GENETIC VARIANTS DO NOT PREDICT ACUTE COPD EXACERBATIONS OR TREATMENT RESPONSE TO FLUTICASONE FUROATE/UMECLIDINIUM/VILANTEROL (FF/UMEC/VI) AND ITS COMPONENTS

Abstract

SESSION TITLE: Obstructive Lung Disease Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Combination treatments, targeting multiple mechanisms, benefit subjects with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, predicting AECOPD and treatment response remains challenging. We investigated genetic effects on AECOPD and response to combination treatment with FF (an inhaled corticosteroid), UMEC (a long-acting muscarinic antagonist), and VI (an ultra-long-acting ß2 adrenoreceptor agonist) and for each component. METHODS: The genetic basis of AECOPD (modelled as rate or risk) was evaluated in samples from 23 clinical studies (n=16,097 subjects) and 2 disease cohort studies (ECLIPSE (n=1,434) and COPDGene (n=2,310)), resulting in a total of 19,841 subjects. Pharmacogenetic (PGx) effects were tested in 8,439 subjects in study NCT02164513 with analysis of 5 co-primary endpoints related to on-treatment exacerbation rate, change from baseline in FEV1 or quality of life score and proportion of subjects with clinically important deterioration. PGx analyses were done within each of 3 treatment arms and 3 molecules. Post-hoc PGx analyses were conducted stratifying by exacerbation history (single moderate, frequent moderate or ≥1 severe exacerbation in the year prior to study). Multiple testing was controlled at the genetic variant level, not by endpoint or arm/molecule. Significance thresholds were 5E-8 in AECOPD, 2.5E-8 in GWAS and 0.001 with candidate variants. Results from the PGx analysis were followed-up in 2,201 subjects from NCT02345161, NCT01009463 and NCT01017952. Endpoints were analyzed using a generalized linear model assuming a negative binomial distribution, linear regression, or logistic regression, as appropriate. RESULTS: Nominal association with an intron variant in SCAPER was observed for AECOPD risk (p=7E-08). In the PGx analysis, rs56195836 (MAPK8) was associated with moderate to severe exacerbation rate in subjects on FF with high baseline blood eosinophil counts (>150cells/µL) (p=1.8E-8). When subjects were stratified by exacerbation history, 3 variants associated with exacerbation endpoints. In subjects with a history of frequent moderate exacerbations treated with FF/VI, rs1962343 (AZUI) associated with moderate to severe exacerbation rate (p=1.1E-8). The ABCB1 variants, rs1128503 and rs2032582, associated with moderate to severe exacerbation rates in white subjects receiving UMEC (p=0.0003) or VI (p=0.0009), respectively, who experienced a single moderate exacrbation the year prior. However, none of these 4 signals replicated in the independent follow-up sample cohort, so are not robust, generalizable effects. CONCLUSIONS: Common genetic variants do not play major roles in exacerbation risk or predict response to FF/UMEC/VI or its components in COPD. CLINICAL IMPLICATIONS: Common genetic variants are unlikely to have clinical utility in predicting FF/UMEC/VI response. DISCLOSURES: Employee relationship with GSK Please note: $5001 - $20000 Added 05/27/2020 by Mathias CHIANO, source=Web Response, value=stock options Employee relationship with Parexel International Please note: >$100000 Added 05/22/2020 by Lynn Condreay, source=Web Response, value=Salary Own stock. relationship with GlaxoSmithKline Please note: $1-$1000 Added 05/22/2020 by Lynn Condreay, source=Web Response, value=Ownership interest Employee relationship with Glaxosmithkline Please note: >$100000 by Charles Cox, source=Admin input, value=Salary Former Employee/Stockholder relationship with Glaxosmithkline Please note: $5001 - $20000 Added 05/22/2020 by Dana Fraser, source=Web Response, value=Stock Employee relationship with GSK Please note: >$100000 by Soumitra Ghosh, source=Admin input, value=Salary No relevant relationships by Joshua Hoffman, source=Admin input recently retired employee relationship with GlaxoSmithKline Please note: $20001 - $100000 by Louise Hosking, source=Admin input, value=shares Employee relationship with GlaxoSmithKline Please note: >$100000 Added 05/22/2020 by David Lipson, source=Web Response, value=Salary Share holder relationship with GSK Please note: >$100000 Added 05/22/2020 by Neil Martin, source=Web Response, value=Salary Employee relationship with Parexel International Please note: >$100000 Added 05/20/2020 by Pamela StJean, source=Web Response, value=Salary Complementary worker relationship with GSK Please note: $1-$1000 Added 05/20/2020 by Pamela StJean, source=Web Response, value=Parexel has a contract with GS Employee relationship with GlaxoSmithKline Please note: $20001 - $100000 Added 05/22/2020 by Astrid Yeo, source=Web Response, value=Salary Stock holder relationship with GlaxoSmithKline Please note: $20001 - $100000 Added 05/22/2020 by Astrid Yeo, source=Web Response, value=Stock