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Hector Ortega - One of the best experts on this subject based on the ideXlab platform.

  • real world effectiveness of Mepolizumab in patients with severe asthma an examination of exacerbations and costs
    Journal of Asthma and Allergy, 2020
    Co-Authors: Jean-pierre Llanos, Hector Ortega, Michael Bogart, E. Packnett, Janna Manjelievskaia, Christopher F Bell, Beth Hahn
    Abstract:

    Rationale Results from clinical trials in patients with severe eosinophilic asthma have demonstrated that Mepolizumab is well tolerated and is associated with improved asthma control as evidenced by reductions in both exacerbations and maintenance oral corticosteroid use, and improvements in lung function, asthma control, and quality of life. However, real-world data are lacking on the impact of Mepolizumab treatment. Objective To assess the effect of Mepolizumab treatment on the rate of asthma exacerbations and asthma exacerbation-related costs in a real-world setting. Methods This retrospective cohort study (GSK ID: 209017; HO-18-19168) analyzed data from patients with severe asthma ≥12 years of age at Mepolizumab treatment initiation (index date) with ≥12 months pre- (baseline) and post-index (follow-up) data from a commercial claims database (patients were identified from November 1, 2015 to March 31, 2017). Asthma exacerbations (primary objective) and asthma exacerbation-related costs (secondary objective) in the baseline and follow-up periods were compared. Other analyses included the number of Mepolizumab administrations and the use of concomitant asthma medications. Results Data were analyzed from 346 patients. Mepolizumab significantly reduced the proportion of patients with any exacerbation and exacerbations requiring hospitalization, compared with baseline. Significant reductions in the rate of all exacerbations of 38.4% (from 2.68 to 1.65 events/patient/year; P<0.001) and of exacerbations requiring hospitalization of 72.7% (from 0.11 to 0.03 events/patient/year; P=0.004) were observed, compared with baseline. Mean total asthma exacerbation-related costs (excluding Mepolizumab acquisition and administrative costs) per person were significantly lower during follow-up compared with baseline (P<0.05) and the use of asthma medications, including oral and inhaled corticosteroids, was also lower. Conclusion This study confirms the clinical benefit observed in previous Mepolizumab clinical trials and demonstrates that Mepolizumab is effective in a real-world setting.

  • Real-World Effectiveness of Mepolizumab in Patients with Severe Asthma: An Examination of Exacerbations and Costs.
    Journal of asthma and allergy, 2020
    Co-Authors: Jean-pierre Llanos, Hector Ortega, Michael Bogart, E. Packnett, Janna Manjelievskaia, Christopher F Bell, Beth Hahn
    Abstract:

    Rationale Results from clinical trials in patients with severe eosinophilic asthma have demonstrated that Mepolizumab is well tolerated and is associated with improved asthma control as evidenced by reductions in both exacerbations and maintenance oral corticosteroid use, and improvements in lung function, asthma control, and quality of life. However, real-world data are lacking on the impact of Mepolizumab treatment. Objective To assess the effect of Mepolizumab treatment on the rate of asthma exacerbations and asthma exacerbation-related costs in a real-world setting. Methods This retrospective cohort study (GSK ID: 209017; HO-18-19168) analyzed data from patients with severe asthma ≥12 years of age at Mepolizumab treatment initiation (index date) with ≥12 months pre- (baseline) and post-index (follow-up) data from a commercial claims database (patients were identified from November 1, 2015 to March 31, 2017). Asthma exacerbations (primary objective) and asthma exacerbation-related costs (secondary objective) in the baseline and follow-up periods were compared. Other analyses included the number of Mepolizumab administrations and the use of concomitant asthma medications. Results Data were analyzed from 346 patients. Mepolizumab significantly reduced the proportion of patients with any exacerbation and exacerbations requiring hospitalization, compared with baseline. Significant reductions in the rate of all exacerbations of 38.4% (from 2.68 to 1.65 events/patient/year; P

  • Outcomes following Mepolizumab treatment discontinuation: real-world experience from an open-label trial.
    Allergy Asthma & Clinical Immunology, 2019
    Co-Authors: Hector Ortega, Frank C Albers, Catherine Lemière, Jean-pierre Llanos, Mark Forshag, Steven W. Yancey, Robert Price, Mario Castro
    Abstract:

    Limited information is available on the clinical course of patients with severe asthma following discontinuation of biologic treatment. Therefore, a post hoc analysis was conducted in patients with severe eosinophilic asthma who participated in the COSMOS trial, where patients received Mepolizumab for more than 1 year of continuous therapy. The objective of this post hoc analysis was to evaluate changes in the Asthma Control Questionnaire (ACQ-5) and blood eosinophil counts 12 weeks after the last administration of Mepolizumab. Cessation of Mepolizumab was associated with a rise in the blood eosinophil count and loss of asthma control after stopping therapy. These data suggest that patients with severe disease require extended and continuous treatment. Further studies evaluating longer duration of continuous treatment with Mepolizumab could help understanding of whether changes in the presentation of the disease (disease modification) are possible with the use of biologics, such as Mepolizumab.

  • long term clinical outcomes of high dose Mepolizumab treatment for hypereosinophilic syndrome
    The Journal of Allergy and Clinical Immunology: In Practice, 2018
    Co-Authors: Fei Li Kuang, Hector Ortega, Michael P Fay, Jean Anne Ware, Lauren Wetzler, Nicole Hollandthomas, Thomas L Brown, Jonathan Steinfeld, Paneez Khoury, Amy D Klion
    Abstract:

