Abstract 14201: ANX-042, a Novel Natriuretic Peptide (NP), is Safe and Stimulates Cyclic Guanosine Monophosphate (cGMP) in Healthy Volunteers
Background: We identified an alternatively spliced mRNA for B-type natriuretic peptide (ASBNP) that includes a unique and distinct longer carboxyl-terminus. Based on this mRNA, we biodesigned a truncated peptide form (ANX-042) containing the first 16 amino acids of its C-terminal. In experimental heart failure ANX-042 has potent diuretic and natriuretic actions without the vasodilatory hypotensive properties.
Methods: Thirty healthy volunteers enrolled in 5 cohorts (n=6) received 12-hour infusions each of placebo and 2 doses of ANX-042 in a randomized sequence over 5 days under relative fluid and sodium (Na) restricted (2.1 L; 2.5 g) or replete (3.6 L; 4gm) conditions. Doses of ANX-042 ranged from 0.001 to 0.065 μg/kg/min. Effects on plasma and urine cGMP, supine and standing blood pressure, urine volume, Na excretion and neurohormones (renin, angiotensin II, aldosterone) were assessed.
Results: Under Na replete conditions, ANX-042 was tolerated up to 0.03 μg/kg/min, with 3 of 4 subjects requiring discontinuation of ANX-042 infusion of 0.065 μg/kg/min due to persistent symptomatic orthostatic hypotension. The effects on cGMP activation at end of infusion are shown Table 1. There were no consistent changes in urinary parameters or neurohormones in these healthy volunteers.
Conclusions: In this first in human study, we have demonstrated that ANX-042 is safe and that it activates its second messenger cGMP at doses that did not result in symptomatic reduction of blood pressure. This lays the foundation for additional studies to define the actions of this novel peptide in acute decompensated heart failure.
- © 2013 by American Heart Association, Inc.