A First-in-Human Study of AMG 986, a Novel Apelin Receptor Agonist, in Healthy Subjects and Heart Failure Patients

Peter Winkle, Steven Goldsmith, Michael J. Koren, Serge Lepage, Jennifer Hellawell*, Ashit Trivedi, Kate Tsirtsonis, Siddique A. Abbasi, Allegra Kaufman, Richard Troughton, Adriaan Voors, Jean Sebastien Hulot, Erwan Donal, Navid Kazemi, Joel Neutel

*Corresponding author voor dit werk

OnderzoeksoutputAcademicpeer review

7 Citaten (Scopus)
347 Downloads (Pure)

Samenvatting

Purpose: AMG 986 is a novel apelin receptor (APJ) agonist that improves cardiac contractility in animal models without adversely impacting hemodynamics. This phase 1b study evaluated the safety/tolerability, pharmacokinetics, and pharmacodynamics of AMG 986 in healthy subjects and patients with heart failure (HF).

Methods: Healthy adults (Parts A/B) and HF patients (Part C) aged 18–85 years were randomized 3:1 to single-dose oral/IV AMG 986 or placebo (Part A); multiple-dose oral/IV AMG 986 or placebo (Part B); or escalating-dose oral AMG 986 or placebo (Part C). Primary endpoint: treatment-emergent adverse events, laboratory values/vital signs/ECGs; others included AMG 986 pharmacokinetics, left ventricular (LV) function.

Results: Overall, 182 subjects were randomized (AMG 986/healthy: n = 116, placebo, n = 38; AMG 986/HF: n = 20, placebo, n = 8). AMG 986 had acceptable safety profile; no clinically significant dose-related impact on safety parameters up to 650 mg/day was observed. AMG 986 exposures increased nonlinearly with increasing doses; minimal accumulation was observed. In HF with reduced ejection fraction patients, there were numerical increases in percent changes from baseline in LV ejection fraction and stroke volume by volumetric assessment with AMG 986 vs placebo (stroke volume increase not recapitulated by Doppler).

Conclusions: In healthy subjects and HF patients, short-term AMG 986 treatment was well tolerated. Consistent with this observation, clinically meaningful pharmacodynamic effects in HF patients were not observed. Changes in ejection fraction and stroke volume in HF patients suggest additional studies may be needed to better define the clinical utility and optimal dosing for this molecule.

Trial Registration Number: ClinicalTrials.gov NCT03276728.

Date of Registration: September 8, 2017

Originele taal-2English
Pagina's (van-tot)743–755
Aantal pagina's13
TijdschriftCardiovascular Drugs and Therapy
Volume37
Vroegere onlinedatum23-apr.-2022
DOI's
StatusPublished - aug.-2023

Vingerafdruk

Duik in de onderzoeksthema's van 'A First-in-Human Study of AMG 986, a Novel Apelin Receptor Agonist, in Healthy Subjects and Heart Failure Patients'. Samen vormen ze een unieke vingerafdruk.

Citeer dit