    Background Conventional therapies for hypereosinophilic syndromes (HES) have variable efficacy and carry significant long-term toxicities. Anti-IL-5 (Mepolizumab) therapy has a glucocorticoid (GC)-sparing effect in GC-sensitive HES, but the efficacy of Mepolizumab in treatment-refractory HES patients with severe disease has not been examined to date. Objective To identify predictors of response to Mepolizumab in subjects with severe treatment-refractory HES and compare long-term outcomes in these subjects with HES subjects treated with conventional therapies. Methods Retrospective analysis of clinical and laboratory data from 35 HES subjects treated with Mepolizumab and 55 HES subjects on conventional therapy, all followed at a single center, was performed. Results Peak eosinophilia, GC sensitivity, pulmonary involvement, HES clinical subtype, and pretreatment serum IL-5 were correlated with Mepolizumab response. Despite evidence of more severe disease at baseline, Mepolizumab-treated subjects had comparable long-term clinical outcomes to HES subjects treated with conventional therapies and reported improvements in therapy-related comorbidities. Subjects managed with Mepolizumab monotherapy had fewer disease flares than HES subjects on conventional therapies or Mepolizumab-treated HES subjects requiring additional HES therapies. Conclusions This study confirms that Mepolizumab is an effective and well-tolerated therapy for HES, but suggests that response is more likely in GC-responsive subjects with idiopathic or overlap forms of HES. A primary benefit of treatment is the reduction of comorbidity due to discontinuation or the reduction of conventional HES therapies. Although subjects who completely discontinued GC had the most benefit, high-dose Mepolizumab was a safe and effective salvage therapy for severe, treatment-refractory HES.

  • Efficacy and safety of Mepolizumab in Japanese patients with severe eosinophilic asthma.
    Allergology international : official journal of the Japanese Society of Allergology, 2017
    Co-Authors: Terufumi Shimoda, Steven W. Yancey, Bhabita Mayer, Hiroshi Odajima, Arisa Okamasa, Minako Kawase, Masaki Komatsubara, Hector Ortega
    Abstract:

    Abstract Background The MENSA trial assessed the efficacy and safety of Mepolizumab in patients with severe eosinophilic asthma. This report describes the efficacy and safety of Mepolizumab in Japanese patients from MENSA. Methods A post hoc analysis of the Japanese subgroup from the randomized, double-blind, placebo-controlled, double-dummy, Phase III MENSA trial (NCT01691521). Patients ≥12 years with severe eosinophilic asthma received Mepolizumab 75 mg intravenously (IV), 100 mg subcutaneously (SC), or placebo, every 4 weeks for 32 weeks. The primary endpoint was the annualized rate of exacerbations. Secondary and other endpoints included annualized rate of exacerbations requiring emergency department (ED) visit/hospitalization, morning peak expiratory flow (PEF), St George's Respiratory Questionnaire (SGRQ) score and eosinophil counts. Adverse events (AEs) were monitored. Results In the Japanese subgroup ( N  = 50), the rate of clinically significant exacerbations was reduced by 90% (rate ratio [RR]: 0.10; 95% confidence interval [CI]: 0.02–0.57; P  = 0.010) with Mepolizumab IV and 62% (RR: 0.38; 95% CI: 0.12–1.18; P  = 0.094) with Mepolizumab SC, versus placebo. No exacerbations requiring ED visit/hospitalization were reported with Mepolizumab IV; exacerbations were reduced by 73% (RR: 0.27; 95% CI: 0.06–1.29; P  = 0.102) with Mepolizumab SC versus placebo. Compared with placebo, Mepolizumab IV and SC numerically increased morning PEF from baseline by 40 L/min and 13 L/min, improved quality of life by greater than the minimal clinically important difference (SGRQ: 9.5 [ P  = 0.083] and 7.9 [ P  = 0.171] points) and reduced eosinophil counts. AE incidence was similar between treatments. Results were broadly consistent with the overall population. Conclusions Mepolizumab was efficacious and well tolerated in Japanese patients with severe eosinophilic asthma, producing similar responses to the overall MENSA population.

Frank C Albers - One of the best experts on this subject based on the ideXlab platform.

  • Response to Mepolizumab treatment is sustained across 4-weekly dosing periods.
    ERJ open research, 2020
    Co-Authors: Ian D. Pavord, Frank C Albers, Roland Buhl, Peter H Howarth, Pascal Chanez, Daniel J Bratton, Elisabeth H. Bel, Eugene R. Bleecker, Steven W. Yancey
    Abstract:

    Background Mepolizumab (100 mg delivered s.c. every 4 weeks) is indicated for add-on maintenance treatment for patients with severe eosinophilic asthma. Mepolizumab has been shown to reduce exacerbations and the requirement for daily oral corticosteroids, and improve asthma control and symptoms. However, data on the durability of the response to Mepolizumab during dosing periods are limited. The aim of this study was to investigate the efficacy profile in patients with severe eosinophilic asthma over the 4-weekly dosing period for various fixed Mepolizumab doses. Methods This was a post hoc analysis of data from the phase IIb/III DREAM study. Patients ≥12 years of age with severe eosinophilic asthma were randomised (1:1:1:1) to receive intravenous Mepolizumab 75 mg (equivalent to 100 mg s.c.), 250 mg, 750 mg or placebo, plus standard of care, every 4 weeks for 52 weeks. The number of exacerbations and eDiary data (peak expiratory flow, rescue medication use and symptom scores) from two periods in each 4-weekly dosing interval (days 1–14 and 15–28) over the 52-week treatment period were analysed. Findings eDiary data and the proportion of patients experiencing ≥1 exacerbation were similar during the first and second 2 weeks of a dosing period across all Mepolizumab doses. Interpretation These results demonstrate that the response to Mepolizumab is sustained over the 4-weekly dosing period with no differences across a 10-fold dose range and supports the use of the current Mepolizumab dosing regimen in patients with severe eosinophilic asthma.

  • baseline blood eosinophil count as a predictor of treatment response to the licensed dose of Mepolizumab in severe eosinophilic asthma
    Respiratory Medicine, 2019
    Co-Authors: Frank C Albers, Steven W. Yancey, Christopher Licskai, Pascal Chanez, Daniel J Bratton, Eric S Bradford, Namhee Kwon, Santiago Quirce
    Abstract:

