Nearly three decades after its failed bid for FDA approval, the cardiovascular drug levosimendan is still struggling to secure a decisive clinical win to enter the U.S. market.
In the latest chapter of the drug’s U.S. odyssey, Tenax Therapeutics reported that an oral version of levosimendan missed the primary endpoint of a phase 3 trial, leaving the biotech to rely on subgroup data to chart a narrow path forward with the FDA.
In the phase 3 Level trial, Tenax’s oral levosimendan, coded TNX-103, failed to outperform placebo in improving 6-minute walk distance in patients with pulmonary hypertension due to heart failure with preserved ejection fraction (PH-HFpEF), the company said Monday. The least-squares mean difference between the levosimendan group and the control arm was merely 3.5 meters, with a p-value of 0.63.
The key secondary endpoint, improvement in Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS), also returned negative, with a least-squares mean difference of 0.1 points.
Despite the flop, Tenax has zeroed in on a prespecified subgroup of patients with greater disease burden and plans to request a meeting with the FDA to discuss a path forward for TNX-103.
Specifically, among 119 patients who walked less than the trial median of 333 meters (about 1,093 feet) at baseline, levosimendan demonstrated an improvement of 26.3 meters versus placebo on the 6-minute walk test, with a nominal p-value of 0.0112. On average, patients on Tenax's drug improved by 26.7 meters, while those on placebo declined by 2.6 meters.
In an Aug. 10 statement, Tenax’s chief medical officer, Stuart Rich, M.D., called this finding “a strong result in a more characteristic HFpEF population that needs this therapy.”
The increase in walking distance was accompanied by a 49% decrease in a heart failure protein biomarker, NT-proBNP, and a reduction in right ventricular systolic pressure by 3.5 mmHg, compared to placebo.
According to the Level trial’s principal investigator, Sanjiv Shah, M.D., from Northwestern University, the 49% NT-proBNP reduction versus placebo is larger than any prior HFpEF trial.
“Taken together, these data support TNX-103’s substantial cardiovascular and pulmonary biologic effects on reducing the severity of disease in patients with pulmonary hypertension due to HFpEF,” Rich said.
“In my opinion, a drug that lowers wall stress and modifies cardiac structure and function this robustly is likely to be disease-modifying,” Shah said. “The improvement in exercise capacity was concentrated in patients with lower baseline walk distance and more advanced disease, which is consistent with a therapy that may improve long-term outcomes in those patients who need it most.”
Originally developed by Orion Pharma, levosimendan got its initial European approval in 2000 under the brand name Simdax, an intravenous infusion for treating acutely decompensated chronic heart failure. But the drug has a difficult clinical and regulatory past in the U.S.
In 1999, Orion withdrew its application with the FDA after the agency requested larger phase 3 outcome trials to support levosimendan’s case. Later, the phase 3 Revive II trial of 600 patients showed some short-term symptomatic improvement with the inodilator on top of standard therapy, but more deaths were recorded in the levosimendan arm at 90 days, along with higher rates of certain adverse events, such as hypotension, raising safety concerns.
In 2007, Abbott terminated its U.S. development efforts for the drug after the large-scale Survive trial of more than 1,300 patients, which compared levosimendan with dobutamine, failed to meet its primary endpoint of a statistically significant reduction in 180-day all-cause mortality. At the time, Abbott concluded that conducting additional phase 3 studies would not be commercially reasonable.
U.S. rights to levosimendan then landed at Tenax. But in 2017, the drug again failed in the phase 3 Levo-CTS trial in patients with left ventricular dysfunction undergoing cardiac surgery. Prophylactic levosimendan did not result in any significant improvement versus placebo on a composite endpoint of death, renal-replacement therapy, perioperative myocardial infarction, or use of a mechanical cardiac assist device.
Tenax licensed North American rights to oral levosimendan from Orion in 2020, then expanded the deal in 2024 to cover oral and subcutaneous levosimendan globally for PH-HFpEF.
Compared with the original intravenous version, a daily oral formulation could offer “an advantage of stable dosing and eliminate the risk of line infections and thrombosis,” a team of researchers, including Shah, wrote in 2023.