Tenax LEVEL Trial Misses Primary Goal, but Subgroup Data Bolsters Levosimendan Case

Key Points

• Tenax’s Phase III LEVEL trial missed its primary endpoint: Oral levosimendan improved six-minute walk distance by 3.5 meters versus placebo, but the difference was not statistically significant; the key quality-of-life endpoint also failed to reach significance.
• Subgroup and biomarker results suggested greater benefit in higher-risk patients: Patients with shorter baseline walk distances, older age, or higher NT-proBNP levels showed larger treatment differences. Tenax also reported a 49% relative reduction in NT-proBNP and lower pulmonary pressures, though subgroup findings had nominal, unadjusted p-values.
• The company is reassessing the development program: Tenax plans to consult the FDA and EMA and may modify the ongoing LEVEL-2 trial or conduct another study with enrollment criteria focused on more severely affected patients. Levosimendan was associated with more adverse events and discontinuations than placebo, while serious adverse-event rates were similar.

Tenax Therapeutics NASDAQ: TENX reported that its Phase III LEVEL trial of oral levosimendan in patients with pulmonary hypertension associated with heart failure with preserved ejection fraction, or PH-HFpEF, did not meet its primary endpoint, though the company said subgroup, biomarker and hemodynamic findings will inform its next steps in the program.

The double-blind, placebo-controlled trial randomized 241 patients across 41 sites in the U.S. and Canada. Participants received oral levosimendan at 1 milligram twice daily for four weeks, followed by 1 milligram three times daily through week 12, or placebo. The primary endpoint was change in six-minute walk distance at week 12.

Levosimendan-treated patients recorded a least-squares mean improvement of 14 meters in six-minute walk distance, compared with 10.4 meters for placebo-treated patients. The 3.5-meter difference was not statistically significant, with a p-value of 0.63. The key secondary endpoint, Kansas City Cardiomyopathy Questionnaire total symptom score, also did not reach statistical significance.

Subgroup Findings Point to Higher-Burden Patients

Chris Giordano, Tenax’s president and chief executive officer, said the company believes the overall result was diluted by enrolling patients with less advanced disease. The median baseline six-minute walk distance in the trial was 333 meters.

Among patients with baseline walk distances below that median, levosimendan produced a placebo-corrected improvement of 26.3 meters at week 12, with a nominal p-value of 0.0112. In patients above the median baseline walk distance, the treatment difference was negative 17.6 meters.

“We did not fail to find a treatment effect in LEVEL,” Giordano said. “We diluted one.”

Stuart Rich, Tenax’s chief medical officer, said the trial’s pre-specified subgroup analyses also showed larger walk-distance treatment differences among older participants and among those with higher baseline NT-proBNP levels, a marker of cardiac wall stress. In patients at or above the median age of 71, the treatment difference was 27.1 meters, while patients in the oldest tertile, above age 74, showed a 37.6-meter difference, according to the company.

Rich cautioned that the subgroup p-values were nominal and had not been adjusted for multiple comparisons. The company said it is continuing multivariable analyses.

Sanjiv Shah, professor of medicine and director of Northwestern University’s HFpEF program and the trial’s principal investigator, said HFpEF is a heterogeneous condition and that the more severely affected patients may be the ones most likely to benefit from treatment.

“The sicker patients really are the ones who benefit,” Shah said. “That’s the most important finding because those are the ones that we need to treat.”

Biomarker and Pulmonary Pressure Results

Tenax reported that levosimendan was associated with a 49% reduction in NT-proBNP relative to placebo. The company also reported a 3.5-millimeter-of-mercury treatment difference in right ventricular systolic pressure, a measure used to estimate pulmonary artery pressure. Pulmonary pressure declined by 3.6 millimeters of mercury in the levosimendan arm and increased by 0.5 millimeters of mercury in the placebo arm, with a nominal p-value of 0.0045.

In participants with baseline walk distances below 333 meters, pulmonary pressure declined by 4.9 millimeters of mercury, according to the company.

Shah said the NT-proBNP result was notable but added that any potential impact on heart failure hospitalizations would need to be demonstrated in a dedicated outcomes trial.

Safety Profile and Program Plans

Adverse events occurred in 86% of levosimendan patients and 72% of placebo patients. Treatment-related adverse events occurred in 38% and 17% of patients, respectively. Discontinuations due to adverse events were 8.3% in the levosimendan group and 1.7% in the placebo group.

Rich said headaches, palpitations and hypotension were consistent with prior oral levosimendan studies and were generally mild to moderate and managed primarily through dose reductions. Serious adverse events occurred in 10.8% of levosimendan patients and 10.7% of placebo patients. There were two deaths during the double-blind phase, both in the levosimendan arm; both were deemed unrelated to study drug by the patients’ physicians, the company said.

Tenax said it plans to request a Type C meeting with the U.S. Food and Drug Administration and seek scientific consultation with the European Medicines Agency. The company is evaluating whether to amend the ongoing LEVEL-2 trial, launch an additional trial, or pursue both options.

Giordano said the company intends to revise enrollment criteria to exclude patients with baseline six-minute walk distances in the range that it believes diluted the LEVEL results. Tenax is considering a lower upper ceiling for walk distance, potentially around 350 meters, or a combined disease-severity score. The exact threshold has not yet been finalized.

Shah is expected to present LEVEL data at the European Society of Cardiology meeting, while Tenax said additional analyses are planned for future publications and presentations.

About Tenax Therapeutics (NASDAQ:TENX)

Tenax Therapeutics, Inc is a clinical-stage specialty pharmaceutical company developing drug delivery technologies designed to improve pain management in acute care settings. The company's proprietary platform leverages biodegradable polymer matrices to create sustained-release formulations of local anesthetics, aiming to extend the duration of pain relief while reducing reliance on opioid medications.

Tenax's lead development programs focus on injectable formulations intended for infiltration and peripheral nerve block applications, with the goal of providing longer-lasting analgesia following surgical and procedural interventions.

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