Istaroxime and Heart Failure Portfolio


Heart failure represents a large market with substantial unmet medical needs. The clinical and pharmacoeconomic burden is pronounced and the demand for alternative therapies is very significant.

The challenge of treating heart failure (HF) is well reported from several sources:

  • One-to-two percent of the adult population have HF, including more than ten percent of all adults over the age of 65. The prevalence of HF is on the rise due, in part, to an aging population and increasing rates of diabetes and hypertension(1)
  • HF is the #1 cause of hospitalizations in the United States with greater than one million admissions annually and the top reason for readmissions in patients over 65 years old. Inpatient mortality is seven percent, whereas 30-day mortality exceeds ten percent and reaches 30 percent at 90 days(2)
  • HF carries a significant rate of morbidity and mortality. In fact, about half of people who develop HF die within five years of diagnosis(3)
  • HF has a tremendous pharmacoeconomic cost. Estimates place the economic burden at $35B annually in the U.S. alone, with over half being direct hospital cost for acute treatment(4)
  • Heart failure is the most expensive of the Medicare diagnoses in the United States and yet, reimbursement often does not keep up with the mean total hospital charges, with the average American hospital losing money on each patient visit(5)
  • HF has a heterogeneous etiology and exists in different phenotypes and is associated with a range of comorbidities

The Heart Failure Condition: Challenges and Need for Improved Therapeutics

Heart failure is a chronic, progressive condition in which the heart muscle is unable to pump enough blood to meet the body’s needs for blood and oxygen. At first the heart tries to make up for this by stretching to contract more strongly and keep up with the demand to pump more blood. Over time this often causes the heart to become enlarged and develop more muscle mass. This lets the heart pump more strongly, at least initially. The heart also often pumps faster. This increased heart rate helps increase the heart’s output. Heart failure continues and worsens until these compensating processes no longer work. Patients will often have episodic periods of crisis called acute decompensated heart failure where the heart’s failure to adequately pump results in pulmonary and peripheral edema and other acute and often severe complications.

Patients presenting with acute decompensated heart failure are often complex and difficult to manage. Many patients have a history of arrythmias and issues with heart pacing. The Acute Decompensated Heart Failure National Registry (ADHERE) tracked over 104,000 patients and found 38 percent presented with low or below normal systolic blood pressure and in these patients, who have hypotension or evidence of inadequate organ perfusion, therapeutic options to increase myocardial performance are limited. Another group of challenging patients are those with preserved ejection fraction (HFpEF) also referred to as diastolic heart failure, where the heart muscle contracts normally, but the ventricles do not relax as they should during ventricular filling (or when the ventricles relax). The proportion of HFpEF among all heart failure cases lies somewhere between 44 percent and 72 percent, with a suggestion of a temporal increase in the proportion of HFPEF cases in recent years. (6)

Therapies including vasodilators, inhibitors of the neurohumoral imbalances of heart failure (angiotensin/renin/aldosterone), beta blockers and diuretics are improving care of chronic HF in the outpatient setting, but effective treatments for acute, decompensated HF are lacking. Patients who experience acute heart failure are generally placed on a strong diuretic such as furosemide. To augment cardiac output, physicians will use a drug class called inotropes to increase cardiac output and improve physiological parameters, however, these short-term improvements have not resulted in improved clinical outcomes. On the contrary, the use of inotropes to directly target the ventricular dysfunction that characterizes HF has generally proven counterproductive. Many traditional agents increase mortality, principally by increasing sudden cardiac death(7). There are multiple reasons for this related to mechanism of action and clinical characteristics of the patients requiring inotropic support. While different therapies have different specific side effect profiles, these inotropes and others that have failed in development have been associated with a high rate of adverse events including arrhythmias, hypotension, worse clinical outcomes and in some settings an increased risk of death. Although these drugs increase the amount of blood pumped from the heart (or stroke volume), this seems to occur at the expense of increasing myocardial oxygen demand in an already compromised heart. In summary, current approaches to acutely improve cardiac function (inotropes) are associated with potential unwanted effects including:

• Heart rhythm disturbances
• Increased heart rate and myocardial oxygen demand
• Decreased blood pressure
• Potential damage to the heart muscle (increased troponin)
• Worsening renal function
• Mortality

Treatment is needed to improve cardiac function without causing other adverse clinical outcomes.

