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TENX: New Indication for Levosimendan

04/12/2018
By John Vandermosten, CFA

NASDAQ:TENX

Levosimendan is a calcium sensitizer and K-ATP channel activator that can improve systolic and diastolic function of the heart as well as provide vasodilatory effects through its ability to relax vascular smooth muscle. This mechanism of action has been shown to lead to important improvements in cardiovascular hemodynamics in previous heart failure studies, including increased cardiac output and reduction in pulmonary capillary wedge pressure which could be very helpful in correcting the reduced cardiac output and pulmonary congestion often seen in PH-HFpEF patients. It is also important to note that Levosimendan has been shown to improve right heart function as well as reduce pulmonary vascular resistance in various patient populations. Improvement in right heart function and reductions in pulmonary vascular resistance could be particularly important to PH-HFpEF patients who often suffer from right heart dysfunction and elevated pulmonary vascular resistance. We believe existing studies provide a compelling rationale to pursue an indication for Levosimendan in PH-HFpEF which has shown potential in multiple unique hemodynamic benefits:

‣ Increased cardiac output,
‣ Reduced pulmonary capillary wedge pressure,
‣ Reduced pulmonary vascular resistance, and
‣ Improved right ventricular function


In addition to the multiple potential clinical benefits of listed above, the drug’s unique long-acting metabolite (half-life of 70-80 hours) allows for the convenience of intermittent, rather than continuous IV infusions that are required for approved IV PAH pulmonary hypertension therapies such as Remodulin and Flolan.

Pulmonary Hypertension associated with Heart Failure and Preserved Ejection Fraction (PH-HFpEF)

Pulmonary hypertension (PH) is high blood pressure in the arteries supplying the lung. PH is a condition where arterial blood pressure is elevated in the lungs and is frequently associated with severe heart and lung conditions.

It is defined as mean pulmonary arterial pressure (mPAP) above 25 mm Hg at rest, secondary to an elevation in pulmonary capillary wedge pressure (PCWP) of greater than or equal to 15 mm Hg. The condition is also defined by a diastolic pressure gradient, or difference between PAP and PCWP, of more than 7 mm Hg. Symptoms of the disease are shortness of breath, dizziness, fatigue, inability to exercise, chest pain, and a fast heartbeat among others. These signs arise due to insufficient oxygenated blood available in the body. PH is more common in females with 69% of the afflicted population suffering, compared to males at 31%.

There are five groups of PH, as classified by the World Health Organization. Group 1, due to the availability of treatment, is most well-known and is also called Pulmonary Arterial Hypertension (PAH); however, it is considered a rare disease. Group 2 is the most common, occurring in about half of all PH patients and is related to patients with left heart disease. Group 3 is PH related to chronic lung disease or conditions that cause hypoxemia. Group 4 results from the obstruction of the pulmonary vascular bed with chronic, organized thromboemboli. Group 5 PH is a heterogenous group that is brought about by several factors.




Group 2, or left heart disease PH, occurs in patients with both reduced ejection fraction and with preserved ejection fraction and valvular heart disease. It is thought to be the most common cause of pulmonary hypertension and is associated with high morbidity and mortality. Some research suggests that Group 2 PH may be caused by elevation in left heart pressure either with or without pulmonary arteriolar diseases. In this category, the left side of the heart is unable to pump sufficiently due to heart failure or valve dysfunction. Mitral valve disease may also contribute to Group 2 PH. However, pulmonary blood vessels are normal and undamaged. Group 2 PH is commonly found in patients with heart failure and may occur with or without normal ejection fraction.

Elderly patients may have a higher incidence of the disease as shown in a study where 56% of this group were associated with Group 2 PH. It is also associated with obesity and has a higher incidence in Western countries.

The subset of PH-HFpEF patients with right heart dysfunction may benefit from Levosimendan as the drug has been shown to improve right heart failure in various studies. Levosimendan’s inotropic and lusitropic effects may allow the right chamber of the heart to eject more volume to the pulmonary vasculature. In addition, opening of ATP-dependent potassium (K) channels in pulmonary vascular smooth muscle cells may further improve right heart function through reduced pulmonary vascular resistance. Below we provide an exhibit which illustrates the relationships between the mechanism of action and the heart.




In patients that are diagnosed with HFpEF, higher mortality is associated with PH supporting the need for a treatment. Some of the factors that contribute to poor mortality include increased pulmonary arterial wedge pressure as well as other pressures throughout the pulmonary vasculature.

