Tenax Therapeutics’ TNX-103 failed to significantly improve 6-minute walk distance in the Phase 3 LEVEL trial in PH-HFpEF, but prespecified analyses showed a 26.3-meter benefit in patients with lower baseline exercise capacity, alongside a 49% reduction in NT-proBNP versus placebo.
Written By: Shaik Yasmeen, PharmD
Reviewed By: Pharmacally Editorial Team
Tenax Therapeutics’ TNX-103 (oral levosimendan) failed to significantly improve 6-minute walk distance in the Phase 3 LEVEL trial in pulmonary hypertension associated with heart failure with preserved ejection fraction (PH-HFpEF). Prespecified analyses showed a stronger treatment effect in patients with lower baseline exercise capacity, alongside substantial reductions in NT-proBNP and right ventricular systolic pressure.
LEVEL Fails to Meet Primary and Key Secondary Endpoints
The registrational Phase 3 LEVEL trial (NCT05983250) evaluated TNX-103 in 241 patients with PH-HFpEF across 41 sites in the United States and Canada. Patients received TNX-103 at 1 mg twice daily, with titration to 1 mg three times daily from Week 5 as tolerated, or placebo. The primary endpoint was change in 6-minute walk distance (6MWD) at Week 12, while the key secondary endpoint was change in Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS).
TNX-103 produced a least-squares mean improvement of 14.0 meters in 6MWD versus 10.4 meters with placebo. The treatment difference was 3.5 meters (p=0.63), meaning the primary endpoint was not met. KCCQ-TSS also showed no meaningful separation, with a least-squares mean treatment difference of 0.1 points.
Greater Treatment Effect in Patients with More Advanced Disease
A prespecified subgroup analysis identified a stronger response among patients whose baseline 6MWD was below the trial median of 333 meters. In this group, TNX-103 improved 6MWD by 26.3 meters versus placebo (95% CI, 6.0-46.7; nominal p=0.0112).
Patients receiving TNX-103 improved by an average of 26.7 meters, while those receiving placebo declined by 2.6 meters. A similar pattern emerged among older patients. Those aged 71 years or older had a 27.1-meter treatment difference, increasing to 37.6 meters in patients older than 74 years.
The company said these findings indicate that treatment benefit may be concentrated in patients with greater disease burden. However, the subgroup analyses do not establish efficacy.
TNX-103 Reduces NT-proBNP and Pulmonary Pressure
TNX-103 produced a 49% placebo-controlled reduction in NT-proBNP across the overall trial population. The geometric least-squares mean ratio was 0.51 (95% CI, 0.43-0.60; nominal p<0.0001). NT-proBNP is an established marker of cardiac wall stress and prognosis in heart failure.
TNX-103 also reduced right ventricular systolic pressure (RVSP) by 3.5 mmHg versus placebo (95% CI, -6.01 to -1.10; nominal p=0.0045). Among patients with baseline 6MWD below 333 meters, the reduction reached 4.9 mmHg.
These biomarker and hemodynamic analyses were prespecified, but their nominal p-values were not adjusted for multiplicity. They therefore do not establish efficacy.
Safety Profile Remains Generally Favorable
TNX-103 was generally safe and well tolerated, with no new safety signals identified in LEVEL. Adverse events occurred in 86.7% of patients receiving TNX-103 compared with 71.9% receiving placebo. Treatment-related adverse events occurred in 38.3% and 17.4% of patients, respectively.
Serious adverse events remained balanced between treatment groups, occurring in 10.8% of patients receiving TNX-103 and 10.7% receiving placebo. Adverse events of special interest occurred in 9.2% and 5.8%, respectively.
Tenax Plans FDA Meeting to Revise Development Strategy
Tenax plans to request a Type C meeting with the U.S. Food and Drug Administration to discuss the complete LEVEL dataset and a revised registrational strategy. The company also plans to seek scientific consultation from the European Medicines Agency.
The proposed strategy would enrich future development for patients with greater disease burden, based on the subgroup findings from LEVEL. Tenax said the FDA had previously agreed that a single Phase 3 trial with a p-value of 0.01 could support an NDA submission for TNX-103 in PH-HFpEF.
Full LEVEL results will be presented in a late-breaking clinical science session at the 2026 European Society of Cardiology Congress in Munich, scheduled for August 28-31.
TNX-103 is Tenax’s oral formulation of levosimendan, a K-ATP channel activator and calcium sensitizer previously developed as an intravenous treatment for acute decompensated heart failure. Levosimendan has market authorization in 60 countries for that indication but is not available in the United States or Canada. Tenax is developing TNX-103 for PH-HFpEF, an area with no approved therapy.
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About the Writer
Shaik Yasmeen (LinkedIn) is a Pharm.D graduate with interests in clinical pharmacy, pharmacovigilance, and medical writing. She has gained experience through hospital clinical postings, patient case reviews, case presentations, and literature evaluation. Passionate about evidence-based healthcare, she is committed to creating accurate and engaging medical content while continuously expanding her professional knowledge.