Abstract 15143: ZD100: BP Lowering, Renal Enhancing and Aldosterone Suppressing Properties via pGC-A in Human Resistant “Like” Hypertension - A First in Human Study
Background: There is an unmet therapeutic need for resistant hypertension (RH). ZD100, a Mayo engineered peptide, is a novel particulate guanylyl-cyclase A (pGC-A) receptor activator with natriuretic, aldosterone inhibiting and blood pressure (BP) reducing properties mediated via cGMP. A two-part first-in-human (FIH), single ascending dose (SAD) and multiple ascending dose (MAD) trial which defined safety, maximum tolerated dose (MTD) with subcutaneous (SQ) administration of ZD100 in hypertensive subjects was completed.
Methods: Part A was an open label sequential SAD design study with 3 cohorts of 4 stable hypertensive subjects in each cohort with BP > 140/90 mmHg while on at least one anti-hypertensive medication. All subjects stopped all anti-hypertensive agents for 14 days and received a single SQ injection of ZD100. Part B was a randomized, double-blind, placebo-controlled MAD design in 3 cohorts of 5 subjects in each cohort with resistant “like” hypertension, on at least 3 medications including a diuretic and ACE inhibitor (ACEI) or ARB and with BP > 145/70 mmHg. SQ ZD100 was administered SQ once daily for three days. All subjects continued their anti-hypertensive medications. The MTD was defined as a decrease in systolic BP of ≥ 30 mmHg.
Results: Part A: 3 cohorts were dosed at 1, 2.5 and 5μg/Kg respectively. The MTD was 5μg/Kg, which resulted in maximal systolic and diastolic BP reductions of -20 ± 18 and -12 ± 5 mmHg respectively. Part B: 4 cohorts were dosed at 0.5, 2.5, 3 and 5μg/Kg respectively; the MTD was 5μg/Kg which resulted in sustained decrease of BP for 24 hours (max reduction systolic BP; ZD100: -26 ± 14 vs placebo: -1 ± 12 mmHg) with reductions in aldosterone and enhanced renal function for 24 hours after each SQ injection. There were no differences in heart rate compared to placebo. ZD100 was well tolerated with no serious adverse events (SAE).
Conclusions: ZD100 in this first-in-human study was safe and highly effective in lowering systolic and diastolic BP with duration of 24 hours with single SQ administration with enhanced renal function and suppression of aldosterone. These studies support further investigations in human RH with this novel peptide that activates the pGC-A receptor/cGMP system with highly favorable BP, renal and aldosterone properties.
Author Disclosures: H.H. Chen: Ownership Interest; Modest; Zumbro Discovery, Anexon Inc, Capricor Therapeutics. J.M. Neutel: Ownership Interest; Significant; Integrium, LLC. D.H. Smith: Ownership Interest; Significant; Integrium, LLC. D. Heublein: Ownership Interest; Modest; Zumbro Discovery. J.C. Burnett: Ownership Interest; Modest; Zumbro Discovery, Capricor Therapeutics, Anexon Inc.
- © 2016 by American Heart Association, Inc.