Windtree Therapeutics (NASDAQ: WINT) Announces Positive Phase 2b Results For Istaroxime In Early Cardiogenic Shock Treatment

Windtree Therapeutics WINT has announced the results from the Phase 2b study of its lead drug candidate, istaroxime, in the treatment of cardiogenic shock due to heart failure. The data from the study will be instrumental in determining the optimal dosing regimen for a potential Phase 3 program. 

Cardiogenic Shock: A Critical Condition With An Unmet Need 

Cardiogenic shock is characterized by low blood pressure and inadequate blood flow to vital organs, accompanied by congestion and high filling pressures of the heart. The life-threatening condition has an alarming mortality rate of 20-30%, and survivors often face long-term complications.

Despite the severity of cardiogenic shock, there is an unmet need for a satisfactory drug treatment. Currently available drugs can have unwanted side effects such as arrhythmias, decreased blood pressure, renal dysfunction and even increases in mortality. There is a need for new innovative treatments that can be used to rapidly improve blood pressure and cardiac function without unwanted side effects.

In a market research study carried out on behalf of Windtree, 99 out of 100 cardiologists agreed that there is a need for new therapeutic options. Moreover, 84 said they would be likely to use istaroxime for early cardiogenic shock patients, while a majority indicated that istaroxime would be their first choice ahead of other available medications.

New Positive Phase 2b Study Results of Istaroxime in Early Cardiogenic Shock

The Phase 2b SEISMiC Part B Extension Study in early cardiogenic shock (SCAI Stage B) randomized 30 subjects and was conducted in the United States, Europe and Latin America (3 subjects have been discharged but have not completed their 30-day visit). 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.

Topline study results:

• The study met its primary endpoint in significantly improving systolic blood pressure over six hours (SBP AUC), 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 (the amount of blood pumped by the heart per minute) 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 (PCWP) 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 (SVO2), an assessment of organ perfusion, was significantly improved by 12 hours (mean difference of the istaroxime group compared to placebo was approximately 9% 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 (eGFR) 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 (NYHA) 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. 

Alexandre Mebazaa. MD, PhD, FESC (Université Paris Cité, France), Professor of Critical Care and heart failure expert, said, "Innovation with drug therapy is needed in cardiogenic shock treatment. Istaroxime has a unique profile. It may be the only drug candidate that has been shown to simultaneously improve blood pressure, cardiac output and renal function without increasing heart rate or risk for cardiac arrhythmias. These are all desirable attributes for a drug treating cardiogenic shock and acute heart failure." 

"We are very pleased with the results of this SEISMiC cardiogenic shock study. Through four positive Phase 2 studies in acute heart failure, with and without early cardiogenic shock, in over 300 patients treated with istaroxime to date, we have observed a unique and attractive profile," said Craig Fraser, CEO and Chairman of Windtree Therapeutics. "We are excited to pursue the next steps of development to potentially deliver an important therapy for patients that need better treatments for this critical condition."

Featured photo by Robina Weermeijer on Unsplash.

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