Background

BAY 60-4552 is a direct soluble guanylate cyclase (sGC) stimulator that acts independently of nitric oxide (NO). In preclinical studies BAY 60-4552 exhibited potent vasorelaxing properties and end-organ protective effects. Secondary pulmonary hypertension is a determinant of morbidity and mortality in patients with biventricular heart failure (bivHF). Weassumed that BAY 60-4552 would improve cardiopulmonary hemodynamics by restoring functionality of the NO/sGC/cGMP pathway and be well tolerated in patients with bivHF.

Methods

This study evaluated safety, tolerability and invasive hemodynamics of 1, 2.5, 5, 7.5 and 10 mg oral BAY 60-4552 in patients with bivHF (LVEF ≤ 45%, mean pulmonary artery pressure (mPAP) ≥ 25 mmHg, pulmonary capillary wedge pressure [PCWP] ≥ 18 mmHg).

Results

31 male and 11 female patients (65 ± 11 years; BMI 27.4 ± 4.4) were included. Mean hemodynamic parameters at baseline were PCWP: 23.9 ± 4.5 mmHg; right atrial pressure (RAP): 10.6 ± 4.3 mmHg; mPAP: 35.7 ± 8 mmHg; systolic blood pressure (SBP): 119.2 ± 17.4 mmHg; systemic vascular resistance (SVR): 1721 ± 534 dyn•s•cm-5; heart rate (HR): 70.6 ± 11.2 bpm; and cardiac index (CI): 1.99 ± 0.48 L/min/m2. Table 1 summarizes peak changes in invasive hemodynamics aftersingle dosesof 2.5, 7.5 and 10 mg. No relevant HR increase was observed. BAY 60-4552 was safe and well tolerated with mild adverse events (asymptomatic hypotension, n = 1; transient facial flushing, n = 5; mild headache, n = 4). Pharmakokinetic parameters were linear and mean elimination half-life ranged between 14 – 20 h.

Table 1 Changes in hemodynamic parameters
Full size table

Conclusion

In patients with bivHF, oral administration of BAY 60-4552 was well tolerated and mediated a potent vasodilation. Biventricular pre- and afterload were improved, which resulted in a significant increase in cardiac index. These first clinical results with an oral sGC stimulator in patients with bivHF demonstrate the potential of this new therapeutic principle.