    Abstract Background Previous analyses examining the relationship between blood eosinophil count and Mepolizumab treatment effects in severe eosinophilic asthma have used a range of doses and administration routes. Methods This post hoc meta-analysis included data from the MENSA (MEA115588/NCT01691521) and MUSCA (200862/NCT02281318) trials. Patients (≥12 years) with severe eosinophilic asthma who experienced ≥2 exacerbations in the prior year received either Mepolizumab 100 mg subcutaneously (SC) or 75 mg intravenously, or placebo plus standard of care every 4 weeks. This meta-analysis reports data from patients receiving the licensed dose of Mepolizumab (100 mg SC) or placebo only. The primary endpoint was the annual rate of clinically significant exacerbations; secondary endpoints included rate of exacerbations requiring hospitalization/emergency room (ER) visit, proportion of patients with no clinically significant exacerbations, and changes from baseline in forced expiratory volume in 1 s, Asthma Control Questionnaire-5 and St George's Respiratory Questionnaire scores. Analyses were stratified by baseline blood eosinophil count ( Results Mepolizumab reduced annual clinically significant exacerbation rates by 45%–85%, exacerbations requiring hospitalization/ER visit by 60%–70%, and increased the odds of no clinically significant exacerbations across all eosinophil threshold subgroups versus placebo, and improved all other secondary endpoints in subgroups ≥150 cells/μL. Greater treatment effects with increasing blood eosinophil count were observed. Conclusions Mepolizumab demonstrated consistent clinical benefits in patients with baseline blood eosinophil counts ≥150 cells/μL, confirming the suitability of this cut-off for identifying patients responsive to the licensed Mepolizumab dose.

  • Durability of Mepolizumab treatment response between doses
    Airway pharmacology and treatment, 2019
    Co-Authors: Ian D. Pavord, Frank C Albers, Peter H Howarth, Daniel J Bratton, Steven W. Yancey
    Abstract:

    Background: Mepolizumab (100 mg delivered subcutaneously every 4 weeks) is approved for use in patients with severe eosinophilic asthma (SEA) and has been shown to reduce exacerbations and improve asthma symptoms vs placebo. There are limited data on the durability of the response to Mepolizumab between doses. Aim: To investigate the efficacy profile in patients with SEA over the 4-week dosing period for various fixed doses of Mepolizumab. Methods: This was a post hoc analysis of data from the Phase IIb DREAM trial. Patients with SEA ≥12 years of age were randomised (1:1:1:1) to receive Mepolizumab 75 mg (equivalent to 100 mg SC), 250 mg or 750 mg, or placebo intravenously (IV) every 4 weeks for 52 weeks. Mean daily peak expiratory flow (PEF) and symptom scores recorded as diary data were compared between days 1–14 and 15–28 days (periods 1 and 2, respectively) in each successive 4-weekly dosing period. Results: All three doses of Mepolizumab showed a similar effect on PEF and symptoms during periods 1 and 2. The number of patients whose symptoms increased by ≥1 point in period 2 vs period 1 was similar to placebo. Conclusions: These results demonstrate the durability of the response to Mepolizumab between doses and that Mepolizumab 75 mg IV has a similar efficacy profile over the 4-weekly dosing period compared with higher doses. Further analysis is needed to determine whether other outcomes show a similar trend. Funding: GSK [MEA112997;NCT01000506].

  • long term safety and clinical benefit of Mepolizumab in patients with the most severe eosinophilic asthma the cosmex study
    Clinical Therapeutics, 2019
    Co-Authors: Sandhya Khurana, Frank C Albers, Eric S Bradford, Elisabeth H. Bel, Guy Brusselle, Mark J Fitzgerald, Matthew Masoli, Stephanie Korn, Motokazu Kato, Martyn J. Gilson
    Abstract:

    Abstract Purpose The goal of this study was to assess the long-term safety and efficacy of Mepolizumab in patients with the most severe eosinophilic asthma. Methods This multicenter, open-label, long-term, Phase IIIb study (COSMEX [COSMOS Extension]; 201312/NCT02135692) enrolled patients from the 52-week, open-label extension study COSMOS (A Study to Determine Long-term Safety of Mepolizumab in Asthmatic Subjects) that previously enrolled patients from the double-blinded, placebo-controlled Phase III studies MENSA (Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma) and SIRIUS (Steroid Reduction with Mepolizumab Study). To enter COSMEX, patients had to have life-threatening/seriously debilitating asthma before entering MENSA or SIRIUS and to have completed these previous studies with demonstrated improvement while receiving Mepolizumab. In COSMEX, patients received Mepolizumab 100 mg subcutaneously every 4 weeks as add-on therapy for up to 172 weeks. Primary endpoints were adverse event frequency and exacerbation rate per year; also assessed were forced expiratory volume in 1 s, Asthma Control Questionnaire-5 score, and daily oral corticosteroid (OCS) use. Findings Of the 340 patients enrolled, 339 received Mepolizumab; median treatment duration within this extension study was 2.2 years, equating to 718 patient-years of additional exposure. No new safety signals were identified. Patients receiving Mepolizumab throughout this study and previous studies had lasting reductions in exacerbation rate and daily OCS use and improvements in forced expiratory volume in 1 s and Asthma Control Questionnaire-5 score. In COSMEX, the on-treatment exacerbation rate (95% CI) was 0.93 (0.81–1.06) event/year for clinically significant exacerbations, 0.13 (0.10–0.18) event/year for exacerbations requiring hospitalization/emergency department visit, and 0.07 (0.05–0.10) event/year for exacerbations requiring hospitalization. In patients requiring systemic/oral corticosteroids with ≥128 weeks of continuous enrollment across SIRIUS, COSMOS, and COSMEX, Mepolizumab maintained the median daily OCS dose at 1.3–2.8 mg during COSMEX, with additional patients no longer requiring OCS after extended Mepolizumab treatment. Implications This study indicates that long-term Mepolizumab treatment is well tolerated and associated with sustained clinical benefits in patients with severe eosinophilic asthma. ClinicalTrials.gov identifier: NCT02135692.

  • Outcomes following Mepolizumab treatment discontinuation: real-world experience from an open-label trial.
    Allergy Asthma & Clinical Immunology, 2019
    Co-Authors: Hector Ortega, Frank C Albers, Catherine Lemière, Jean-pierre Llanos, Mark Forshag, Steven W. Yancey, Robert Price, Mario Castro
    Abstract:

    Limited information is available on the clinical course of patients with severe asthma following discontinuation of biologic treatment. Therefore, a post hoc analysis was conducted in patients with severe eosinophilic asthma who participated in the COSMOS trial, where patients received Mepolizumab for more than 1 year of continuous therapy. The objective of this post hoc analysis was to evaluate changes in the Asthma Control Questionnaire (ACQ-5) and blood eosinophil counts 12 weeks after the last administration of Mepolizumab. Cessation of Mepolizumab was associated with a rise in the blood eosinophil count and loss of asthma control after stopping therapy. These data suggest that patients with severe disease require extended and continuous treatment. Further studies evaluating longer duration of continuous treatment with Mepolizumab could help understanding of whether changes in the presentation of the disease (disease modification) are possible with the use of biologics, such as Mepolizumab.

