Levosimendan's long story took a new turn with results from a phase II trial testing chronic administration of the calcium sensitizer in patients with pulmonary hypertension associated with heart failure and preserved ejection fraction (PH-HFpEF). The trial, aimed at defining a potential development pathway to pursue in phase III and beyond, achieved that goal, with top-line data demonstrating a significant reduction in right atrial and pulmonary capillary wedge pressures in a significant improvement with six-minute walk distance, said developer Tenax Therapeutics Inc.
Tenax shares (NASDAQ:TENX) rose 13% to close June 2 at $1.64.
PH-HFpEF is a common form of pulmonary hypertension with an estimated U.S. prevalence exceeding 1.5 million patients, the company said. No pharmacologic therapies are approved for treatment of PH-HFpEF. Despite the fact that many therapies have been studied in PH-HFpEF patients, including therapies approved to treat pulmonary arterial hypertension (PAH), no therapies have been shown to be effective in treating PH-HFpEF patients.
"This is a complex disease, and the study was a complex study," said Stuart Rich, a professor of medicine at the Bluhm Cardiovascular Institute at Northwestern University, who led the study, which aimed to make an acute assessment of the efficacy of levosimendan (levo) in PH-HFpEF patients.
The trial started with an open-label lead-in phase during which participants who came to the medical center serving as the trial site had a right ventricle heart catheterization performed at rest and during exercise. They were then admitted overnight to the hospital, where they received a 24-hour infusion of levosimendan. The following day, they returned to the catheterization lab to repeat the process. Of 37 patients enrolled, 36 were randomized to either levosimendan or placebo, to be infused via PICC line over 24 hours once per week, starting at a dose of 0.075 micrograms per kilogram per minute. At week four, the dose was then increased to 0.1 micrograms before patients returned to the medical center for another right heart catheterization at rest and with exercise.
Among participants enrolled in the study, baseline pulmonary capillary wedge pressure (PCWP) with exercise, which provides an indirect estimate of left atrial pressure, was about 35 mmHg vs. a more normal 12 mm to 15 mmHg, a range that "really represents how sick these patients were," Rich said.
PCWP change during exercise served as the primary endpoint of the study, a measure chosen because it was the hemodynamic characteristic thought to best capture the impact of levosimendan. "If your wedge pressure goes up when you exercise, it's like putting your head underwater. You just can't breathe, and you can't do anything," Rich said.
While there was a small decrease in PCWP during the exercise portion of the study of 1.9 mm with levosimendan vs. 0.5 mm with placebo, it was not statistically significant.
However, a secondary endpoint, a six-minute walk test (6MWT), showed greater effect for levo. Patients in the levo arm saw a statistically significant improvement in 6MWT distance of 29 meters. (p=0.0329), the company reported. The typical change in 6MWT in all of the pulmonary hypertension trials has been a difference of about 10% and that is right about at the 10% mark, Rich said, making it comparable to the success of PAH trial with pulmonary vasodilator therapies.
"We chose six-minute walk because this has been the primary endpoint of virtually all the pulmonary hypertension trials," Rich said.
The rates of adverse events or severe adverse events between the control and treated groups were similar, Tenax reported. With those safety data in hand, which Tenax CEO Anthony DiTonno said he expects will be "very comforting to the FDA," and the encouraging 6MWT data, the Morrisville, N.C.-based company now has "a very strong clue" about how to best power a trial appropriately to detect the difference that we would expect to see," he said.
Levosimendan, a drug that was initially developed for I.V. use for the short-term I.V. treatment of hospitalized patients with acutely decompensated heart failure, was discovered and developed by Orion Corp., of Espoo, Finland, in collaboration with Abbott (now Abbvie Inc.). It's currently approved in more than 60 countries for that indication in situations where conventional therapy is not sufficient, and in cases where inotropic support is considered appropriate.
Tenax acquired North American rights to develop and commercialize levosimendan from Phyxius Pharma Inc. However, advancement of the drug by Tenax (formerly Oxygen Biotherapeutics Inc.) has encountered significant barriers in the U.S., where efforts to win regulatory support for its use in patients with coronary artery bypass grafting and low cardiac output syndrome have fallen flat.
As it moves ahead toward a potential registrational trial in PH-HFpEF, DiTonno said his team would continue to analyze the results of the phase II study on the way to an end-of-phase II meeting with the FDA.