PGx7683_Exploratory PGx analysis for GSK1325760 (Ambrisentan) in 112565

Trial description: The AMBITION, AMB112565 study was conducted to compare the safety and efficacy of initiating pharmacotherapy for subjects with World Health Organization/ New York Heart Association (WHO/NYHA) functional class (FC) II and III pulmonary arterial hypertension (PAH) with combination therapy composed of ambrisentan and tadalafil or monotherapy composed of ambrisentan or tadalafil. This initial pharmacotherapy is referred to as “first-line” subsequently in this document as it was the first line of treatment for subjects enrolled in the study. The hypothesis tested by the AMBITION study was that initiating pharmacotherapy with the combination of the endothelin receptor antagonist (ERA) ambrisentan plus the PDE-5 inhibitor tadalafil provides better efficacy (as measured by time to first clinical failure event) and comparable safety to initiating treatment with monotherapy with either drug in subjects with WHO FC II and or III PAH. The purpose of this pharmacogenetic study, 207927, is to evaluate the genetic effects of candidate and genome-wide variation on response to ambrisentan and tadalafil combination therapy in study AMB112565. The ambrisentan monotherapy and tadalafil monotherapy arms will also be analyzed to aid in interpretation of the combination therapy arm results and to allow for estimation of genotype by treatment interactions using appropriate contrasts of linear combinations of the genetic effect size estimates obtained within the treatment arms.The primary endpoint is time (days) from randomization to the first clinical failure adjudicated (TtCF) event of PAH. This includes events from randomization to the final assessment visit (FAV). The genetic main effect on TtCF event within treatment will use a Cox proportional hazards regression model to generate hazards ratios (HR) and 95% confidence intervals (CI). Covariates will include age, sex and genetic ancestry principal components. Strata include PAH etiology (idiopathic or heritable versus (vs) non-idiopathic associated), WHO Functional class score (Class II vs III). The secondary endpoint is change from baseline in the six minute walk distance (6MWD) measured at week 24. The genetic main effect on change from baseline in 6MWD measured at week 24 within treatment will use a linear regression model adjusting for covariates PAH etiology (idiopathic or heritable vs non-idiopathic associated), WHO Functional class score (Class II vs III), baseline 6MWD, age, sex and genetic ancestry principal components. Effect estimates and standard errors will be generated. In 2015, Benza et al reported an evaluation of 749 endothelin-1 pathway variants in 715 PAH patients of European descent treated with ERAs (Am J Respir Crit Care Med 192 [11)]: 1345-54.) They reported a significant association between the rs11157866 variant in the GNG2 gene and clinical improvement. Subjects homozygous for the minor T allele were more likely to attain clinical improvement sooner than subjects with CT or CC genotypes (log HR 2.09, no confidence interval given). With a minor allele frequency of 12.7% only 1.6% of subjects would be expected to be TT homozygotes. Effect estimates were not provided for an additive model. The Affymetrix Axiom Biobank array with GSK custom content v2 in conjunction with a reference set of haplotypes will be used to impute approximately 30+ million variants across the genome including the HLA region. Analysis will be conducted on genome-wide variants with a minor allele frequency ≥0.01 and an imputation r2 ≥0.30. A single candidate variant, rs11157866, in the GNG2 gene (Benza, 2015), will be analyzed. This variant is present on the Axiom Biobank array. An additive genetic model will be used for all variants. A sensitivity analysis using a recessive genetic model for candidate variant rs11157866 may be conducted. The significance threshold for the candidate variant, rs11157866, is 0.025 and for genome-wide variants is <=2.5x10-8 (50% of conventional genome-wide analysis threshold of 5x10-8). No adjustment will be made for multiple endpoints.