Intravenous Infusion of the Novel HNO Donor BMS-986231 Is Associated With Beneficial Inotropic, Lusitropic, and Vasodilatory Properties in 2 Canine Models of Heart Failure

Hartman, J. Craig; Río, Carlos del; Reardon, John E.; Zhang, Kefei; Sabbah, Hani N.

doi:10.1016/j.jacbts.2018.07.003

Cited by 15 publications

(18 citation statements)

References 28 publications

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“…Nitroxyl donors release HNO via chemical breakdown upon exposure to the physiological aqueous environment. In large animal models of HF, HNO donors directly enhance both contractility and relaxation and reduce both preload and afterload . Despite reliable augmentation of inotropy and lusitropy in these models, HNO donors do not increase heart rate or myocardial oxygen consumption, nor do they result in QT prolongation .…”

Section: Rationale For Nitroxyl Therapy In Heart Failurementioning

confidence: 98%

“…In large animal models of HF, HNO donors directly enhance both contractility and relaxation and reduce both preload and afterload . Despite reliable augmentation of inotropy and lusitropy in these models, HNO donors do not increase heart rate or myocardial oxygen consumption, nor do they result in QT prolongation . This combination of physiological effects makes HNO donors potentially attractive therapeutic candidates in HF.…”

Section: Rationale For Nitroxyl Therapy In Heart Failurementioning

confidence: 99%

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

Felker

Borentain

Cleland

et al. 2019

European J of Heart Fail

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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.

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Section: Rationale For Nitroxyl Therapy In Heart Failurementioning

confidence: 98%

Section: Rationale For Nitroxyl Therapy In Heart Failurementioning

confidence: 99%

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

Felker

Borentain

Cleland

et al. 2019

European J of Heart Fail

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“…BMS‐986231 is a novel HNO donor that induces positive inotropy and lusitropy, along with vasodilatory effects, through mechanisms distinct from any currently available HF therapies . Animal HF models have demonstrated that BMS‐986231 reduces peripheral resistance and enhances cardiac contractility without increasing myocardial oxygen consumption, heart rate, or risk of arrhythmias …”

Section: Discussionmentioning

confidence: 99%

“…BMS‐986231 (formerly CXL‐1427), a novel second‐generation HNO donor, delivers HNO via pH‐dependent chemical breakdown when exposed to the neutral pH environment of the bloodstream. Increasing BMS‐986231 dose infusions in dogs with induced cardiomyopathy resulted in reductions in mean arterial pressure, systemic vascular resistance, Tau, and the end‐diastolic pressure volume relationship; increased left ventricular ejection fraction/fractional area shortening, end‐systolic pressure volume, and preload‐recruitable stroke work relationship parameters were also noted . These findings suggest that BMS‐986231 possesses positive lusitropic and inotropic as well as vasodilatory effects.…”

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confidence: 81%

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A Phase 1 Randomized Study of Single Intravenous Infusions of the Novel Nitroxyl Donor BMS‐986231 in Healthy Volunteers

Cowart

Venuti

Lynch³

et al. 2019

The Journal of Clinical Pharma

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Nitroxyl (HNO) is a reactive nitrogen molecule that has potential therapeutic benefits for patients with acute heart failure. The results of the first‐in‐human study for BMS‐986231, a novel HNO donor, are reported. The aim of this sequential cohort study was to evaluate the safety, tolerability, and pharmacokinetic profile of BMS‐986231 after 24‐ and 48‐hour intravenous infusions in healthy volunteers. Eighty subjects were randomized and dosed. Seven cohorts (stratum A) received BMS‐986231 0.1, 0.33, 1, 3, 5, 10, and 15 μg/kg/min or placebo, infused over 24 hours. An additional cohort (stratum B) received 10 μg/kg/min or placebo, infused over 48 hours. Adverse events (AEs) were reported for 30 days after completion of infusion. Blood/urine samples were collected at regular intervals; other parameters (blood pressure, heart rate/rhythm, cardiac index) were also assessed. Headaches were the most commonly reported drug‐related AE (48%) in those who received BMS‐986231, although their severity was reduced by hydration. No other significant drug‐related AEs were noted. BMS‐986231 was associated with dose‐dependent and well‐tolerated reductions in systolic and diastolic blood pressure versus baseline; cardiac index, as measured noninvasively, was increased. BMS‐986231 had no clinically significant effect on heart rate/rhythm or laboratory parameters. Its mean elimination half‐life was 0.7‐2.5 hours. BMS‐986231 was safe and well‐tolerated for up to 24 hours (15 μg/kg/min) or 48 hours (10 μg/kg/min), with a favorable hemodynamic profile observed. Ongoing studies continue to evaluate the potential benefit of BMS‐986231 in patients with acute heart failure.

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The multifaceted mechanisms of nitroxyl in heart failure: inodilator or ‘only’ vasodilator?

Tocchetti

Mercurio

Maack

2021

European J of Heart Fail

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Intravenous Infusion of the Novel HNO Donor BMS-986231 Is Associated With Beneficial Inotropic, Lusitropic, and Vasodilatory Properties in 2 Canine Models of Heart Failure

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Cited by 15 publications

References 28 publications

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

A Phase 1 Randomized Study of Single Intravenous Infusions of the Novel Nitroxyl Donor BMS‐986231 in Healthy Volunteers

The multifaceted mechanisms of nitroxyl in heart failure: inodilator or ‘only’ vasodilator?

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