Tenax Therapeutics has announced that the phase 3 LEVEL trial of TNX-103 (oral levosimendan) did not 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).1
The 241-patient trial also missed its key secondary endpoint of change in Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score. Orion Corporation, Tenax's license partner, disclosed the topline results on August 10, 2026, as part of the registrational program for TNX-103 in a population with no approved therapies.1,2
“Having reviewed the available trial results, I am encouraged we have a clear path forward,” Chris Giordano, President and Chief Executive Officer of Tenax Therapeutics, said in a statement. “Our entry criteria enrolled a broad population, including too many patients with less severe disease. The prespecified subgroup analyses demonstrate that there is a meaningful beneficial treatment effect of TNX0-103 in patients with more disease burden, which is the patient population with the greatest unmet need.”2
According to Tenax, broad trial entry criteria enrolled a substantial proportion of patients with less severe disease, diluting the overall treatment effect. Prespecified subgroup and biomarker analyses point toward a population more likely to benefit from oral levosimendan. The company is now recalibrating its regulatory strategy around this narrower population rather than filing on the intent-to-treat results.1,2
LEVEL enrolled 241 patients with PH-HFpEF across sites in the United States and Canada in a randomized, placebo-controlled design testing oral levosimendan, a first-in-class K-ATP channel activator and calcium sensitizer. The trial's primary endpoint was change in 6MWD from baseline versus placebo.2
TNX-103 produced a 14-meter improvement in 6MWD compared with a 10.4-meter improvement for placebo, a least-squares mean difference of 3.5 meters that was not statistically significant (P = .63). The KCCQ total symptom score, the key secondary endpoint, also failed to separate from placebo.2
Tenax attributed the missed primary endpoint partly to trial entry criteria, which the company said enrolled too many patients with less severe disease. A prespecified blinded sample size re-estimation completed in December 2025 confirmed LEVEL was powered above 90% to detect a 25-meter change in 6MWD, underscoring adequate study power for the population as enrolled.2,3
TNX-103 secondary endpoints, subgroup findings, and safety
In a prespecified subgroup of patients with baseline 6MWD below the trial median of 333 meters, TNX-103 improved walk distance by 26.3 meters versus placebo (95% CI, 6.0-46.7; P = .0112). Tenax highlighted this subgroup as more representative of the intended PH-HFpEF treatment population.2
Across the overall trial population, TNX-103 was associated with a 49% greater reduction in NT-proBNP versus placebo (P < .0001) and a 3.5 mmHg reduction in right ventricular systolic pressure versus placebo (P = .0045). Tenax described these biomarker and hemodynamic changes as clinically meaningful, though nominal significance does not carry the same statistical weight as the trial's prespecified primary analysis.2
Oral levosimendan was generally safe and well tolerated, with serious adverse events occurring at similar rates between arms (10.8% versus 10.7%). Overall adverse event rates were higher with TNX-103 than placebo, and adjudicated clinical worsening events were balanced across treatment groups, according to Tenax.1,2
“Although the result in the overall population was not statistically significant, the LEVEL trial is an important advancement for patients with pulmonary hypertension due to HFpEF, a disease that still has no approved therapy,” Sanjiv Shah, MD, director of the HFpEF program at Northwestern University Feinberg School of Medicine and principal investigator of LEVEL, said in a statement. “In my opinion, a drug that lowers wall stress and modifies cardiac structure and function this robustly is likely to be disease-modifying.”2
Tenax intends to request a Type C meeting with the FDA to discuss revisions to the ongoing registrational development plan for TNX-103 in PH-HFpEF, and plans to seek parallel scientific consultation from the EMA. The company is also conducting a global, multicenter, open-label extension study of TNX-103, initiated following the December 2025 sample size re-estimation for LEVEL.1,3
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