A Phase 1 Study of the Safety and Pharmacokinetics of the Intravenous Nitroxyl Prodrug, CXL-1427

Cowart, D.; Venuti, Robert P.; Guptill, Jeffrey T.; Noveck, Robert J.; Foo, ShiYin

doi:10.1016/s0735-1097(15)60876-2

Cited by 16 publications

(11 citation statements)

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“…It has low potential for drug–drug interactions at anticipated plasma concentrations. In euvolemic healthy volunteers, BMS‐986231 reduced blood pressure at escalating doses but did not cause symptomatic hypotension . BMS‐986231 was generally well tolerated, with the emergence of headache as a likely drug‐related adverse event at higher doses.…”

Section: Rationale For Nitroxyl Therapy In Heart Failurementioning

confidence: 94%

“…In euvolemic healthy volunteers, BMS-986231 reduced blood pressure at escalating doses but did not cause symptomatic hypotension. 20 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.…”

Section: Rationale For Nitroxyl Therapy In Heart Failurementioning

confidence: 96%

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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: 94%

Section: Rationale For Nitroxyl Therapy In Heart Failurementioning

confidence: 96%

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, formerly CXL‐1427, is a novel second‐generation HNO donor with a half‐life of approximately 40–144 min in healthy individuals . Preliminary Phase 1 study data for BMS‐986231 in healthy volunteers demonstrated that it was well tolerated up to a dose of 10 µg/kg/min for 48 h and produced dose‐dependent changes in haemodynamic parameters without affecting HR .…”

Section: Introductionmentioning

confidence: 99%

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

Gilbert

Bakel

et al. 2017

European J of Heart Fail

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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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“…[10] Early attempts at using Angelis salt (Na 2 N 2 O 3 )a nd other HNO donors in the clinic were hampered by short half-lives,poor pharmacokinetics,and byproducts. [12,13] HNO can be produced in vitro by enzymes such as nitric oxide synthase, [14] the reaction of S-nitrosoglutathione with glutathione, [15] and the reduction of NO by H 2 S, [16] thiols, [17] and other biological molecules. [12,13] HNO can be produced in vitro by enzymes such as nitric oxide synthase, [14] the reaction of S-nitrosoglutathione with glutathione, [15] and the reduction of NO by H 2 S, [16] thiols, [17] and other biological molecules.…”

mentioning

confidence: 99%

“…[11] Newer N-hydroxysulfonamide donors CXL-1020 and CXL-1427, however, have shown promise in clinical trials for treatment of congestive heart failure. [12,13] HNO can be produced in vitro by enzymes such as nitric oxide synthase, [14] the reaction of S-nitrosoglutathione with glutathione, [15] and the reduction of NO by H 2 S, [16] thiols, [17] and other biological molecules. [18] Intriguingly,c ellular generation of HNO from the reaction between H 2 Sa nd NO has been implicated in regulating vascular tone and blood flow through an HNO/ TRPA1/CGRP pathway.…”

mentioning

confidence: 99%

A Chemiluminescent Probe for HNO Quantification and Real‐Time Monitoring in Living Cells

Ryan

Reeves

et al. 2018

Angewandte Chemie

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Azanone (HNO) is ar eactive nitrogen species with pronounced biological activity and high therapeutic potential for cardiovascular dysfunction. Ac ritical barrier to understanding the biology of HNO and furthering clinical development is the quantification and real-time monitoring of its delivery in living systems.H erein, we describe the design and synthesis of the first chemiluminescent probe for HNO, HNOCL-1,w hich can detect HNO generated from concentrations of Angeliss alt as lowa s1 38 nm with high selectivity based on the reaction with ap hosphine group to form as elfcleavable azaylide intermediate.W eh ave capitalized on this high sensitivity to develop ag eneralizable kinetics-based approach,whichprovides real-time quantitative measurements of HNO concentration at the picomolar level. HNOCL-1 can monitor dynamics of HNO delivery in living cells and tissues, demonstrating the versatility of this method for tracking HNO in living systems.Azanone (HNO,n itroxyl), is chemically related to nitric oxide (NO) by the addition of one electron and one proton. HNO rapidly dimerizes and eliminates to form nitrous oxide (k = 8 10 6 m À1 s À1 at 23 8 8C) [1] and reacts with molecular oxygen with estimated rate constants that range from 10 3 to 10 4 m À1 s À1 (k = 3 10 3 m À1 s À1 at 37 8 8C; [2] k = 1 10 4 m À1 s À1 at 23 8 8C; [3] k = 1.8 10 4 m À1 s À1 at 25 8 8C [4,5] ). Tw omajor biological targets responsible for HNO bioactivity are thiols,which react directly with HNO to form sulfinamides (k = 2 10 6 m À1 s À1 at 37 8 8C) [2] and the iron in heme-containing proteins. [6] While both HNO and NO can activate soluble guanylyl cyclase,only HNO acts apositive cardiac inotrope by direct reaction with cysteine residues on cardiac ryanodine receptors and the sarcoplasmic reticulum Ca 2+

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A Phase 1 Study of the Safety and Pharmacokinetics of the Intravenous Nitroxyl Prodrug, CXL-1427

Cited by 16 publications

References 0 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 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

A Chemiluminescent Probe for HNO Quantification and Real‐Time Monitoring in Living Cells

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