PRODUCT DEVELOPMENT

Relaxin

Relaxin is a naturally occurring polypeptide hormone (5963 Molecular Weight) that is believed to orchestrate many of the maternal physiological responses to pregnancy, including renal function, decreases in systemic vascular resistance, and increases in cardiac output, mediated largely by increased stroke volume. Consistent with its role during pregnancy, relaxin increases global arterial compliance as shown during non-clinical studies. In addition, relaxin results in systemic and renal vasodilation in non-clinical pharmacology models. Thus, due to its systemic and renal vasodilatory effects, relaxin is believed to be a strong candidate for the treatment of heart failure.

Along those lines, relaxin was shown to prevent and reverse the effects of two vasoconstrictors, angiotensin (Ang) II and endothelin in numerous non-clinical studies. These vasoconstrictors are important in the pathophysiology of acute decompensated heart failure (AHF). In rat studies, renal vasoconstriction induced by Ang II was reversed by infusion of relaxin, as measured by glomerular filtration rate (GFR) and renal blood flow (RBF). In addition, acute infusion of relaxin in rats also restored arterial compliance, cardiac output, and systemic vascular resistance which were dysregulated by infusion of Ang II.

Since relaxin is a strong candidate for treatment of heart failure, it was tested in a pilot, open label, dose ranging study in patients with compensated CHF. Relaxin administration resulted in decreases in pulmonary wedge pressure (PCWP) and systemic vascular resistance (SVR) and in increases in cardiac index (CI) during infusion, with a return to baseline values by 24 hour post dosing. Administration of relaxin also led to decreases in serum creatinine, BUN and uric acid which are consistent with its ability to increase GFR. These findings are promising and suggest that relaxin may be useful in the treatment of compensated CHF.

Until now, no clinical study has been conducted to investigate if relaxin administration would benefit humans who are afflicted with AHF. Since AHF is primarily a cardiorenal disease, its pathophysiology is complicated. The company has embarked on a global Phase 2/3 study designed to test relaxin for safety and efficacy in patients with AHF (http://clinicaltrials.gov). Multiple centers in the US, Israel, Russia, Italy, Poland, Hungary, Belgium, and Romania are participating in this study. Primary endpoints in the trial are signs and symptoms of heart failure and secondary outcomes related to renal function. Relaxin is believed to alleviate systemic and renal vasoconstriction in humans who are afflicted with AHF. Thus, the company’s development program is designed to provide information about the safety and efficacy of relaxin as a targeted vasodilator that achieves systemic vasodilation while providing renal protection. This constitutes a major advance in AHF treatment since it addresses two of the most important aspects of treating AHF–hemodynamic improvement and renal protection.