Windtree Therapeutics announces Phase 2b topline results of istaroxime

Windtree Therapeutics announced topline clinical results for its Phase 2b SEISMiC Extension Study of istaroxime in heart failure patients in early cardiogenic shock. Early cardiogenic shock is caused by a failing heart and is characterized by low blood pressure, leaving the patient at risk of developing inadequate blood flow to vital organs leading to high morbidity and mortality. Istaroxime is a novel first-in-class investigational therapy that is intended to improve systolic contraction and diastolic relaxation of the heart while also increasing blood pressure and maintaining renal function with a generally favorable safety profile. Istaroxime has been studied in four positive Phase 2 trials enrolling patients with acute heart failure and early cardiogenic shock due to heart failure. The Phase 2b SEISMiC Part B Extension Study in early cardiogenic shock randomized 30 subjects and was conducted in the United States, Europe and Latin America. The study is focused on istaroxime’s observed ability to correct low blood pressure and to improve cardiac function and other parameters over 96 hours of close monitoring with the final visit at 30 days. The results build upon the positive results reported previously in the Phase 2b SEISMiC Part A study. The Part B study included hospitalized patients with SCAI Stage B cardiogenic shock with persistent hypotension due to acute heart failure and evaluated two different dose regimens of istaroxime compared to placebo. Patients in the active treatment groups received infusions of istaroxime for up to 60 hours, with one group receiving a decreasing istaroxime dose over time and the second group receiving a constant istaroxime dose. The study tested an extended dosing duration of istaroxime compared to previous studies, where treatment was limited to 24 hours, to determine the potential for additional benefit and, along with dose titration, to determine the optimal dosing regimen for an anticipated late-stage Phase 3 clinical trial. For the primary endpoint evaluating blood pressure, subjects from Part A and Part B of SEISMiC were prospectively combined for analysis. In the analysis of Part B, all istaroxime-treated patients were compared to the placebo group. For certain endpoints in Part B, the dose-response between the two different istaroxime dose regimens was compared. The study met its primary endpoint in significantly improving systolic blood pressure over six hours, with the combined Part A and Part B SEISMiC istaroxime group performing significantly better compared to the placebo group. Despite the smaller number of patients in SEISMiC Part B, the SBP AUC was also significantly improved by istaroxime compared to placebo. The improvements in SBP AUC at 24 hours in the combined Part A and Part B analysis were also significantly increased by istaroxime. In Part B alone, the istaroxime group was significantly better compared to the placebo group. With the longer istaroxime dosing in Part B, the SBP AUC was significantly improved at 48 hours and 60 hours as well. SEISMiC Part B results: Cardiac output was improved during the infusion by approximately 15% in the istaroxime group over the course of treatment. Heart rate tended to decrease and there was no statistically significant increase in heart rate versus placebo in the istaroxime group. At 12 and 24 hours, patients in the istaroxime group experienced statistically significant reductions in heart rate. Increasing heart rate contributes to greater cardiac oxygen demand and workload, and therefore can lead to deleterious effects in heart failure patients. Pulmonary capillary wedge pressure is elevated in this patient population and also was elevated in our study subjects at baseline. Istaroxime treatment reduced PCWP significantly more than placebo within six hours and the effect persisted through 60 hours. PCWP is a measure of cardiac filling pressure and when high contributes to worsening heart failure and pulmonary edema. Mixed venous oxygen saturation, an assessment of organ perfusion, was significantly improved by 12 hours, and remained significant through 48 hours. The improvement versus placebo generally persisted through a 60-hour assessment. A low SVO2 can indicate that cardiac output is not high enough to meet the tissue oxygen needs. Renal function measured by estimated glomerular filtration rate was improved in this study in the istaroxime group compared to placebo at all time points reaching statistical significance at 48 hours. Clinical signs and symptoms of congestion and heart failure improved in both groups. The New York Heart Association classification of heart failure severity significantly decreased in the istaroxime group at 24 hours, 48 hours, and 72 hours and was similar to placebo at 96 hours. Worsening heart failure reported as a serious adverse event occurred less frequently in the istaroxime group compared to placebo 5.3% versus 18.2%, respectively. The istaroxime safety profile in Part B was favorable and generally consistent with what has been previously reported in other istaroxime clinical trials. Treatment-emergent adverse events were reported more frequently in the istaroxime group at 78.9% compared to 45.5% in the placebo group, predominantly due to nausea, vomiting, infusion site discomfort and headache that have been observed previously with istaroxime. Serious adverse events were infrequent and occurred at a similar frequency in both the istaroxime and placebo groups. Importantly, consistent with previous findings, istaroxime did not increase clinically significant arrythmias compared to the placebo group.