Steven W. Yancey - One of the best experts on this subject based on the ideXlab platform.

  • Response to Mepolizumab treatment is sustained across 4-weekly dosing periods.
    ERJ open research, 2020
    Co-Authors: Ian D. Pavord, Frank C Albers, Roland Buhl, Peter H Howarth, Pascal Chanez, Daniel J Bratton, Elisabeth H. Bel, Eugene R. Bleecker, Steven W. Yancey
    Abstract:

    Background Mepolizumab (100 mg delivered s.c. every 4 weeks) is indicated for add-on maintenance treatment for patients with severe eosinophilic asthma. Mepolizumab has been shown to reduce exacerbations and the requirement for daily oral corticosteroids, and improve asthma control and symptoms. However, data on the durability of the response to Mepolizumab during dosing periods are limited. The aim of this study was to investigate the efficacy profile in patients with severe eosinophilic asthma over the 4-weekly dosing period for various fixed Mepolizumab doses. Methods This was a post hoc analysis of data from the phase IIb/III DREAM study. Patients ≥12 years of age with severe eosinophilic asthma were randomised (1:1:1:1) to receive intravenous Mepolizumab 75 mg (equivalent to 100 mg s.c.), 250 mg, 750 mg or placebo, plus standard of care, every 4 weeks for 52 weeks. The number of exacerbations and eDiary data (peak expiratory flow, rescue medication use and symptom scores) from two periods in each 4-weekly dosing interval (days 1–14 and 15–28) over the 52-week treatment period were analysed. Findings eDiary data and the proportion of patients experiencing ≥1 exacerbation were similar during the first and second 2 weeks of a dosing period across all Mepolizumab doses. Interpretation These results demonstrate that the response to Mepolizumab is sustained over the 4-weekly dosing period with no differences across a 10-fold dose range and supports the use of the current Mepolizumab dosing regimen in patients with severe eosinophilic asthma.

  • Characterising individual response to Mepolizumab treatment
    Airway pharmacology and treatment, 2020
    Co-Authors: David J. Jackson, Roland Buhl, Steven W. Yancey, R Price, Sally E. Wenzel
    Abstract:

    Background: Patients with severe eosinophilic asthma (SEA) often have heterogenous phenotypes with periods of asthma worsening, making it difficult to assess Mepolizumab treatment response. Aims: To define patient level variables for Mepolizumab treatment response. Methods: In this post-hoc analysis we examined Mepolizumab response in patients with SEA (≥2 exacerbations in prior year) in the 32-week, randomised, placebo-controlled MENSA study and the following 52-week, open-label COSMOS study. Patients who completed both studies and received Mepolizumab throughout were included (n=311). Results: In MENSA, 67% and 21% of patients had 0 or 1 exacerbations, respectively, and were considered responders; 12% (n=37) with ≥2 exacerbations were considered non-responders and assessed against four variables of clinical benefit. Of these non-responders, 89% (n=33) had evidence of response when other variables were assessed (Table). Of the 37 non-responders in MENSA, 38% (n=14) responded in COSMOS, having either 0 (n=3) or 1 (n=11) exacerbations. Conclusions: These data highlight the difficulty in defining individual response to Mepolizumab treatment. Responder classification should ideally take into account several clinical measures of improvement beyond exacerbation reduction. The relative importance of each of these measures may differ between patients, therefore doctors should set realistic treatment goals with each patient. Funding: GSK[NCT01691521/NCT01842607]

  • efficacite et tolerance a long terme de Mepolizumab chez les enfants âges de 6 a 11 ans atteints d asthme severe a eosinophiles
    Revue des Maladies Respiratoires Actualités, 2020
    Co-Authors: A Gruber, Eric S Bradford, R Price, Jonathan Steinfeld, Atul Gupta, I Masonori, Bob Geng, J Azmi, Steven W. Yancey
    Abstract:

    Introduction Le Mepolizumab est approuve pour le traitement de l’asthme severe a eosinophiles (ASE) chez les adultes et, dans certaines regions, chez les adolescents (12–17 ans). En aout 2018, l’Agence europeenne des medicaments a approuve le Mepolizumab a 40 mgSC pour les enfants de 6 a 11 ans avec un ASE. L’efficacite et la tolerance du Mepolizumab a long terme chez les enfants de 6 a 11 ans n’ont pas ete evaluees. Methodes Il s’agissait d’une etude ouverte, non controlee avec 2 parties A et B, chez les enfants atteint d’ASE. Les patients ayant termine la partie A (semaine 0–20) de l’etude sur la pharmacocinetique et pharmacodynamique etaient eligibles a la partie B de 52 semaines (semaine 20–72) de l’etude pour evaluer la tolerance et la pharmacodynamie a long terme du Mepolizumab. Dans la partie B, les patients ont recu 40 mgSC de Mepolizumab si   40 kg en plus de leur traitement de fond de depart. La dose de Mepolizumab etait augmentee a 100 mgSC si le patient atteignait 40 kg pendant la phase B. Les criteres d’evaluation comprenaient le taux d’exacerbations, le controle de l’asthme et la tolerance. Resultats Trente patients sont entres dans la partie B et 29 ont termine les 52 semaines de traitement. Une amelioration du controle de l’asthme a ete observee via les questionnaires ACQ-7 et ACQ-5, avec respectivement 55 % et 59 % de repondeurs (amelioration ≥ 0,5 points par rapport a l’inclusion) a la visite de fin d’etude (semaine 72). Une augmentation du score ACT pour les enfants a ete egalement observee, qui montre une amelioration du controle de l’asthme et ce independamment du groupe de traitement (sur le poids des patients). Les taux annuels d’exacerbations pendant le traitement etaient inferieurs aux valeurs initiales pour chaque groupe. Dans l’ensemble, 80 % des sujets ont presente une reduction ≥ 50 % du taux d’exacerbations pendant la partie B par rapport a l’annee precedant l’inclusion. Le Mepolizumab a ete bien tolere dans la partie B, aucun nouveau probleme de tolerance n’a ete rapporte chez les enfants par rapport au profil de tolerance connu des adultes/adolescents. La bronchite (30 %) etait l’effet indesirable le plus souvent rapporte. Aucun patient n’a eu d’anticorps anti-Mepolizumab pendant la partie B ( Tableau 1 ). Conclusion Chez les enfants de 6 a 11 ans, le traitement par Mepolizumab a entraine pendant 52 semaines une amelioration du controle de l’asthme et une reduction du taux annuel d’exacerbations par rapport a l’annee precedant l’inclusion. Le Mepolizumab a ete bien tolere chez les enfants de 6 a 11 ans.

