Levosimendan Shows Benefits in 84% of Patients in Small PH-HFpEF Trial

Treatment with the investigational medication levosimendan was found to improve exercise tolerance, and some parameters related to heart function, in a small clinical trial of people with pulmonary hypertension and heart failure with preserved ejection fraction — a condition known as PH-HFpEF.

In fact, 84% of patients in the trial’s initial lead-in phase responded to levosimendan based on prespecified criteria, according to Tenax Therapeutics, the company developing levosimendan in North America.

“This is the first multi-center, randomized, placebo-controlled trial in PH-HFpEF patients to report a statistically significant improvement in 6-minute walk distance” in a test of aerobic capacity, Stuart Rich, chief medical officer at Tenax, said in a press release.

The effects of the medication were “impressive, especially in the first 24 hours,” said Daniel Burkhoff, MD, PhD, the study’s principal investigator.

“Levosimendan has the potential to have a major impact on the treatment of PH-HFpEF,” said Burkhoff, of the Cardiovascular Research Foundation.

The trial’s results were published in the Journal of American College of Cardiology: Heart Failure, in a study titled “Levosimendan Improves Hemodynamics and Exercise Tolerance in PH-HFpEF: Results of the Randomized Placebo-Controlled HELP Trial.” The study was funded by Tenax.

PH-HFpEF is a type of pulmonary hypertension in which the heart beats normally, but the heart muscles are too weak to properly pump blood. Currently, there are no approved therapies for this disease.

Originally developed to treat acute heart failure, levosimendan is a calcium sensitizer and potassium channel activator that has several effects on the body that could be beneficial in PH-HFpEF, according to investigators. Specifically, levosimendan can improve heart muscle contractions and widen blood vessels to enhance blood flow.

Now, researchers from Tenax and other institutions reported on the results of a double-blind Phase 2 trial called HELP (NCT03541603), which was completed last year.

HELP, which enrolled 44 people with PH-HFpEF, was conducted in two parts. In the first, participants underwent a 24-hour treatment with levosimendan and then were assessed to determine whether they had “responded” to the therapy. Such a response was defined by improvement on certain heart health parameters.

Those who “responded” had to have a reduction of at least 4 mmHg in their pulmonary capillary wedge pressure, or PCWP — a measure of pressure on the left side of the heart — during exercise, while laying down, and undergoing standard right heart catheterization. Of note, right heart catheterization is a common approach to assess how well the heart is pumping and to measure blood pressure in the heart and lungs.

Among the 44 participants, 37 (84%) were considered responders, and progressed to the next part of the trial.

“The fact that 84% of the patients enrolled in the initial lead-in phase had a significant hemodynamic [blood flow] response at rest and with exercise during cardiac catheterization provides confidence that levosimendan may be an important treatment for these patients who have a large unmet need,” Rich said.

In the trial’s second part, which took six weeks, the responders were randomly assigned to receive either levosimendan or a placebo, given via weekly 24-hour infusions. After this treatment period, the participants underwent a battery of assessments, and results were compared with findings from before treatment.

The trial’s main goal was to determine whether levosimendan treatment reduced PCWP during exercise, relative to the placebo. Although exercise-PCWP measurements were generally lower among levosimendan-treated participants than those given the placebo, the difference was not statistically significant — meaning that, mathematically, there is a considerable likelihood the results could be due to random chance.

However, additional analyses that accounted for data from the start of the study (before treatment), as well as various PCWP measurements taken in different positions, revealed a statistically significant effect of levosimendan, amounting to an average reduction of 3.9 mm Hg.

“Although levosimendan treatment for 6 weeks did not significantly lower exercise PCWP, it showed effects at rest and with legs raised,” the researchers wrote.

The trial also evaluated exercise capacity using the six-minute walk test (6MWT). As its name suggests, this test measures how far a person can walk in six minutes and is used to assess aerobic activity.

Over the course of the trial, 6MWT increased by an average of 16.6 m (about 55 feet) in the levosimendan group. In contrast, in the placebo group, 6MWT decreased by an average of 12.7 m (about 42 feet). The difference between groups was statistically significant.

According to Rich, this is the first trial involving PH-HFpEF patients to report such statistically significant improvements.

Other efficacy measurements generally did not reveal a statistically significant difference between the levosimendan and placebo groups.

Levosimendan was generally well-tolerated. The occurrence of adverse events (side effects) was similar between the levosimendan and placebo groups. Six were serious, including heart failure and infection, and occurred in four participants (three on levosimendan and one on placebo).

Limitations of this study include the small number of participants. Additionally, since this was the first trial to test chronic levosimendan in PH-HFpEF, a relatively low dose of the medication was used “out of an abundance of caution,” the scientists wrote.

Collectively, the findings from the HELP trial “justify further study of levosimendan in PH-HFpEF, a population without any approved therapy,” the researchers concluded.