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Tenax Therapeutics Announces Topline Results from Phase 3 Level Clinical Trial of Tnx-103 in Patients with Ph-Hfpef
Tenax Therapeutics announced topline results from the Phase 3 LEVEL clinical trial of TNX-103 in patients with PH-HFpEF. TNX-103 did not meet statistical significance on the primary endpoint of improvement in 6-minute walk distance versus placebo. In prespecified exploratory analyses in the overall trial population, treatment with TNX-103 resulted in a 49% greater reduction in NT-proBNP compared to placebo. LEVEL (NCT05983250) was a registrational Phase 3, double-blind, randomized, placebo-controlled clinical trial evaluating TNX-103 in patients with PH-HFpEF across 41 sites in the United States and Canada. 241 patients were randomized to TNX-103 1 mg twice daily, titrated to 1 mg three times daily starting at Week 5 as tolerated, versus placebo. The primary endpoint was change in 6-minute walk distance (6MWD) at Week 12, and a key secondary endpoint was change in Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS). N-terminal pro-B natriuretic peptide (NT-proBNP), a measure of cardiac wall stress, and right ventricular systolic pressure (RVSP) by echocardiography, were exploratory endpoints. Patients completing the double-blind period were eligible to enter an open-label extension of up to two years, which is ongoing. 6MWD at Week 12: least-squares means +14.0 meters (SE 7.7) on TNX-103 (n=116) versus +10.4 meters (SE 7.6) on placebo (n=120); least-squares mean difference 3.5 meters (SE 7.3), p=0.63. The primary endpoint was not met. Estimates are from a mixed model for repeated measures in all 241 randomized patients (120 TNX-103, 121 placebo), adjusted for baseline 6MWD and randomization strata with missing Week 12 values handled by the prespecified estimand strategies. Among patients with an observed Week 12 walk test, the mean change from baseline was +17.7 meters (SD 40.2) on TNX-103 (n=116) versus +9.8 meters (SD 54.7) on placebo (n=120), an unadjusted difference of +8.0 meters. KCCQ-TSS at Week 12: least-squares mean +6.6 (SE 2.4) on TNX-103 (n=114) versus +6.5 (SE 2.3) on placebo (n=120); least-squares mean difference 0.1 points (SE 2.2). Baseline 6MWD below the trial median of 333 meters (n=119): least-squares mean treatment difference +26.3 meters (95% confidence interval 6.0, 46.7), nominal p=0.0112. On average, patients on TNX-103 in this sub-group improved 26.7 meters while patients on placebo declined 2.6 meters. Patients aged 71 years and older: least squares mean treatment difference +27.1 meters (95% confidence interval 9.9, 44.4), nominal p=0.0021. In the oldest tertile (>74 years): +37.6 meters (95% confidence interval 14.7, 60.5), nominal p=0.0013. Mean age was 71.8 years among patients walking less than 333 meters at baseline, versus 66.5 years among those at or above that threshold. NT-proBNP (overall population): geometric least-squares mean ratio of 0.51 versus placebo (95% confidence interval 0.43, 0.60), nominal p264–333 meters), -10.7 meters in the third (>333–384 meters) and -27.3 meters in the fourth (>384 meters). TNX-103 was generally safe and well-tolerated in the LEVEL trial, and no new safety signals were observed. Adverse events were reported in 86.7% of patients on TNX-103 versus 71.9% on placebo. Treatment-related adverse events were reported in 38.3% of patients in the treatment group versus 17.4% on placebo. Serious adverse events were balanced across arms, at 10.8% on TNX-103 and 10.7% on placebo. Adverse events of special interest occurred in 9.2% versus 5.8%. The biomarker and hemodynamic analyses described above were prespecified in the statistical analysis plan; the quartile analysis was post hoc. Nominal p-values are not adjusted for multiplicity and these analyses do not establish efficacy. Multivariable analyses are ongoing. Tenax intends to request a Type C meeting with the FDA to present the complete LEVEL dataset together with the Company's recommendations, and in parallel to seek scientific consultation from the European Medicines Agency. The Company intends to enrich the study population to ensure a robust treatment effect, as demonstrated in the subgroup findings observed in LEVEL. Full results from LEVEL will be presented in a Late-Breaking Clinical Science session at the European Society of Cardiology Congress 2026, being held August 28-31 in Munich, Germany. Levosimendan is a novel, first-in-class K-ATP channel activator/calcium sensitizer currently being evaluated to treat pulmonary hypertension (PH) associated with heart failure with preserved ejection fraction (PH-HFpEF). Levosimendan was first developed for intravenous use in hospitalized patients with acutely decompensated heart failure, and it has received market authorization in 60 countries in this indication, although it is not available in the United States or Canada. Tenax’s Phase 2 HELP study, including its open-label extension stage, demonstrated the potential of IV (TNX-101) and oral (TNX-103) levosimendan to bring durable improvements in exercise capacity and quality of life, as well as other clinical assessments, in patients with PH-HFpEF. TNX-103 (oral levosimendan) is currently being evaluated in LEVEL-2, a Phase 3, double-blind, randomized, placebo-controlled clinical trial in patients with PH-HFpEF.