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TRVO27 is a β-arrestin biased ligand at the angiotensin 2 type 1 receptor (AT1R); it antagonizes G-protein coupling while stimulating β-arrestin-mediated signaling. TRVO27 inhibits ang2-mediated systemic and renal vasoconstriction while, via β-arrestin, it increases cardiac contractility and anti-apoptotic signaling. TRVO27's novel pharmacology at a precedented target suggests that TRVO27 may be an effective and safe new therapy for heart failure (HF).
This was a randomized, double-blind, placebo-controlled, titration study to evaluate the safety and pharmacology of TRVO27 in patients with stable HF. Inclusion criteria: ≥3-month history of systolic HF, systolic blood pressure ≥100 mmHg, average pulmonary capillary wedge pressure (PCWP) ≥20 mmHg. Other HF medications were withheld for 6 hrs.
Four cohorts of 8 patients were enrolled. Subjects were randomized 1:3 to receive either placebo (PBO) or a dose regimen of TRVO27. Study drug was administered by i.v. infusion for 14 hrs: a 5 hr dose escalation phase and a 9 hr maintenance phase, followed by a 4 hr washout phase. Maintenance doses in each cohort were 1 mcg/kg/min (cohort 1), 3 mcg/kg/min (cohorts 2 and 4), and 10 mcg/kg/min (cohort 3). Mean arterial pressure (MAP) decreased during dose escalation in patients with high plasma renin activity exposed to TRVO27 (high-PRA), but not in the normal PRA TRVO27 group (normal-PRA) or in PBO. This decreased MAP was sustained during the maintenance phase and reversed in the washout phase. PCWP declined during dose escalation in high-PRA and PBO. PCWP increased back to baseline during washout in high-PRA, suggesting reversible pharmacology, while PCWP was unchanged in PBO and normal-PRA during washout. Cardiac index did not change in subjects with either high or normal PRA in this small sample size.
TRVO27 a β-arrestin biased AT1R ligand produced reversible improvements in hemodynamics and was well-tolerated in patients with advanced stable HF. As expected, pharmacologic effects of TRVO27 were dependent on PRA elevation, a common feature of acute HF. Studies are planned to evaluate TRVO27's efficacy and safety in patients hospitalized for HF.
Poster Sessions, Expo North
Sunday, March 10, 2013, 9:45 a.m.-10:30 a.m.
Session Title: Novel and Standard Pharmacological Therapies in Heart Failure: Which Treatment for Which Patient
Abstract Category: 15. Heart Failure: Clinical
Presentation Number: 1221-284
- 2013 American College of Cardiology Foundation