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.

Keywords: BMS-986231; CXL-1427; Heart failure; Human; Nitroxyl.

Figure 1

CONSORT diagram. ^aOne patient in the placebo group was randomized and dosed, but was excluded from the modified intent‐to‐treat (mITT) analysis set because screening and baseline pulmonary capillary wedge pressure (<20 mmHg) was below the minimum required for inclusion, and thus was not eligible for study entry as acknowledged by the investigator and confirmed by the study medical monitor and dose‐escalation review committee. AE, adverse event; HF, heart failure; PK, pharmacokinetic.

Figure 2

(A) Time course of mean change and (B) mean time‐averaged change (to 6 h) from baseline over the course of infusion of BMS‐986231 or placebo in adjudicated pulmonary capillary wedge pressure (PCWP) on a modified intent‐to‐treat basis. SEM, standard error of the mean.

Figure 3

Mean time‐averaged change from baseline in adjudicated (A) pulmonary arterial diastolic pressure, (B) pulmonary arterial systolic pressure, and (C) right atrial pressure during infusion of BMS‐986231 or placebo on a modified intent‐to‐treat basis. SEM, standard error of the mean.

Figure 4

Mean time‐averaged change from baseline in (A) systolic blood pressure, (B) diastolic blood pressure, and (C) mean arterial pressure during infusion of BMS‐986231 or placebo on a modified intent‐to‐treat basis. SEM, standard error of the mean.