  • baseline blood eosinophil count as a predictor of treatment response to the licensed dose of Mepolizumab in severe eosinophilic asthma
    Respiratory Medicine, 2019
    Co-Authors: Frank C Albers, Steven W. Yancey, Christopher Licskai, Pascal Chanez, Daniel J Bratton, Eric S Bradford, Namhee Kwon, Santiago Quirce
    Abstract:

    Abstract Background Previous analyses examining the relationship between blood eosinophil count and Mepolizumab treatment effects in severe eosinophilic asthma have used a range of doses and administration routes. Methods This post hoc meta-analysis included data from the MENSA (MEA115588/NCT01691521) and MUSCA (200862/NCT02281318) trials. Patients (≥12 years) with severe eosinophilic asthma who experienced ≥2 exacerbations in the prior year received either Mepolizumab 100 mg subcutaneously (SC) or 75 mg intravenously, or placebo plus standard of care every 4 weeks. This meta-analysis reports data from patients receiving the licensed dose of Mepolizumab (100 mg SC) or placebo only. The primary endpoint was the annual rate of clinically significant exacerbations; secondary endpoints included rate of exacerbations requiring hospitalization/emergency room (ER) visit, proportion of patients with no clinically significant exacerbations, and changes from baseline in forced expiratory volume in 1 s, Asthma Control Questionnaire-5 and St George's Respiratory Questionnaire scores. Analyses were stratified by baseline blood eosinophil count ( Results Mepolizumab reduced annual clinically significant exacerbation rates by 45%–85%, exacerbations requiring hospitalization/ER visit by 60%–70%, and increased the odds of no clinically significant exacerbations across all eosinophil threshold subgroups versus placebo, and improved all other secondary endpoints in subgroups ≥150 cells/μL. Greater treatment effects with increasing blood eosinophil count were observed. Conclusions Mepolizumab demonstrated consistent clinical benefits in patients with baseline blood eosinophil counts ≥150 cells/μL, confirming the suitability of this cut-off for identifying patients responsive to the licensed Mepolizumab dose.

  • Durability of Mepolizumab treatment response between doses
    Airway pharmacology and treatment, 2019
    Co-Authors: Ian D. Pavord, Frank C Albers, Peter H Howarth, Daniel J Bratton, Steven W. Yancey
    Abstract:

    Background: Mepolizumab (100 mg delivered subcutaneously every 4 weeks) is approved for use in patients with severe eosinophilic asthma (SEA) and has been shown to reduce exacerbations and improve asthma symptoms vs placebo. There are limited data on the durability of the response to Mepolizumab between doses. Aim: To investigate the efficacy profile in patients with SEA over the 4-week dosing period for various fixed doses of Mepolizumab. Methods: This was a post hoc analysis of data from the Phase IIb DREAM trial. Patients with SEA ≥12 years of age were randomised (1:1:1:1) to receive Mepolizumab 75 mg (equivalent to 100 mg SC), 250 mg or 750 mg, or placebo intravenously (IV) every 4 weeks for 52 weeks. Mean daily peak expiratory flow (PEF) and symptom scores recorded as diary data were compared between days 1–14 and 15–28 days (periods 1 and 2, respectively) in each successive 4-weekly dosing period. Results: All three doses of Mepolizumab showed a similar effect on PEF and symptoms during periods 1 and 2. The number of patients whose symptoms increased by ≥1 point in period 2 vs period 1 was similar to placebo. Conclusions: These results demonstrate the durability of the response to Mepolizumab between doses and that Mepolizumab 75 mg IV has a similar efficacy profile over the 4-weekly dosing period compared with higher doses. Further analysis is needed to determine whether other outcomes show a similar trend. Funding: GSK [MEA112997;NCT01000506].

Ian D. Pavord - One of the best experts on this subject based on the ideXlab platform.

  • Response to Mepolizumab treatment is sustained across 4-weekly dosing periods.
    ERJ open research, 2020
    Co-Authors: Ian D. Pavord, Frank C Albers, Roland Buhl, Peter H Howarth, Pascal Chanez, Daniel J Bratton, Elisabeth H. Bel, Eugene R. Bleecker, Steven W. Yancey
    Abstract:

    Background Mepolizumab (100 mg delivered s.c. every 4 weeks) is indicated for add-on maintenance treatment for patients with severe eosinophilic asthma. Mepolizumab has been shown to reduce exacerbations and the requirement for daily oral corticosteroids, and improve asthma control and symptoms. However, data on the durability of the response to Mepolizumab during dosing periods are limited. The aim of this study was to investigate the efficacy profile in patients with severe eosinophilic asthma over the 4-weekly dosing period for various fixed Mepolizumab doses. Methods This was a post hoc analysis of data from the phase IIb/III DREAM study. Patients ≥12 years of age with severe eosinophilic asthma were randomised (1:1:1:1) to receive intravenous Mepolizumab 75 mg (equivalent to 100 mg s.c.), 250 mg, 750 mg or placebo, plus standard of care, every 4 weeks for 52 weeks. The number of exacerbations and eDiary data (peak expiratory flow, rescue medication use and symptom scores) from two periods in each 4-weekly dosing interval (days 1–14 and 15–28) over the 52-week treatment period were analysed. Findings eDiary data and the proportion of patients experiencing ≥1 exacerbation were similar during the first and second 2 weeks of a dosing period across all Mepolizumab doses. Interpretation These results demonstrate that the response to Mepolizumab is sustained over the 4-weekly dosing period with no differences across a 10-fold dose range and supports the use of the current Mepolizumab dosing regimen in patients with severe eosinophilic asthma.

