A Phase 2a dose-escalation study of the safety, tolerability, pharmacokinetics and haemodynamic effects of BMS-986231 in hospitalized patients with heart failure with reduced ejection fraction

Cristina Tita, Edward M. Gilbert, Adrian B. Van Bakel, Jacek Grzybowski, Garrie J. Haas, Mohammad Jarrah, Stephanie Hope Dunlap, Stephen S. Gottlieb, Marc Klapholz, Parag C. Patel, Roman Pfister, Tim Seidler, Keyur B. Shah, Tomasz Zieliński, Robert P. Venuti, Douglas Cowart, Shi Yin Foo, Alexander Vishnevsky, Veselin Mitrovic

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Aims: This study was designed to evaluate the safety, tolerability and haemodynamic effects of BMS-986231, a novel second-generation nitroxyl donor with potential inotropic, lusitropic and vasodilatory effects in patients hospitalized with decompensated heart failure and reduced ejection fraction (HFrEF). Methods and results: Forty-six patients hospitalized with decompensated HFrEF were enrolled into four sequential dose-escalation cohorts in this double-blind, randomized, placebo-controlled Phase 2a study. Patients with baseline pulmonary capillary wedge pressure (PCWP) of ≥20 mmHg and a cardiac index of ≤2.5 L/min/m2 received one 6-h i.v. infusion of BMS-986231 (at 3, 5, 7 or 12 µg/kg/min) or placebo. BMS-986231 produced rapid and sustained reductions in PCWP, as well as consistent reductions in time-averaged pulmonary arterial systolic pressure, pulmonary arterial diastolic pressure and right atrial pressure. BMS-986231 increased non-invasively measured time-averaged stroke volume index, cardiac index and cardiac power index values, and decreased total peripheral vascular resistance. There was no evidence of increased heart rate, drug-related arrhythmia or symptomatic hypotension with BMS-986231. Analyses of adverse events throughout the 30-day follow-up did not identify any toxicities specific to BMS-986231, with the potential exception of infrequent mild-to-moderate headaches during infusion. There were no treatment-related serious adverse events. Conclusions: BMS-986231 demonstrated a favourable safety and haemodynamic profile in patients hospitalized with advanced heart failure. Based on preclinical data and these study's findings, it is possible that the haemodynamic benefits may be mediated by inotropic and/or lusitropic as well as vasodilatory effects. The therapeutic potential of BMS-986231 should be further assessed in patients with heart failure.

Original languageEnglish (US)
Pages (from-to)1321-1332
Number of pages12
JournalEuropean Journal of Heart Failure
Volume19
Issue number10
DOIs
StatePublished - Oct 1 2017

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Heart Failure
Pharmacokinetics
Hemodynamics
Safety
Pulmonary Wedge Pressure
Vascular Resistance
Arterial Pressure
Placebos
Blood Pressure
Lung
Atrial Pressure
Stroke Volume
Hypotension
Headache
Cardiac Arrhythmias
Heart Rate
Tissue Donors
Therapeutics
Pharmaceutical Preparations

Keywords

  • BMS-986231
  • CXL-1427
  • Heart failure
  • Human
  • Nitroxyl

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

A Phase 2a dose-escalation study of the safety, tolerability, pharmacokinetics and haemodynamic effects of BMS-986231 in hospitalized patients with heart failure with reduced ejection fraction. / Tita, Cristina; Gilbert, Edward M.; Van Bakel, Adrian B.; Grzybowski, Jacek; Haas, Garrie J.; Jarrah, Mohammad; Dunlap, Stephanie Hope; Gottlieb, Stephen S.; Klapholz, Marc; Patel, Parag C.; Pfister, Roman; Seidler, Tim; Shah, Keyur B.; Zieliński, Tomasz; Venuti, Robert P.; Cowart, Douglas; Foo, Shi Yin; Vishnevsky, Alexander; Mitrovic, Veselin.

In: European Journal of Heart Failure, Vol. 19, No. 10, 01.10.2017, p. 1321-1332.

