Genetic effects on treatment response of umeclidinium/vilanterol in chronic obstructive pulmonary disease.
Treatment with long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) for chronic obstructive pulmonary disease (COPD) is standard, but response varies. We investigated genetic association with treatment response to umeclidinium (UMEC, a LAMA), vilanterol (VI, a LABA), and combination therapy.



Data from 17 clinical trials (N = 6075) in patients with COPD receiving once-daily UMEC/VI (125/25mcg or 62.5/25mcg), UMEC (125 or 62.5mcg), VI (25mcg) or placebo were used. Genetic association with change from baseline in trough forced expiratory volume in 1 s (FEV1) ∼24 h post-dosing was assessed for: (i) 3 β2-adrenoceptor (ADRB2) gene variants; (ii) 298 single-nucleotide polymorphisms (SNPs) with prior evidence of associations; (iii) human leukocyte antigen (HLA) alleles and (iv) genome-wide association study (GWAS) SNPs. Other endpoints were (i) reversibility at screening; and at baseline: (ii) FEV1; (iii) forced vital capacity (FVC), and (iv) FEV1/FVC ratio. Using linear regression, the inverse normal transformed residuals were pooled together, first across treatment group, then across studies for each monotherapy, then combination therapy and finally for every treated patient.



Of 6075 patients, 1849 received UMEC/VI, 1390 received UMEC, 1795 received VI, and 1041 received placebo. None of the ADRB2 variants, HLA alleles or GWAS variants tested were associated with treatment response or baseline endpoints. Four SNPs in FAM13A (rs7671167, rs2869967, rs1964516, rs1903003) were significantly associated with baseline FEV1/FVC ratio (p < 3 × 10(-5)) after adjusting for multiple testing.



No genetic association was found with treatment response to UMEC or VI when administered as monotherapies or in combination.
GlaxoSmithKline, Research Triangle Park, NC, USA. Electronic address: Lynn.Condreay@parexel.com.
Lynn
L
Condreay
GlaxoSmithKline, Research Triangle Park, NC, USA.
Lingkang
L
Huang
GlaxoSmithKline, Research Triangle Park, NC, USA.
Elizabeth
E
Harris
GlaxoSmithKline, Stockley Park West, Middlesex, UK.
Jean
J
Brooks
GlaxoSmithKline, Stockley Park West, Middlesex, UK.
John H
JH
Riley
GlaxoSmithKline, Research Triangle Park, NC, USA.
Alison
A
Church
GlaxoSmithKline, King of Prussia, PA, USA.
Soumitra
S
Ghosh
D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000627:therapeutic use; D000368:Aged; D001592:Benzyl Alcohols / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000627:therapeutic use; D002722:Chlorobenzenes / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D002986:Clinical Trials as Topic; D004338:Drug Combinations; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects / Q000235:genetics*; D055106:Genome-Wide Association Study; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000627:therapeutic use; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D011812:Quinuclidines / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D016896:Treatment Outcome; D014797:Vital Capacity / Q000187:drug effects / Q000235:genetics*
D058666:Adrenergic beta-2 Receptor Agonists; D001592:Benzyl Alcohols; D001993:Bronchodilator Agents; D002722:Chlorobenzenes; D004338:Drug Combinations; C573971:GSK573719; D006680:HLA Antigens; D018727:Muscarinic Antagonists; D011812:Quinuclidines; C550468:vilanterol
ADRB2; Chronic obstructive pulmonary disease; Genome-wide association study; Single nucleotide polymorphism; Umeclidinium; Vilanterol