  • late breaking abstract efficacy of oral prednisolone in patients with stable severe eosinophilic asthma sea treated with Mepolizumab
    European Respiratory Journal, 2020
    Co-Authors: J F Yang, Rahul Shrimanker, Christopher E. Brightling, Liam G. Heaney, Ian D. Pavord, John Busby, Katie Borg, Pamela Jane Mcdowell, Sarah Diver, S J Smith
    Abstract:

    Background: Mepolizumab and prednisolone have overlapping anti-inflammatory effects so the clinical effects of prednisolone might be absent in stable patients on treatment with Mepolizumab. Methods: We tested this hypothesis in a randomized, double-blind, placebo-controlled, crossover trial of prednisolone (0.5mg/kg/day for 2 weeks) after ≥12 weeks of Mepolizumab. Results: Blood and sputum eosinophil count decreased post-prednisolone (-0.02x109/L, p=0.003; -10.5x109/L, p=0.004); differences compared to placebo were -0.02x109/L (p Conclusions: In patients with SEA treated with Mepolizumab, prednisolone has no significant effects on symptoms or QoL but improves FEV1 and small airway function and reduces FeNO, potentially reflecting suppression of persisting IL-4/IL-13 pathways.

  • Clinical Development of Mepolizumab for the Treatment of Severe Eosinophilic Asthma: On The Path to Personalized Medicine
    The journal of allergy and clinical immunology. In practice, 2020
    Co-Authors: Ian D. Pavord, Roland Buhl, Pascal Chanez, Eric S Bradford, Oliver N. Keene, Andrew Menzies-gow, Mark T. Dransfield, Njira L Lugogo, Steve Yancey
    Abstract:

    The development of Mepolizumab, an anti-IL-5 monoclonal antibody for the treatment of severe eosinophilic asthma, is an example of a clinical development program that evolved over time based on sound, basic scientific principles. Initial clinical data on the effects of Mepolizumab on lung function in a general asthmatic population were disappointing. However, it became clear that Mepolizumab may be more effective against other clinical endpoints, particularly asthma exacerbations, in patients with more severe disease. Furthermore, a developing understanding of asthma disease pathobiology led to the identification of an appropriate target population and predictive biomarker for Mepolizumab treatment: patients with severe eosinophilic asthma and blood eosinophil count. Mepolizumab use provides clinically meaningful benefits in this target population, fulfilling an unmet need. This Clinical Commentary Review describes the clinical development of Mepolizumab and details of how this program informed the development of other biologic therapies in patients with severe asthma. This account highlights how a personalized approach toward treatment of patients with severe eosinophilic asthma, supported by a large body of scientific evidence, ultimately led to new and effective treatments and improved patient outcomes.

  • S51 Characterisation of exacerbations of severe eosinophilic asthma on Mepolizumab compared to placebo
    Increasing experience of biologics and asthma, 2019
    Co-Authors: Rahul Shrimanker, Daniel J Bratton, Liam G. Heaney, Oliver N. Keene, Sw Yancey, Ian D. Pavord
    Abstract:

    Mepolizumab reduces exacerbations of severe eosinophilic asthma. However, even with Mepolizumab treatment, exacerbations still occur in this population. We have previously shown that exacerbations on Mepolizumab are associated with lower sputum eosinophil counts and lower decrements in symptoms measured by the visual analogue scale compared to placebo. To further characterise exacerbations on Mepolizumab, we carried out a post-hoc comparison of exacerbations on treatment with Mepolizumab or placebo in three previously reported placebo-controlled trials. We investigated whether exacerbations in each group differ with respect to change in lung function and symptoms in the period before and after starting oral corticosteroid (OCS) rescue treatment. Methods Diary card data was reviewed from the 3 studies; DREAM, a 52-week study of 3 doses of Mepolizumab (75, 250 or 750 mg IV 4 weekly) versus placebo; MENSA, an 32-week study of 2 doses of Mepolizumab (75 mg IV or 100 mg s/c 4 weekly) versus placebo; and MUSCA, a 24-week study of Mepolizumab 100 mg s/c 4 weekly versus placebo. All studies recruited patients with severe eosinophilic asthma and a history of 2 or more exacerbations in the previous year. Mepolizumab dose groups were combined for analysis. Patients completed a daily diary card including a 6 point symptom score assessing asthma symptoms in the previous 24 hours and a best-of-three morning peak expiratory flow (PEF). Exacerbations requiring rescue OCS with at least 20 days of diary data in the period from 14 days prior to starting OCS (Day -14) to 14 days (Day 14) after starting OCS were included in the analysis. Results 1026 exacerbations were analysed. 476 occurred in 248 subjects on placebo and 550 occurred in 338 subjects on Mepolizumab. Exacerbations on placebo were associated with a larger drop in PEF (-41.0 L/min [95% CI -47.3, -34.7]) compared to Mepolizumab (-26.9 L/min [-32.7, -21.1]) over the 14 days prior to starting OCS. Exacerbations on placebo also tended to have a larger increase in daily symptom score compared to Mepolizumab (0.81 points [0.68, 0.94] vs 0.65 points [0.54, 0.76] respectively). Conclusion Exacerbations that occur on Mepolizumab are less severe in terms of worsening in PEF and symptom scores.

