reslizumab (a humanized anti-IL-5 monoclonal antibody) in patients aged 12 to 75 years with asthma inadequately controlled by at least a medium-dose inhaled corticosteroid and with a blood eosinophil count ≥ 400 cells/μL. Methods Patients were randomized to receive Reslizumab 0.3 or 3.0 mg/kg or placebo administered once every 4 weeks for 16 weeks (total four doses). The primary end point was change from baseline in pre-bronchodilator FEV 1 over 16 weeks. Secondary end points included FVC, forced expiratory flow at 25% to 75% of FVC (FEF 25%-75% ), patient-reported control of asthma symptoms, short-acting β-agonist (SABA) use, blood eosinophil levels, and safety. Results Reslizumab significantly improved FEV 1 (difference vs placebo [Reslizumab 0.3 and 3.0 mg/kg], 115 mL [95% CI, 16-215; P = .0237] and 160 mL [95% CI, 60-259; P = .0018]). Clinically meaningful increases in FVC (130 mL) and FEF 25%-75% (233 mL/s) were observed with Reslizumab 3.0 mg/kg. Reslizumab improved scores on the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ) vs placebo (greater effects seen with 3.0 mg/kg; P Conclusions Reslizumab improved lung function, asthma control and symptoms, and quality of life. It was well tolerated in patients with inadequately controlled asthma (despite standard therapy) and elevated blood eosinophil levels. Overall, the 3.0-mg/kg dose of Reslizumab provided greater improvements in asthma outcomes vs the 0.3-mg/kg dose, with comparable safety. Trial Registry ClinicalTrials.gov; No.: NCT01270464; URL: www.clinicaltrials.gov.
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Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts results from two multicentre parallel double blind randomised placebo controlled phase 3 trials
The Lancet Respiratory Medicine, 2015Co-Authors: Mario Castro, Kevin R Murphy, James Zangrilli, Jorge Maspero, Guy Brusselle, Philip G Bardin, Eric D Bateman, Michael E Wechsler, C D Obrien, Stephanie KornAbstract:Summary Background Elevated numbers of blood eosinophils are a risk factor for asthma exacerbations. Reslizumab is a humanised anti-interleukin 5 monoclonal antibody that disrupts eosinophil maturation and promotes programmed cell death. We aimed to assess the efficacy and safety of Reslizumab in patients with inadequately controlled, moderate-to-severe asthma. Methods We did two duplicate, multicentre, double-blind, parallel-group, randomised, placebo-controlled phase 3 trials. Both trials enrolled patients with asthma aged 12–75 years (from 128 clinical research centres in study 1 and 104 centres in study 2) from Asia, Australia, North America, South America, South Africa, and Europe, whose asthma was inadequately controlled by medium-to-high doses of inhaled corticosteroid based therapy and who had blood eosinophils of 400 cells per μL or higher and one or more exacerbations in the previous year. Patients were randomly assigned (1:1) to receive either intravenous Reslizumab (3·0 mg/kg) or placebo every 4 weeks for 1 year by computerised central randomisation. Patients and investigators were masked to treatment assignment during the study. Each patient received a specific volume of study drug (Reslizumab or matching placebo) on the basis of the patient's body weight and randomly assigned treatment group. Additionally, the sponsor's clinical personnel involved in the study were masked to the study drug identity until the database was locked for analysis and the treatment assignment revealed. The primary outcome was the annual frequency of clinical asthma exacerbations and was analysed by intention to treat. We assessed safety outcomes in the patients who had received one or more dose of the drug. The trials have been completed and are registered with ClinicalTrials.gov, numbers NCT01287039 (study 1) and NCT01285323 (study 2). Findings Study 1 was done between April 12, 2011, and March 3, 2014 and study 2 between March 22, 2011, and April 9, 2014. Of 2597 patients screened, 953 were randomly assigned to receive either Reslizumab (n=477 [245 in study 1 and 232 in study 2]) or placebo (n=476 [244 and 232]). In both studies, patients receiving Reslizumab had a significant reduction in the frequency of asthma exacerbations (study 1: rate ratio [RR] 0·50 [95% CI 0·37–0·67]; study 2: 0·41 [0·28–0·59]; both p Interpretation These results support the use of Reslizumab in patients with asthma and elevated blood eosinophil counts who are inadequately controlled on inhaled corticosteroid-based therapy. Funding Teva Branded Pharmaceutical Products R&D.
