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

Published online

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Felker, GM; Borentain, M; Cleland, JG; DeSouza, MM; Kessler, PD; O'Connor, CM; Seiffert, D; Teerlink, JR; Voors, AA; McMurray, JJV

Published Date

  • June 6, 2019

Published In

PubMed ID

  • 31168885

Pubmed Central ID

  • 31168885

Electronic International Standard Serial Number (EISSN)

  • 1879-0844

Digital Object Identifier (DOI)

  • 10.1002/ejhf.1504

Language

  • eng

Conference Location

  • England