No genetic association detected with mepolizumab efficacy in severe asthma. (November 2017)

• Record Type: Journal Article
• Authors: Condreay, Lynn; Chiano, Mathias; Ortega, Hector; Buchan, Natalie; Harris, Elizabeth; Bleecker, Eugene R.; Thompson, Philip J.; Humbert, Marc; Gibson, Peter; Yancey, Steven; Ghosh, Soumitra
• Is Part Of: Respiratory medicine. Volume 132(2017)
• Page Start: 178
• Page End: 180
• Publication Date: 2017-11
• Subjects: Severe asthma -- Mepolizumab -- Pharmacogenetics -- Exacerbation; Chest -- Diseases -- Periodicals; Chest -- Diseases -- Great Britain -- Periodicals; Respiratory organs -- Diseases -- Periodicals; Respiratory Tract Diseases -- Periodicals; Appareil respiratoire -- Maladies -- Périodiques; Thorax -- Maladies -- Périodiques; Appareil respiratoire -- Maladies -- Traitement -- Périodiques; Electronic journals; 616.2
• DOI: 10.1016/j.rmed.2017.10.019
• Languages: English
• ISSNs: 0954-6111

Abstract

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. Highlights: Efficacy pharmacogenetics of mepolizumab treatment in patients with severe asthma was investigated. A candidate polymorphism analysis and an unbiased genome-wide association analyses were performed. No genetic effect on mepolizumab treatment response was identified.