Symptoms

The primary symptom of PH due to left heart disease (PH-LHD) is an elevated left atrial and pulmonary venous pressure. PH due to left ventricular (LV) systolic or diastolic dysfunction, valvular heart disease, and pulmonary vein stenosis are included in this group. PH due to left heart disease is the most common type of pulmonary hypertension, with more than one-half of those with heart failure thought to have HFpEF.

There are a variety of symptoms related to pulmonary hypertension and heart failure. Obvious signs and symptoms include shortness of breath after minimal physical activity, tiredness, chest pain and a racing heartbeat. This can progress to lightheadedness, fainting and swelling of legs and ankles. Insufficient gas exchange in the pulmonary arterioles may lead to a bluish color in the lips and skin. Upon further examination, other symptoms include pulmonary edema, right ventricle hypertrophy and orthopnea.

Diagnosis

A proper diagnosis of PH and by extension PH-HFpEF, requires catheterization; however, many times the diagnosis is made based on an echocardiogram, Doppler echocardiography or magnetic resonance imaging. A physician will first narrow down the likelihood of the condition with a physical exam and non-invasive diagnostic testing, then perform a right heart catheterization to accurately measure the pressure in pulmonary arteries and measure how well the heart is pumping blood.

Treatment

Currently there is no approved treatment for Group 2 PH, but supplemental oxygen may be given to alleviate symptoms. Some investigational work has also been done in endothelin 1 (ET1), nitric oxide (NO) and phosphodiesterase 5 inhibitors (PDE5Is). ET1 is a potent vasoconstrictor and antagonist therapies were thought to address Group 2 PH. However, several studies conducted failed to show efficacy and some serious adverse events were noted. NO shows some efficacy, but requires constant administration and may involve risk in wedge pressure due to unbalanced pulmonary vasodilation. PDE5Is (such as sildenafil) function by increasing cGMP levels. Early research indicated efficacy for the class for reducing pulmonary pressure in Group 2 PH. A one-year placebo controlled study showed that sildenafil improved life quality, reduced pulmonary artery, wedge and right atrial pressures and right ventricular end-diastolic pressure and dimension; however, larger subsequent studies failed to show a consistent response. PDE5Is have the benefit of relaxing pulmonary vessels and avoiding tachyphylaxis. PH-HFpEF represents an unmet need.

Levosimendan for PH-HFpEF

Levosimendan has several mechanisms that can potentially address the underlying reasons behind PH-HFpEF. The compound is both inotropic and lusitropic, which can alter the force of the heart and allow it to relax more completely. This allows more efficient pumping of blood. The drug also has a vasodilatory effect achieved by opening adenosine triphosphate (ATP)-sensitive potassium channels in vascular smooth muscle. There are a number of publications that have conducted preliminary work evaluating the safety and efficacy of Levosimendan in patients with PH which we discuss in greater depth in our full report.

Market Size

PH-HFpEF is an attractive indication as it addresses a large unmet need where mortality is up to 50% in the five years following diagnosis. A successful treatment could improve quality of life, as disease sufferers have difficulty exerting themselves. Further, there are no other treatments for WHO Group 2 PH, which can both allow for expedited development and approval of the drug as well as a strong competitive position in the market. PH is underdiagnosed, which suggests that the number of afflicted could be much larger than we estimate. The condition is found and quantified by employing echocardiography or right heart catheterization, which are infrequently used in the general population. Therefore, the condition is usually not detected until it has progressed to an advanced state and when the heart begins to fail. Due to the infrequent and onerous burden of performing these diagnostic tests, the condition is not widely diagnosed.

Conclusion

Tenax (NASDAQ:TENX) has identified a new indication in PH-HFpEF that is expected to benefit from Levosimendan’s mechanism of action and can be pursued with a reasonable cost and time commitment. The indication was also in an area with no other approved treatments. With a body of literature that supports Levosimendan’s use in PH-HFpEF, Tenax is meeting with the FDA under the existing IND to identify a successful trial design for the drug. Based on the evidence provided in studies cited and input from medical advisors and the scientific advisory board, we see a strong argument for pursuing this indication. Market size is material and with no other approved therapy available, pricing should be strong and penetration high.

Please refer to our full report for additional information and citations.

READ THE FULL RESEARCH REPORT HERE.

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