Haemodynamic effects, safety, and pharmacokinetics of human stresscopin in heart failure with reduced ejection fraction

• Published in: European journal of heart failure Vol. 15; no. 6; pp. 679 - 689
• Main Authors: Gheorghiade, Mihai, Greene, Stephen J., Ponikowski, Piotr, Maggioni, Aldo P., Korewicki, Jerzy, Macarie, Cezar, Metra, Marco, Grzybowski, Jacek, Bubenek-Turconi, Serban-Ion, Radziszewski, Waldemar, Olson, Allan, Bueno, Orlando F., Ghosh, Atalanta, Deckelbaum, Lawrence I., Li, Lilian Y., Patel, Ayan R., Koester, Andreas, Konstam, Marvin A.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-06-2013
• Subjects: Adult; Aged; Biomarkers - blood; Blood Pressure - drug effects; Cardiac Output - drug effects; Corticotropin-releasing factor type 2 receptor; Corticotropin-Releasing Hormone - pharmacokinetics; Corticotropin-Releasing Hormone - pharmacology; Dose-Response Relationship, Drug; Double-Blind Method; Female; Haemodynamics; Heart failure; Heart Failure - metabolism; Heart Rate - drug effects; Hemodynamics - drug effects; Human stresscopin; Humans; Infusions, Intravenous; Male; Middle Aged; Pharmacokinetics; Pulmonary Wedge Pressure - drug effects; Stroke Volume - physiology; Urocortins - pharmacokinetics; Urocortins - pharmacology; Heart failure; Haemodynamics; Corticotropin-releasing factor type 2 receptor; Pharmacokinetics; Human stresscopin
• ISSN: 1388-9842; 1879-0844
• DOI: 10.1093/eurjhf/hft023

Aims
Human stresscopin is a corticotropin‐releasing factor (CRF) type 2 receptor (CRFR2) selective agonist and a member of the CRF peptide family. Stimulation of CRFR2 improves cardiac output and left ventricular ejection fraction (LVEF) in patients with stable heart failure (HF) with reduced LVEF. We examined the safety, pharmacokinetics, and effects on haemodynamics and serum biomarkers of intravenous human stresscopin acetate (JNJ‐9588146) in patients with stable HF with LVEF ≤35% and cardiac index (CI) ≤2.5 L/min/m2.
Methods and results
Sixty‐two patients with HF and LVEF ≤35% were instrumented with a pulmonary artery catheter and randomly assigned (ratio 3:1) to receive an intravenous infusion of JNJ‐9588146 or placebo. The main study was an ascending dose study of three doses (5, 15, and 30 ng/kg/min) of study drug or placebo administered in sequential 1 h intervals (3 h total). Statistically significant increases in CI and reduction in systemic vascular resistance (SVR) were observed with both the 15 ng/kg/min (2 h time point) and 30 ng/kg/min (3 h time point) doses of JNJ‐9588146 without significant changes in heart rate (HR) or systolic blood pressure (SBP). No statistically significant reductions in pulmonary capillary wedge pressure (PCWP) were seen with any dose tested in the primary analysis, although a trend towards reduction was seen.
Conclusion
In HF patients with reduced LVEF and CI, ascending doses of JNJ‐9588146 were associated with progressive increases in CI and reductions in SVR without significant effects on PCWP, HR, or SBP.
Trial registration: NCT01120210