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

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.

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

“…BMS‐986231 was generally well tolerated, with the emergence of headache as a likely drug‐related adverse event at higher doses. In a study of patients with HF and hypervolaemia, BMS‐986231 reduced blood pressure to a much lesser extent and headaches were infrequent during the infusion . In this early proof of concept study, a 6 h infusion of BMS‐986231 produced rapid and sustained decreases in intracardiac filling pressures and suggested improvements in non‐invasively measured cardiac index (by thermodilution but not by Fick) in 46 patients with advanced HF with reduced ejection fraction (HFrEF).…”

“…In a study of patients with HF and hypervolaemia, BMS-986231 reduced blood pressure to a much lesser extent and headaches were infrequent during the infusion. 21 In this early proof of concept study, a 6 h infusion of BMS-986231 produced rapid and sustained decreases in intracardiac filling pressures and suggested improvements in non-invasively measured cardiac index (by thermodilution but not by Fick) in 46 patients with advanced HF with reduced ejection fraction (HFrEF). There was also no increase in tachycardia, arrhythmia or symptomatic hypotension with BMS-986231 compared with placebo.…”

“…In this early proof of concept study, a 6 h infusion of BMS‐986231 produced rapid and sustained decreases in intracardiac filling pressures and suggested improvements in non‐invasively measured cardiac index (by thermodilution but not by Fick) in 46 patients with advanced HF with reduced ejection fraction (HFrEF). There was also no increase in tachycardia, arrhythmia or symptomatic hypotension with BMS‐986231 compared with placebo . However, BMS‐986231 was administered for a short duration and vasoactive medications, including IV or oral diuretics, were prohibited for ≥ 4 h prior to baseline haemodynamic assessment until completion of the 6 h infusion.…”

“…There was also no increase in tachycardia, arrhythmia or symptomatic hypotension with BMS-986231 compared with placebo. 21 However, BMS-986231 was administered for a short duration and vasoactive medications, including IV or oral diuretics, were prohibited for ≥ 4 h prior to baseline haemodynamic assessment until completion of the 6 h infusion.…”

Highlights in heart failure

“…246 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), was safe and had beneficial haemodynamic effects. 247 A major trial is ongoing. 248 Loop diuretics represent the first option for the treatment of congestion in acute HF and diuretic resistance is associated with poorer outcomes.…”