  • Durability of Mepolizumab treatment response between doses
    Airway pharmacology and treatment, 2019
    Co-Authors: Ian D. Pavord, Frank C Albers, Peter H Howarth, Daniel J Bratton, Steven W. Yancey
    Abstract:

    Background: Mepolizumab (100 mg delivered subcutaneously every 4 weeks) is approved for use in patients with severe eosinophilic asthma (SEA) and has been shown to reduce exacerbations and improve asthma symptoms vs placebo. There are limited data on the durability of the response to Mepolizumab between doses. Aim: To investigate the efficacy profile in patients with SEA over the 4-week dosing period for various fixed doses of Mepolizumab. Methods: This was a post hoc analysis of data from the Phase IIb DREAM trial. Patients with SEA ≥12 years of age were randomised (1:1:1:1) to receive Mepolizumab 75 mg (equivalent to 100 mg SC), 250 mg or 750 mg, or placebo intravenously (IV) every 4 weeks for 52 weeks. Mean daily peak expiratory flow (PEF) and symptom scores recorded as diary data were compared between days 1–14 and 15–28 days (periods 1 and 2, respectively) in each successive 4-weekly dosing period. Results: All three doses of Mepolizumab showed a similar effect on PEF and symptoms during periods 1 and 2. The number of patients whose symptoms increased by ≥1 point in period 2 vs period 1 was similar to placebo. Conclusions: These results demonstrate the durability of the response to Mepolizumab between doses and that Mepolizumab 75 mg IV has a similar efficacy profile over the 4-weekly dosing period compared with higher doses. Further analysis is needed to determine whether other outcomes show a similar trend. Funding: GSK [MEA112997;NCT01000506].

Eric S Bradford - One of the best experts on this subject based on the ideXlab platform.

  • Continued long-term Mepolizumab in severe eosinophilic asthma protects from asthma worsening versus stopping Mepolizumab: COMET trial
    Allergy and immunology, 2020
    Co-Authors: Elisabeth H. Bel, Wendy C Moore, Robert Price, Oliver Kornmann, Claude Poirier, Nirihiro Kaneko, Steven Smith, Neil Martin, Martyn J. Gilson, Eric S Bradford
    Abstract:

    Background: The long-term efficacy and safety of Mepolizumab in severe eosinophilic asthma (SEA) have been shown. Aims: To assess the impact of stopping versus continuing long-term Mepolizumab on asthma worsening. Methods: COMET (NCT02555371) was a randomised, double-blind, placebo-controlled study. Patients had completed COLUMBA (NCT01691859) or COSMEX (NCT02135692), had continuous Mepolizumab for ≥3 years (mean 46.6 months), and stayed on asthma controller therapy. Randomisation was 1:1 to stop (switch to placebo) or continue subcutaneous Mepolizumab 100 mg for 52 weeks. Composite endpoint: time to first asthma worsening (defined in Table). Daily eDiary data were analysed using Kaplan–Meier estimates and a Cox proportional hazards model adjusted for covariates. Results: Treatment differences for those who stopped versus continued Mepolizumab emerged by Week 4 (8 weeks post last open-label Mepolizumab dose). For those who stopped Mepolizumab, 51.7% reported asthma worsening by Week 52 versus 35.0% who continued Mepolizumab (Table), leading to a significantly shorter time to first asthma worsening in those who stopped Mepolizumab. Conclusion: Stopping Mepolizumab in patients with SEA led to an increased risk of asthma worsening with a significantly shorter time to first asthma worsening versus those continuing long-term Mepolizumab. Funding: GSK [201810/NCT02555371].

  • Clinical Development of Mepolizumab for the Treatment of Severe Eosinophilic Asthma: On The Path to Personalized Medicine
    The journal of allergy and clinical immunology. In practice, 2020
    Co-Authors: Ian D. Pavord, Roland Buhl, Pascal Chanez, Eric S Bradford, Oliver N. Keene, Andrew Menzies-gow, Mark T. Dransfield, Njira L Lugogo, Steve Yancey
    Abstract:

    The development of Mepolizumab, an anti-IL-5 monoclonal antibody for the treatment of severe eosinophilic asthma, is an example of a clinical development program that evolved over time based on sound, basic scientific principles. Initial clinical data on the effects of Mepolizumab on lung function in a general asthmatic population were disappointing. However, it became clear that Mepolizumab may be more effective against other clinical endpoints, particularly asthma exacerbations, in patients with more severe disease. Furthermore, a developing understanding of asthma disease pathobiology led to the identification of an appropriate target population and predictive biomarker for Mepolizumab treatment: patients with severe eosinophilic asthma and blood eosinophil count. Mepolizumab use provides clinically meaningful benefits in this target population, fulfilling an unmet need. This Clinical Commentary Review describes the clinical development of Mepolizumab and details of how this program informed the development of other biologic therapies in patients with severe asthma. This account highlights how a personalized approach toward treatment of patients with severe eosinophilic asthma, supported by a large body of scientific evidence, ultimately led to new and effective treatments and improved patient outcomes.

  • efficacite et tolerance a long terme de Mepolizumab chez les enfants âges de 6 a 11 ans atteints d asthme severe a eosinophiles
    Revue des Maladies Respiratoires Actualités, 2020
    Co-Authors: A Gruber, Eric S Bradford, R Price, Jonathan Steinfeld, Atul Gupta, I Masonori, Bob Geng, J Azmi, Steven W. Yancey
    Abstract:

