Lynn Condreay1, Mathias Chiano2, Hector Ortega3, Natalie Buchan2, Elizabeth Harris3, Eugene R Bleecker4, Philip J Thompson5, Marc Humbert6, Peter Gibson7, Steven Yancey3, Soumitra Ghosh8. 1. GSK, Research Triangle Park, NC, USA. Electronic address: Lynn.Condreay@parexel.com. 2. GSK, Stevenage, UK. 3. GSK, Research Triangle Park, NC, USA. 4. Center for Genomics and Personalized Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA. 5. Lung Institute of Western Australia and Centre for Asthma, Allergy, and Respiratory Research, University of Western Australia, Perth, WA, Australia. 6. Assistance Publique-Hôpitaux de Paris, Département Hospitalo-Universitaire Thorax Innovation, Service de Pneumologie, Hôpital Bicêtre, Université Paris-Sud, INSERM Unités Mixte de Recherche 999, Le Kremlin-Bicêtre, France. 7. Department of Respiratory and Sleep Medicine, John Hunter Hospital, Hunter Medical Research Institute, Kookaburra Circuit, New Lambton Heights, NSW, Australia. 8. GSK, King of Prussia, PA, USA.
Abstract
BACKGROUND AND OBJECTIVES: Treatment with mepolizumab, a humanized monoclonal antibody to interleukin-5, reduces the rate of asthma exacerbations and the requirement for systemic glucocorticoids while maintaining asthma control. Treatment decisions are guided by predictors of response, including blood eosinophil thresholds in patients with frequent exacerbations despite intensive anti-inflammatory and controller treatment. Identification of additional predictors of response could aid treatment decisions. We investigated genetic associations that may predict response to mepolizumab-treatment. METHODS: In this post hoc analysis of DREAM and MENSA, association of genetic markers was tested in patients with severe asthma treated with mepolizumab who provided consent for pharmacogenetic research. Association was tested in a tiered approach with alpha spend differing for candidate genetic markers selected for prior history of association with relevant traits or pathways and in a genome-wide analyses (p < 4.7 × 10-4 and p < 5 × 10-8, respectively). Efficacy endpoints included: clinically significant exacerbation rate (tested using a negative binomial model), time to first exacerbation (tested with a Cox proportional hazards model), change in exacerbation rate, change in eosinophil count, and change in IgE level (tested by linear regression). RESULTS: No genetic marker was significantly associated with the primary endpoint, clinically significant exacerbation rate. One genetic marker was associated with time to first clinically significant exacerbation, but this association was driven by the DREAM data and was not supported in additional sensitivity analyses by treatment regimen/dose. CONCLUSION: No genetic effect on mepolizumab-treatment response was identified in this population on intensive asthma treatment, with history of frequent exacerbations and pre-selected for airway eosinophilia.
BACKGROUND AND OBJECTIVES: Treatment with mepolizumab, a humanized monoclonal antibody to interleukin-5, reduces the rate of asthma exacerbations and the requirement for systemic glucocorticoids while maintaining asthma control. Treatment decisions are guided by predictors of response, including blood eosinophil thresholds in patients with frequent exacerbations despite intensive anti-inflammatory and controller treatment. Identification of additional predictors of response could aid treatment decisions. We investigated genetic associations that may predict response to mepolizumab-treatment. METHODS: In this post hoc analysis of DREAM and MENSA, association of genetic markers was tested in patients with severe asthma treated with mepolizumab who provided consent for pharmacogenetic research. Association was tested in a tiered approach with alpha spend differing for candidate genetic markers selected for prior history of association with relevant traits or pathways and in a genome-wide analyses (p < 4.7 × 10-4 and p < 5 × 10-8, respectively). Efficacy endpoints included: clinically significant exacerbation rate (tested using a negative binomial model), time to first exacerbation (tested with a Cox proportional hazards model), change in exacerbation rate, change in eosinophil count, and change in IgE level (tested by linear regression). RESULTS: No genetic marker was significantly associated with the primary endpoint, clinically significant exacerbation rate. One genetic marker was associated with time to first clinically significant exacerbation, but this association was driven by the DREAM data and was not supported in additional sensitivity analyses by treatment regimen/dose. CONCLUSION: No genetic effect on mepolizumab-treatment response was identified in this population on intensive asthma treatment, with history of frequent exacerbations and pre-selected for airway eosinophilia.
Authors: Lynn D Condreay; Laura R Parham; Xiaoyan A Qu; Jonathan Steinfeld; Michael E Wechsler; Benjamin A Raby; Steven W Yancey; Soumitra Ghosh Journal: Rheumatol Int Date: 2020-02-03 Impact factor: 2.631
Authors: Jesús Miguel García-Menaya; Concepción Cordobés-Durán; Elena García-Martín; José A G Agúndez Journal: Front Pharmacol Date: 2019-05-21 Impact factor: 5.810
Authors: Stefania Principe; Celeste Porsbjerg; Sisse Bolm Ditlev; Ditte Kjaersgaard Klein; Korneliusz Golebski; Nanna Dyhre-Petersen; Yoni E van Dijk; Job J M H van Bragt; Lente L H Dankelman; Sven-Erik Dahlen; Christopher E Brightling; Susanne J H Vijverberg; Anke H Maitland-van der Zee Journal: Clin Exp Allergy Date: 2021-05-21 Impact factor: 5.018