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

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

  • Eur J Heart Fail. 2019 Aug;21(8):1022-1031. doi: 10.1002/ejhf.1504.
G Michael Felker 1,  Maria Borentain 2,  John G Cleland 3 4,  Mary M DeSouza 2,  Paul D Kessler 2,  Christopher M O'Connor 5,  Dietmar Seiffert 2,  John R Teerlink 6,  Adriaan A Voors 7,  John J V McMurray 8
Affiliations

Affiliations

  • 1 Duke Clinical Research Institute (DCRI), Duke University School of Medicine, Durham, NC, USA.
  • 2 Bristol-Myers Squibb, Princeton, NJ, USA.
  • 3 Robertson Centre for Biostatistics & Clinical Trials, University of Glasgow, Glasgow, UK.
  • 4 National Heart & Lung Institute, Royal Brompton & Harefield Hospitals, Imperial College, London, UK.
  • 5 Inova Heart & Vascular Institute, Falls Church, VA, USA.
  • 6 San Francisco Veterans Affairs Medical Center and School of Medicine, University of California, San Francisco, San Francisco, CA, USA.
  • 7 University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
  • 8 Institute of Cardiovascular & Medical Sciences, University of Glasgow, Glasgow, UK.
PMID: 31168885 DOI: 10.1002/ejhf.1504
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.

Keywords

BMS-986231; Clinical trial design; HNO donor; Heart failure; Inotropy; Nitroxyl.

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