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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT03016325.

Keywords: HNO donor; heart failure; humans; nitroxyl; pharmacokinetics; phase 1.

© 2019, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Subject flow. aAny other reason in the investigator's opinion that would make it inappropriate for the subject to participate. bThree subjects did not complete the infusion because of headache. cOne subject did not receive a full 24 hours of intravenous placebo infusion because of catheter displacement at approximately hour 21 (lost infusion time/volume unknown — see text). dOne subject withdrew consent during follow‐up. IV, intravenous.

Figure 2

Mean changes from baseline in systolic blood pressures over time. (A) Stratum A, 24‐hour infusion. (B) Stratum B, 48‐hour infusion. SBP ranges at baseline (active treatment): 103‐153 mm Hg (stratum A) and 112‐126 mm Hg (stratum B). Mean SBPs over time are shown in Supplementary Figure S2. SBP, systolic blood pressure.

Figure 3

Mean changes from baseline in heart rates over time. (A) Stratum A, 24‐hour infusion. (B) Stratum B, 48‐hour infusion. HR ranges at baseline (active treatment): 43‐98 bpm (stratum A) and 40‐59 bpm (stratum B). Mean HRs over time are shown in Figure S5. bpm, beats per minute; HR, heart rate.

Figure 4

Mean change from baseline in cardiac index over time (stratum A only).

Figure 5

Mean ± SD BMS‐986231 plasma concentration‐time profiles after intravenous administration. (A) Linear plot. (B) Log‐linear plot. SD, standard deviation.

Figure 6

Mean ± SD BMT‐284730 plasma concentration‐time profiles after intravenous administration of BMS‐986231. (A) Linear plot. (B) Log‐linear plot. SD, standard deviation.