Tenax Therapeutics (Nasdaq: TENX) reported on August 10 that the Phase III LEVEL trial of levosimendan failed to meet its primary endpoint of improvement in six-minute walk distance (6MWD) versus placebo in patients with pulmonary hypertension due to heart failure with preserved ejection fraction (PH-HFpEF). The key secondary endpoint, improvement in Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score, was also not met.
Levosimendan is a calcium sensitizer and ATP-sensitive potassium channel activator designed to improve cardiac contractility and reduce pulmonary vascular resistance without raising intracellular calcium. The 241-patient double-blind, randomized, placebo-controlled trial enrolled patients across 41 sites in the US and Canada. At Week 12, the least-squares mean difference in 6MWD between the oral levosimendan arm and placebo was 3.5 meters (p=0.63), well short of the 25-meter improvement the trial was powered to detect. KCCQ total symptom score was virtually identical across arms.
Despite the overall miss, Tenax pointed to biomarker, hemodynamic and subgroup findings that it said could inform a revised development strategy. In the overall trial population, treatment produced a 49% greater reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) compared with placebo (nominal p<0.0001) and a 3.5 mmHg reduction in right ventricular systolic pressure by echocardiography (nominal p=0.0045). In a prespecified subgroup of patients with a baseline 6MWD below the trial median of 333 meters — representing more advanced disease — the treatment difference was 26.3 meters (95% CI 6.0, 46.7; nominal p=0.0112). A post-hoc quartile analysis showed the treatment effect diminished consistently as baseline exercise capacity increased, from +32.4 meters in the lowest quartile to -27.3 meters in the highest. Tenax attributed the overall miss to enrollment of a population that included too many patients with less severe disease. Adverse events were reported in 86.7% of patients on levosimendan versus 71.9% on placebo, though serious adverse events were balanced at approximately 11% in each arm.
No drug is currently approved specifically for PH-HFpEF. The approved standard of care addresses the underlying HFpEF rather than the pulmonary vascular component, with agents including Boehringer Ingelheim and Eli Lilly's Jardiance (empagliflozin), AstraZeneca's Farxiga (dapagliflozin), Novartis's Entresto (sacubitril/valsartan), and Bayer's Kerendia (finerenone). Merck's Winrevair (sotatercept), an activin signaling inhibitor approved for pulmonary arterial hypertension, reported positive Phase II data in combined post- and pre-capillary pulmonary hypertension in early 2026 but does not yet hold an approval in PH-HFpEF.
The NT-proBNP finding is the most analytically striking element of the dataset. A 49% reduction relative to placebo exceeds what has been observed in prior HFpEF trials with approved agents, and was accompanied by echocardiographic improvements across multiple cardiac structural and functional parameters, according to Tenax's principal investigator Sanjiv Shah of Northwestern University. Whether those biological effects translate into clinical benefit in a more enriched population is the central question the company now faces.