    Introduction Le Mepolizumab est approuve pour le traitement de l’asthme severe a eosinophiles (ASE) chez les adultes et, dans certaines regions, chez les adolescents (12–17 ans). En aout 2018, l’Agence europeenne des medicaments a approuve le Mepolizumab a 40 mgSC pour les enfants de 6 a 11 ans avec un ASE. L’efficacite et la tolerance du Mepolizumab a long terme chez les enfants de 6 a 11 ans n’ont pas ete evaluees. Methodes Il s’agissait d’une etude ouverte, non controlee avec 2 parties A et B, chez les enfants atteint d’ASE. Les patients ayant termine la partie A (semaine 0–20) de l’etude sur la pharmacocinetique et pharmacodynamique etaient eligibles a la partie B de 52 semaines (semaine 20–72) de l’etude pour evaluer la tolerance et la pharmacodynamie a long terme du Mepolizumab. Dans la partie B, les patients ont recu 40 mgSC de Mepolizumab si   40 kg en plus de leur traitement de fond de depart. La dose de Mepolizumab etait augmentee a 100 mgSC si le patient atteignait 40 kg pendant la phase B. Les criteres d’evaluation comprenaient le taux d’exacerbations, le controle de l’asthme et la tolerance. Resultats Trente patients sont entres dans la partie B et 29 ont termine les 52 semaines de traitement. Une amelioration du controle de l’asthme a ete observee via les questionnaires ACQ-7 et ACQ-5, avec respectivement 55 % et 59 % de repondeurs (amelioration ≥ 0,5 points par rapport a l’inclusion) a la visite de fin d’etude (semaine 72). Une augmentation du score ACT pour les enfants a ete egalement observee, qui montre une amelioration du controle de l’asthme et ce independamment du groupe de traitement (sur le poids des patients). Les taux annuels d’exacerbations pendant le traitement etaient inferieurs aux valeurs initiales pour chaque groupe. Dans l’ensemble, 80 % des sujets ont presente une reduction ≥ 50 % du taux d’exacerbations pendant la partie B par rapport a l’annee precedant l’inclusion. Le Mepolizumab a ete bien tolere dans la partie B, aucun nouveau probleme de tolerance n’a ete rapporte chez les enfants par rapport au profil de tolerance connu des adultes/adolescents. La bronchite (30 %) etait l’effet indesirable le plus souvent rapporte. Aucun patient n’a eu d’anticorps anti-Mepolizumab pendant la partie B ( Tableau 1 ). Conclusion Chez les enfants de 6 a 11 ans, le traitement par Mepolizumab a entraine pendant 52 semaines une amelioration du controle de l’asthme et une reduction du taux annuel d’exacerbations par rapport a l’annee precedant l’inclusion. Le Mepolizumab a ete bien tolere chez les enfants de 6 a 11 ans.

  • baseline blood eosinophil count as a predictor of treatment response to the licensed dose of Mepolizumab in severe eosinophilic asthma
    Respiratory Medicine, 2019
    Co-Authors: Frank C Albers, Steven W. Yancey, Christopher Licskai, Pascal Chanez, Daniel J Bratton, Eric S Bradford, Namhee Kwon, Santiago Quirce
    Abstract:

    Abstract Background Previous analyses examining the relationship between blood eosinophil count and Mepolizumab treatment effects in severe eosinophilic asthma have used a range of doses and administration routes. Methods This post hoc meta-analysis included data from the MENSA (MEA115588/NCT01691521) and MUSCA (200862/NCT02281318) trials. Patients (≥12 years) with severe eosinophilic asthma who experienced ≥2 exacerbations in the prior year received either Mepolizumab 100 mg subcutaneously (SC) or 75 mg intravenously, or placebo plus standard of care every 4 weeks. This meta-analysis reports data from patients receiving the licensed dose of Mepolizumab (100 mg SC) or placebo only. The primary endpoint was the annual rate of clinically significant exacerbations; secondary endpoints included rate of exacerbations requiring hospitalization/emergency room (ER) visit, proportion of patients with no clinically significant exacerbations, and changes from baseline in forced expiratory volume in 1 s, Asthma Control Questionnaire-5 and St George's Respiratory Questionnaire scores. Analyses were stratified by baseline blood eosinophil count ( Results Mepolizumab reduced annual clinically significant exacerbation rates by 45%–85%, exacerbations requiring hospitalization/ER visit by 60%–70%, and increased the odds of no clinically significant exacerbations across all eosinophil threshold subgroups versus placebo, and improved all other secondary endpoints in subgroups ≥150 cells/μL. Greater treatment effects with increasing blood eosinophil count were observed. Conclusions Mepolizumab demonstrated consistent clinical benefits in patients with baseline blood eosinophil counts ≥150 cells/μL, confirming the suitability of this cut-off for identifying patients responsive to the licensed Mepolizumab dose.

  • long term safety and clinical benefit of Mepolizumab in patients with the most severe eosinophilic asthma the cosmex study
    Clinical Therapeutics, 2019
    Co-Authors: Sandhya Khurana, Frank C Albers, Eric S Bradford, Elisabeth H. Bel, Guy Brusselle, Mark J Fitzgerald, Matthew Masoli, Stephanie Korn, Motokazu Kato, Martyn J. Gilson
    Abstract:

    Abstract Purpose The goal of this study was to assess the long-term safety and efficacy of Mepolizumab in patients with the most severe eosinophilic asthma. Methods This multicenter, open-label, long-term, Phase IIIb study (COSMEX [COSMOS Extension]; 201312/NCT02135692) enrolled patients from the 52-week, open-label extension study COSMOS (A Study to Determine Long-term Safety of Mepolizumab in Asthmatic Subjects) that previously enrolled patients from the double-blinded, placebo-controlled Phase III studies MENSA (Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma) and SIRIUS (Steroid Reduction with Mepolizumab Study). To enter COSMEX, patients had to have life-threatening/seriously debilitating asthma before entering MENSA or SIRIUS and to have completed these previous studies with demonstrated improvement while receiving Mepolizumab. In COSMEX, patients received Mepolizumab 100 mg subcutaneously every 4 weeks as add-on therapy for up to 172 weeks. Primary endpoints were adverse event frequency and exacerbation rate per year; also assessed were forced expiratory volume in 1 s, Asthma Control Questionnaire-5 score, and daily oral corticosteroid (OCS) use. Findings Of the 340 patients enrolled, 339 received Mepolizumab; median treatment duration within this extension study was 2.2 years, equating to 718 patient-years of additional exposure. No new safety signals were identified. Patients receiving Mepolizumab throughout this study and previous studies had lasting reductions in exacerbation rate and daily OCS use and improvements in forced expiratory volume in 1 s and Asthma Control Questionnaire-5 score. In COSMEX, the on-treatment exacerbation rate (95% CI) was 0.93 (0.81–1.06) event/year for clinically significant exacerbations, 0.13 (0.10–0.18) event/year for exacerbations requiring hospitalization/emergency department visit, and 0.07 (0.05–0.10) event/year for exacerbations requiring hospitalization. In patients requiring systemic/oral corticosteroids with ≥128 weeks of continuous enrollment across SIRIUS, COSMOS, and COSMEX, Mepolizumab maintained the median daily OCS dose at 1.3–2.8 mg during COSMEX, with additional patients no longer requiring OCS after extended Mepolizumab treatment. Implications This study indicates that long-term Mepolizumab treatment is well tolerated and associated with sustained clinical benefits in patients with severe eosinophilic asthma. ClinicalTrials.gov identifier: NCT02135692.