‘Very Important’ Mechanism of Action Discovered for Levosimendan

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by Marisa Wexler MS |

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Levosimendan, an investigational treatment for pulmonary hypertension and heart failure with preserved ejection fraction, or PH-HFpEF — which showed positive results in a recent clinical trial — may work by reducing the amount of blood putting pressure on the walls of blood vessels, a new analysis suggests.

The findings were published in the Journal of Cardiac Failure, in a study titled “Changes in Stressed Blood Volume with Levosimendan in Pulmonary Hypertension from Heart Failure with Preserved Ejection Fraction: Insights Regarding Mechanism of Action From the HELP Trial.”

“This publication shares new, and very important mechanistic knowledge about the effects of levosimendan in PH-HFpEF patients,” Chris Giordano, CEO of Tenax Therapeutics, said in a press release. Tenax is developing levosimendan in North America and sponsored the now-completed Phase 2 HELP trial (NCT03541603).

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PH-HFpEF is a form of pulmonary hypertension in which the heart beats normally, but is too stiff to fill properly during the diastolic (filling) phase.

“There are currently no approved therapies for these patients,” Giordano said.

Originally developed to treat heart failure, levosimendan is an investigational medication that is pleiotropic — that is, it simultaneously affects several different systems within the body in varying ways. Levosimendan was tested in 44 PH-HFpEF patients across 16 study sites in HELP.

Results from HELP were published earlier this year, and showed that the medication improved exercise tolerance, as well as measurements related to heart function. In the study’s initial phase, 84% of participants were responders, meaning they experienced a meaningful decrease in pressure on the left side of the heart.

In the new analysis, researchers from several academic institutions examined patient data from HELP in an effort to better understand the mechanism by which levosimendan achieved its effect. Of note, while none of the study authors were employees of Tenax, several disclosed receiving funding or consulting fees from the company.

From their investigations, the scientists were able to rule out certain potential mechanisms of action. For example, there were no treatment-associated changes in how fast participants’ hearts were beating, or how much blood they were pumping. That means the medication was not working by improving the heart’s function, the scientists said.

They similarly determined that it also wasn’t altering the resistance to blood flow from the pulmonary artery to the heart’s left atrium, nor was it impacting the participants’ total blood volume — which, as its name suggests, is the amount of blood in a person’s body.

However, the researchers found that treatment was associated with decreases in stressed blood volume, or SBV. SBV basically is a measure of the quantity of blood that is pushing on the body’s blood vessels.

Like any closed container, the body’s circulatory system can hold a certain amount of liquid before it reaches the point where it exerts force on the vessel walls — think of how a person can breathe a small amount of air into a balloon, but the balloon does not yet start expanding from the pressure of the air inside of it. That’s the unstressed volume. SBV, then, is all the additional volume on top of that.

After the double-blind portion of the HELP trial, in which participants who responded to treatment were randomly assigned to either levosimendan or a placebo for six weeks, those on the active medication had a significantly larger decrease in estimated SBV (366.7 mL vs. 144.7 mL).

Since levosimendan was causing a decrease in SBV — but not total blood volume — the researchers reasoned that the most likely explanation is that the medication was widening blood vessels in the abdomen, called the splanchnic blood vessels. This widening essentially increased the amount of liquid the entire circulatory system can hold (the unstressed volume), thereby decreasing the SBV.

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“Levosimendan is now the first drug ever to demonstrate dilatation of the splanchnic blood vessels,” according to Stuart Rich, MD, Tenax’s chief medical officer.

“As a result, it now is the only medication shown to improve exercise capacity in PH-HFpEF as well,” Rich added.

The researchers postulated that levosimendan probably achieved this effect by activating proteins called ATP-dependent potassium channels. This effect has previously been demonstrated in preclinical experiments.

“To the best of our knowledge, these data from the HELP study provide the first in vivo [in-the-body] clinical evidence supporting this hypothesis,” the researchers wrote.

“Levosimendan has been acknowledged for years to be a pleiotropic drug with vasodilatory properties,” Giordano said. “This explanation of its impact on splanchnic venous capacity, in the light of the HELP primary analysis that showed levosimendan improves significantly patients’ 6-minute walk distance [exercise tolerance], provides further evidence that levosimendan is a novel therapy with the potential to provide important benefits to PH-HFpEF patients.”

Tenax said it expects to launch a Phase III study of levosimendan in this patient population in the first half of 2022.