The influence of VTP-27999 on renal and hormonal responses

Blockade of Renin-Angiotensin-System (RAS), using either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, halts the progression of chronic kidney disease (CKD). In addition, measurements of Renal Plasma Flow (RPF), as a marker of renal vascular function, and the renal hormonal profile guide our understanding of RAS blockades’ effects. Small mechanistic studies showed encouraging results when Aliskiren, the first approved renin inhibitor, was used; however, its clinical application in CKD was unfavorable in a large clinical trial. We tested the impact of a novel renin inhibitor (VTP-27999) on the kidneys in a single-center, double-blinded study. VTP-27999 (at 4 doses 75, 150, 300 and 600 mg) was compared to either placebo or aliskiren at 300 mg dosing in salt restricted normal volunteers. To determine the impact of the interventions, we measured hourly the change of RPF from baseline using para-aminohippurate infusion along with the change of plasma levels of renin, prorenin, trapping plasma renin activity (PRA) and Angiotensin II (Ang II) after 5 hours from administration. In 6 groups of 9 to 12 subjects, the observed RPF response to VTP22799 administration was dose-dependent and was significantly higher than placebo (Fig1). The respective changes in RPF ( SEM), were as follows: Placebo 5.7% 14.3%, aliskiren 18.1% 17%, VTP-27999 75 mg 8.1% 10.2%, VTP-27999 150 mg 16% 9.5%, 300 mg 22.8% 13.8%, and 600 mg 26.8% 13.2%. In addition, administration of VTP-27999 reduced both PRA and Ang II and increased renin and prorenin levels significantly (p u003c0.05 for all VTP-27999 dosing higher than 75mg) (Table1). Both renal and hormonal responses were higher in the VTP27999 group at 600 mg dosing than those in the aliskiren’s. The favorable renal function and hormonal responses to VTP-27999 exceeded placebo at all doses and aliskiren at maximum dose. VTP27999 may offer a sufficient RAS blockade and it might be of therapeutic application in CKD.