Istaroxime – A Novel Approach to Acute Heart Failure Treatments

Istaroxime is a first-in-class, dual action, luso-inotropic agent in clinical development for the treatment of acute decompensated heart failure. Istaroxime is an intravenously administered agent with a potent positive inotropic agent that increases myocardial contractility through inhibition of Na+/K+-ATPase. In addition, it facilitates myocardial relaxation through activation of the SERCA2a calcium pump on the sarcoplasmic reticulum and reduction in cytoplasmic calcium in order to increase fill and follow on stroke volume.

Based on its clinical findings to date, Istaroxime has demonstrated the potential to deliver the desired clinical effects in decompensated heart failure without the deleterious effects of increased heart rate, increased risk of arrhythmia, hypotension or increased oxygen consumption and myocardial damage

Istaroxime has been studied in two phase 2 clinical trials to date. A phase 2a trial called the HORIZON study was completed in 120 patients studying three doses of Istaroxime and produced statistically significant (p<0.05) improvements of the primary endpoint measuring lowering of pulmonary capillary wedge pressure (PCWP) by all three doses of istaroxime and positive trending on secondary hemodynamic endpoints improvements, measuring increased systolic blood pressure and decreasing heart rate as well. The main side effects were vomiting (7.9 percent) and pain at the infusion site when a short catheter was used (5.6 percent).

The favorable effects on PCWP, blood pressure and heart rate with potential luso-intropic effects provided the basis for the program to move forward into a phase 2b trial, which was successfully completed in 120 patients studying two doses vs. placebo with a longer infusion. The primary endpoint of cardiac function assessment using a non-invasive echocardiography utilizing a single, central reader measuring E/Ea ratio (reflecting changes in PCWP or left ventricular filing pressure), was significantly (p<0.05) improved by both doses of istaroxime. Stroke volume was substantially increased as well. As important as the efficacy assessments was the toxicities and complications that seemed to be avoided during istaroxime infusion, including no signals of increased arrhythmias, no signals of increased troponin levels (a marker of heart muscle damage). Additionally, heart rate was decreased, and blood pressure increased during the infusion. This study confirmed the physiologic improvements seen in the phase 2a study and replicates the effects of istaroxime in acute decompensated heart failure.

Windtree is working with top heart failure experts, as well as regulators in the U.S. and Europe to determine the next steps in clinical development in our pursuit of a potential new therapy for acute heart failure patients.

A Portfolio Approach Additional Heart Failure Pre-Clinical Programs

While istaroxime represents our most advanced heart failure program, Windtree also has follow on compounds in early development. These pre-clinical programs build upon our expertise with the SERCA2a mechanism and are also being developed as oral agents (with capabilities to be IV) and thus could potentially address the chronic heart failure (CHF) market as well. Together these represent a heart failure platform for increased potential opportunity.

Selective SERCA2a Activators
The selective SERCA2a Activators are devoid of any Na/K pump inhibitory activities. These compounds are intended to be oral (with IV possible) therapies for AHF and/or CHF.

Dual Mechanism SERCA2a Activators
Like istaroxime, these compounds are mixed mechanism of action as SERCA2a activators with Na/K pump inhibitory activities as well. These product candidates are intended to be oral and IV therapies for AHF and/or CHF and have patents starting in 2018.

Windtree is advancing all our heart failure programs and will be engaged in potential partnering and/or licensing discussions to foster development.


  1. American Heart Association and references in the 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure
  2. Abraham et al, In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications. An analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). Am J Cardiol 2005. 46:57-64
  3. Mozzafarian et al, 2016 Update: a report from the American Heart Association, Circulation. 2016; 133:e38-e360)
  4. Data from American Heart Association
  5. Peacock 2003; Ashish et al. 2004
  6. Hogg K, Swedberg K, McMurray J. Heart failure with preserved left ventricular systolic function; epidemiology, clinical characteristics, and prognosis. Journal of the American College of Cardiology. 2004;43:317–327.
  7. Samuel et al, Correcting calcium dysregulation in chronic heart failure using SERCA2a gene therapy 2018. Int J Mol Sci 19, 1086