PGX7647 (205878): Exploratory Pharmacogenetic GWAS meta-analysis of efficacy response to GSK1278863 by using subjects with CKD from phase 2 studies; 116581, 116582, 112844, 113633, 113747, and 116099

Trial description: GSK1278863 (daprodustat) is a novel small molecule agent that inhibits prolyl hydroxylases [egg-laying deficiency protein nine-like protein (EGLNs)] associated with hypoxia inducible factor (HIF). Inhibition of EGLNs prevents breakdown of HIFalpha. This activity results in the accumulation of HIFalpha transcription factors, which leads to increased transcription of HIF responsive genes. This biological activity stimulates components of the natural response to exposure to hypoxia. Erythropoiesis is thus induced by increased production of natural erythropoietin (EPO) and enhanced iron metabolism. Currently, oral daprodustat is being studied for treatment of anemia of chronic kidney disease (CKD) (RM2008/00267/07).A previous focused pharmacogenetic analysis (201099, also known as PGx7532) assessed relationships between genetic variants in the CYP2C8 and ABCG2 genes and pharmacokinetic (PK) variability of GSK1278863 using dose normalized AUC (area under the curve) from eight phase 1 and 2 studies, and explored effects of genetic variation in the genes of drug mechanism of action (MOA) on pharmacodynamic (PD) variability of GSK1278863 as measured by change in hemoglobin (Hgb) in three phase 2 studies (116581, 116582 and 112844, which were also included in this analysis). No genetic markers met the pre-specified criteria for association in either the PK or PD PGx analyses.This pharmacogenetic (PGx) analysis has been undertaken to evaluate genetic effects of genome-wide variation on differential response in subjects with anemia of CKD receiving daprodustat from six phase 2 studies, 116581, 116582, 112844, 113633, 113747, and 116099.