Research output: Contribution to journalArticle

Tita, C, Gilbert, EM, Van Bakel, AB, Grzybowski, J, Haas, GJ, Jarrah, M, Dunlap, SH, Gottlieb, SS, Klapholz, M, Patel, PC, Pfister, R, Seidler, T, Shah, KB, Zieliński, T, Venuti, RP, Cowart, D, Foo, SY, Vishnevsky, A & Mitrovic, V 2017, 'A Phase 2a dose-escalation study of the safety, tolerability, pharmacokinetics and haemodynamic effects of BMS-986231 in hospitalized patients with heart failure with reduced ejection fraction', European Journal of Heart Failure, vol. 19, no. 10, pp. 1321-1332. https://doi.org/10.1002/ejhf.897
Tita, Cristina ; Gilbert, Edward M. ; Van Bakel, Adrian B. ; Grzybowski, Jacek ; Haas, Garrie J. ; Jarrah, Mohammad ; Dunlap, Stephanie Hope ; Gottlieb, Stephen S. ; Klapholz, Marc ; Patel, Parag C. ; Pfister, Roman ; Seidler, Tim ; Shah, Keyur B. ; Zieliński, Tomasz ; Venuti, Robert P. ; Cowart, Douglas ; Foo, Shi Yin ; Vishnevsky, Alexander ; Mitrovic, Veselin. / A Phase 2a dose-escalation study of the safety, tolerability, pharmacokinetics and haemodynamic effects of BMS-986231 in hospitalized patients with heart failure with reduced ejection fraction. In: European Journal of Heart Failure. 2017 ; Vol. 19, No. 10. pp. 1321-1332.
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abstract = "Aims: This study was designed to evaluate the safety, tolerability and haemodynamic effects of BMS-986231, a novel second-generation nitroxyl donor with potential inotropic, lusitropic and vasodilatory effects in patients hospitalized with decompensated heart failure and reduced ejection fraction (HFrEF). Methods and results: Forty-six patients hospitalized with decompensated HFrEF were enrolled into four sequential dose-escalation cohorts in this double-blind, randomized, placebo-controlled Phase 2a study. Patients with baseline pulmonary capillary wedge pressure (PCWP) of ≥20 mmHg and a cardiac index of ≤2.5 L/min/m2 received one 6-h i.v. infusion of BMS-986231 (at 3, 5, 7 or 12 µg/kg/min) or placebo. BMS-986231 produced rapid and sustained reductions in PCWP, as well as consistent reductions in time-averaged pulmonary arterial systolic pressure, pulmonary arterial diastolic pressure and right atrial pressure. BMS-986231 increased non-invasively measured time-averaged stroke volume index, cardiac index and cardiac power index values, and decreased total peripheral vascular resistance. There was no evidence of increased heart rate, drug-related arrhythmia or symptomatic hypotension with BMS-986231. Analyses of adverse events throughout the 30-day follow-up did not identify any toxicities specific to BMS-986231, with the potential exception of infrequent mild-to-moderate headaches during infusion. There were no treatment-related serious adverse events. Conclusions: BMS-986231 demonstrated a favourable safety and haemodynamic profile in patients hospitalized with advanced heart failure. Based on preclinical data and these study's findings, it is possible that the haemodynamic benefits may be mediated by inotropic and/or lusitropic as well as vasodilatory effects. The therapeutic potential of BMS-986231 should be further assessed in patients with heart failure.",
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T1 - A Phase 2a dose-escalation study of the safety, tolerability, pharmacokinetics and haemodynamic effects of BMS-986231 in hospitalized patients with heart failure with reduced ejection fraction

AU - Tita, Cristina

AU - Gilbert, Edward M.

AU - Van Bakel, Adrian B.

AU - Grzybowski, Jacek

AU - Haas, Garrie J.

AU - Jarrah, Mohammad

AU - Dunlap, Stephanie Hope

AU - Gottlieb, Stephen S.

AU - Klapholz, Marc

AU - Patel, Parag C.

AU - Pfister, Roman

AU - Seidler, Tim

AU - Shah, Keyur B.

AU - Zieliński, Tomasz

AU - Venuti, Robert P.

AU - Cowart, Douglas

AU - Foo, Shi Yin

AU - Vishnevsky, Alexander

AU - Mitrovic, Veselin

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N2 - Aims: This study was designed to evaluate the safety, tolerability and haemodynamic effects of BMS-986231, a novel second-generation nitroxyl donor with potential inotropic, lusitropic and vasodilatory effects in patients hospitalized with decompensated heart failure and reduced ejection fraction (HFrEF). Methods and results: Forty-six patients hospitalized with decompensated HFrEF were enrolled into four sequential dose-escalation cohorts in this double-blind, randomized, placebo-controlled Phase 2a study. Patients with baseline pulmonary capillary wedge pressure (PCWP) of ≥20 mmHg and a cardiac index of ≤2.5 L/min/m2 received one 6-h i.v. infusion of BMS-986231 (at 3, 5, 7 or 12 µg/kg/min) or placebo. BMS-986231 produced rapid and sustained reductions in PCWP, as well as consistent reductions in time-averaged pulmonary arterial systolic pressure, pulmonary arterial diastolic pressure and right atrial pressure. BMS-986231 increased non-invasively measured time-averaged stroke volume index, cardiac index and cardiac power index values, and decreased total peripheral vascular resistance. There was no evidence of increased heart rate, drug-related arrhythmia or symptomatic hypotension with BMS-986231. Analyses of adverse events throughout the 30-day follow-up did not identify any toxicities specific to BMS-986231, with the potential exception of infrequent mild-to-moderate headaches during infusion. There were no treatment-related serious adverse events. Conclusions: BMS-986231 demonstrated a favourable safety and haemodynamic profile in patients hospitalized with advanced heart failure. Based on preclinical data and these study's findings, it is possible that the haemodynamic benefits may be mediated by inotropic and/or lusitropic as well as vasodilatory effects. The therapeutic potential of BMS-986231 should be further assessed in patients with heart failure.

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KW - CXL-1427

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KW - Human

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