Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Of Amg 986, a Novel Small Molecule Apelin Receptor Agonist, in Healthy Subjects and Heart Failure Patients

Abstract

Background Heart failure (HF) refers to a clinical condition in which the cardiac output is insufficient to meet the metabolic needs of the body and is marked by cardiac systolic and/or diastolic dysfunction. The apelin receptor (APJ) counteracts the pressor effect of angiotensin II, attenuates ischemic injury, and contributes to neovascularization in HF. AMG 986 is a first-in-class, novel APJ small molecule agonist that binds and activates the APJ receptor to improve cardiac contractility without adversely impacting hemodynamics. Methods This phase 1b study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AMG 986 in healthy subjects and HF patients. Healthy adults, 18 to 55 years of age (Parts A & B), and HF patients, 18 to 85 years of age (Part C), were randomized 3:1 to receive a single dose (Part A: 5 IV infusion dose cohorts and 6 oral dose cohorts, n = 8 each) or multiple doses of AMG 986 (Part B: 2 IV infusion dose cohorts and 6 oral dose cohorts, n = 8-9 each; Part C: 21 days escalating oral daily doses of AMG 986 in patients with HF, n = 19 or placebo, n = 8). The primary endpoints were the incidence of adverse events (AEs), safety laboratory analytes, vital signs and ECGs. Other endpoints included AMG 986 PK and change from baseline in biomarkers of HF and echocardiographic parameters ofleft ventricular (LV) function. Results Overall, 181 subjects were randomized and administered (AMG 986 healthy subjects, n = 116; placebo, n = 38; AMG 986 HF patients, n = 19; placebo, n = 8). Across all dosing cohorts, AMG 986 exposures increased non-linearly with increasing doses and an oral bioavailability of 40 - 80%. Mean AMG 986 exposures demonstrated minimal accumulation and a trend of decreasing dose normalized exposures were observed across multiple ascending dose (MAD) groups. AMG 986 had an acceptable safety profile. The most common AEs were headache (n = 8; 5%), vomiting (n = 3; 2%) and dizziness (n = 4; 2%). Conclusion In healthy subjects and in HF patients, short-term treatment with AMG 986 was well tolerated.