Enrollment has begun in Phase 3 trial of oral levosimendan

LEVEL is recruiting up to 152 adults with PH-HFpEF in the US

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A Phase 3 trial of an oral formulation of levosimendan, dubbed TNX-103, in people with pulmonary hypertension and heart failure with preserved ejection fraction (PH-HFpEF), has enrolled the first participant.

LEVEL (NCT05983250) is recruiting up to 152 adults with PH-HFpEF, ages 18-85, at three U.S. sites. LEVEL stands for LEVosimendan to Improve Exercise Limitation in PH-HFpEF Patients. TNX-103 is being developed by Tenax Therapeutics.

“We are pleased to announce the enrollment of our first patient in the Phase 3 LEVEL study and delighted we are progressing rapidly from identification to initiation of investigator sites,” Chris Giordano, president and CEO of Tenax, said in a company press release. “Our study is generating enthusiasm among North American cardiologists who treat PH-HFpEF.”

TNX-103 will be compared to a placebo and given at a dose of 2 mg/day for weeks 1 to 4 and 3 mg/day for weeks 5 to 12. The study’s primary outcome measure is six-minute walk distance, which assesses exercise capacity. All the participants will be able to enter a nearly two-year open-label extension.

According to Tenax, the U.S. Food and Drug Administration (FDA) is not requiring a long-term study of TNX-103 in this population, significantly reducing costs and time. LEVEL is the first of two planned Phase 3 trials of TNX-103 for PH-HFpEF.

“We are thrilled to be working with some of the largest, most prestigious cardiovascular research institutes in North America, if not the world,” said Stuart Rich, MD, chief medical officer of Tenax. “Nine of the 10 investigators who randomized patients in our previous levosimendan study – at sites like Mayo, Harvard, Northwestern – have agreed to enroll patients in LEVEL. This reflects a growing interest among these academic medical experts in the novel mechanism of action of levosimendan, and a new approach to this disease.”

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 Patented solution to PH-HFpEF

Tenax this week received a notice of allowance from the U.S. Patent and Trademark Office (USPTO) for a patent to cover  TNX-103 and two other levosimendan formulations in PH-HFpEF.

This means the USPTO has given the green light to patent “Levosimendan for treating pulmonary hypertension and heart failure with preserved ejection fraction (PH-HFpEF).” If issued, the patent would be valid through 2040, unless extended beyond that date.

The patent covers a range of doses of levosimendan given by mouth (TNX-103), into a vein (TNX-101), or by injection under the skin (TNX-102), as well as its active metabolites, alone or with a number of cardiovascular drugs to treat heart and blood vessel diseases.

“Today’s patent news adds to the excitement generated by the recent initiation of investigative sites for our Phase 3 LEVEL study,” Giordano said in a separate press release.

PH-HFpEF occurs when the heart muscle is too stiff to relax properly and the left side of the heart fails to keep up with the blood returning from the lungs, even if the amount of blood pumped out with each heartbeat is within the normal range.

The disease is more common than doctors once thought, according to Rich. It’s estimated that by 2030, about 2 million North Americans will have PH-HFpEF. No medications are approved for the disease, however.

“With no drugs yet approved for PH-HFpEF, levosimendan has already demonstrated its unique mechanism of action,” Rich said. Levosimendan activates a potassium channel that controls the ability of blood vessels to relax as needed, which should lower blood pressure.

“Its use in combination with other cardiovascular drugs, and via multiple routes of administration, affords Tenax the opportunity to evaluate the clinical utility of levosimendan in other related areas of cardiovascular disease,” Rich said.

Tenax was granted two patents last year that cover its intravenous (into-the-vein) and oral formulations of levosimendan for PH-HFpEF. Both are set to provide intellectual property protection through 2040.

In HELP (NCT03541603), a Phase 2 clinical study that tested the intravenous formulation against a placebo in 38 adults with PH-HFpEF, weekly infusions of levosimendan reduced pressure on the left heart and improved exercise capacity.

Data from an open-label extension to HELP showed that switching from intravenous to once-daily oral levosimendan was well tolerated and further improved exercise capacity. These findings formed the basis for launching LEVEL. 

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