Transient receptor potential vanilloid 4 (TRPV4) channels expressed on pulmonary endothelial cells are activated by elevated pulmonary vascular pressure, resulting in endothelial shape change, pulmonary barrier disruption, and
edema. As such, TRPV4 blocker
GSK2798745 was recently investigated in phase I/IIa trials to reduce
pulmonary edema caused by
heart failure (HF). In the absence of a suitable TRPV4 target engagement
biomarker, we hypothesized that an ex vivo assay could be used to predict pharmacological activity at the intended site of action (endothelial cells) of subjects. In this assay, the ability of
GSK2798745 to block TRPV4 agonist GSK1016790-induced impendence reduction in human umbilical vein endothelial cells (HUVECs) in the presence of human whole blood was assessed. Blood from healthy volunteers drawn 1-12 hours after single or repeated dose of
GSK2798745 (5 mg) inhibited GSK1016790-induced impedance reduction by ≥85%. Similarly, blood samples from 16 subjects with HF dosed with
GSK2798745 (2.4 mg) inhibited GSK1016790-induced HUVEC impedance reduction by ≥58% 1-24 hours after single dosing and ≥78% 1-24 hours after 7 days of repeated dosing. No inhibition was detected using blood from placebo subjects. Using matched
GSK2798745 plasma levels, a pharmacokinetic/pharmacodynamic (PK/PD) relationship was calculated as 2.9 nM IC50, consistent with the 6.5 nM IC50 of
GSK2798745 obtained from a rat in vivo PK/PD model of
pulmonary edema after correcting for rat-to-human differences. These results indicate that circulating levels of
GSK2798745 in the recently completed phase I/IIa trials were sufficient to block TRPV4 in lung vascular endothelial cells to a large extent, supporting this dosing regimen for assessing efficacy in HF. SIGNIFICANCE STATEMENT: In the absence of a suitable target engagement
biomarker, we developed an ex vivo assay to predict the pharmacological activity of the transient receptor potential vanilloid 4 (TRPV4) blocker
GSK2798745 in healthy volunteers and subjects with
heart failure (HF) from phase I/IIa trials. The potency values from the ex vivo assay were consistent with those predicted from a rat in vivo pharmacokinetic/pharmacodynamic model of
pulmonary edema, strongly suggesting that circulating levels of
GSK2798745 were sufficient to robustly block TRPV4, supporting use of
GSK2798745 for assessing efficacy in HF.