Pharmacogenetics and obesity: common gene variants influence weight loss response of the norepinephrine/dopamine transporter inhibitor GW320659 in obese subjects

Abstract

GW320659, a highly selective neuronal norepinephrine and dopamine re-uptake inhibitor, has been evaluated for the treatment of obesity. Scrutiny of the weight loss data from a phase II study (GlaxoSmithKline study OBS20001) showed a wide variation in weight loss response following GW320659 treatment and the possibility that the study population might include subgroups with enhanced weight loss response. Pharmacogenetic analysis was performed in 191 subjects prospectively ascertained from a Phase II dose ranging study to evaluate the influence of genotype on weight loss efficacy and safety of GW320659 in obese subjects. Common genetic polymorphisms in the drug target (norepinephrine transporter protein 1, SLC6A2) and mechanism pathway (NMDA receptor channel NR1 subunit, GRIN1) were associated with increased weight loss following GW320659 treatment in a proportion (36%) of the study population. In the patient subgroup selected for these genotypes, GW320659 (15 mg/day) produced a significant difference in mean weight loss of 7.84 kg (SD 5.23, n = 14), compared to 2.53 kg (SD 5.17, n = 24) in the subgroup that did not possess the genotypes (P = 0.006). This subgroup also showed a highly significant weight loss response for GW320659 compared to placebo (+0.31 kg, SD 3.32, n = 16) with the same genotypes (P < 0.0001). In addition, there was no difference in placebo response between either subgroup. Polymorphisms in SLC6A2 and GRIN1 could be used to maximize effective obesity pharmacotherapy by norepinephrine/dopamine transporter inhibitors by identifying patients that may be predisposed to particularly good treatment weight loss response.