Rationale and design for the development of a novel nitroxyl donor in patients with acute heart failure

Felker, G. M., Borentain, M., Cleland, J. G.F. , DeSouza, M. M., Kessler, P. D., O'Connor, C. M., Seiffert, D., Teerlink, J. R., Voors, A. A. and McMurray, J. J.V. (2019) Rationale and design for the development of a novel nitroxyl donor in patients with acute heart failure. European Journal of Heart Failure, 21(8), pp. 1022-1031. (doi: 10.1002/ejhf.1504) (PMID:31168885)

[img]
Preview
Text
190807.pdf

898kB

Abstract

Hospitalisation for acute heart failure remains a major public health problem with high prevalence, morbidity, mortality, and cost. Prior attempts to develop new therapies for this condition have not been successful. Nitroxyl (HNO) plays a unique role in cardiovascular physiology by direct post‐translational modification of thiol residues on target proteins, specifically SERCA2a, phospholamban, the ryanodine receptor and myofilament proteins in cardiomyocytes. In animal models, these biological effects lead to vasodilatation, increased inotropy and lusitropy, but without tachyphylaxis, pro‐arrhythmia or evidence of increased myocardial oxygen demand. BMS‐986231 is an HNO donor being developed as a therapy for heart failure, and initial studies in patients with heart failure support the potential clinical value of these physiological effects. In this manuscript, we describe the ongoing phase II development programme for BMS‐986231, which consists of three related randomised placebo‐controlled clinical trials, StandUP‐AHF, StandUP‐Imaging and StandUP‐Kidney, which are designed to provide evidence of tolerability and efficacy as well as confirm the anticipated physiological effects in patients with heart failure with reduced ejection fraction. These studies will set the stage for the further study of BMS‐986231 in future phase III clinical trials.

Item Type:Articles
Additional Information:This work was supported by Bristol‐Myers Squibb (Princeton, NJ, USA).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cleland, Professor John and McMurray, Professor John
Authors: Felker, G. M., Borentain, M., Cleland, J. G.F., DeSouza, M. M., Kessler, P. D., O'Connor, C. M., Seiffert, D., Teerlink, J. R., Voors, A. A., and McMurray, J. J.V.
Subjects:R Medicine > R Medicine (General)
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Robertson Centre
Journal Name:European Journal of Heart Failure
Publisher:Wiley
ISSN:1388-9842
ISSN (Online):1879-0844
Published Online:06 June 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in European Journal of Heart Failure 21(8):1022-1031
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

University Staff: Request a correction | Enlighten Editors: Update this record