8-K: Tenax Therapeutics LEVEL Trial: Mixed Results, Future Strategy Outlined

Tenax Therapeutics presented results from its LEVEL trial, which did not meet its primary endpoint but revealed significant biomarker improvements and a refined patient selection strategy for future development.

Summary

• Tenax Therapeutics presented findings from its Phase 3 LEVEL trial for PH-HFpEF, which did not achieve statistical significance on its primary endpoint of 6-minute walk distance (6MWD).
• However, the trial demonstrated a significant reduction in NT-proBNP by approximately 49% and a decrease in right ventricular systolic pressure (RVSP) by 3.5 mmHg.
• Analysis indicates a strong treatment effect in patients with greater baseline disease severity, particularly those with a baseline 6MWD below 333 meters, showing a 26.3m improvement.
• These insights are being used to strategically reshape the upcoming LEVEL-2 trial, aiming to de-risk the levosimendan development program through optimized patient selection.
• The drug, oral levosimendan (TNX-103), was found to be safe and well-tolerated, with PK concentrations comparable to previous studies.

Sentiment

Score: 6

Explanation: StockSavvy.ai views this as a mixed result. While the primary endpoint was not met, significant biomarker improvements and a clear patient selection strategy for future trials offer a path forward.

Positives

• Demonstrated a significant reduction in NT-proBNP by approximately 49% across the overall population.
• Showed a reduction in pulmonary arterial pressure (RVSP) by 3.5 mmHg.
• Identified a strong treatment effect in patients with greater disease burden (baseline 6MWD < 333m), with a 26.3m improvement in 6MWD.
• Oral levosimendan (TNX-103) was confirmed to be safe and well-tolerated.
• The trial provided valuable insights for optimizing patient selection in the future LEVEL-2 trial, de-risking the development program.
• The company confirmed successful trial execution by its sites and clinical development team.

Negatives

• The primary endpoint of 6-minute walk distance (6MWD) did not reach statistical significance in the overall population.
• The Kansas City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS) did not show a significant improvement compared to placebo.
• Higher rates of treatment-related adverse events, dose reductions, and discontinuations were observed in the TNX-103 arm compared to placebo.

Risks

• Risks associated with clinical trials, including potential delays, costs, and enrollment challenges for future trials.
• Potential delays in regulatory review and approval of product candidates.
• Risks related to formulation, production, marketing, customer acceptance, and clinical utility of product candidates.
• Reliance on third parties, including manufacturers and CROs.
• Uncertainty regarding cash usage and runway potentially falling outside expected ranges.
• Volatility and uncertainty in the global economy and financial markets.
• Changes in legal, regulatory, and legislative environments impacting regulatory approval.

Future Outlook

The company is strategically reshaping the LEVEL-2 trial based on learnings from the LEVEL trial, focusing on enriched patient populations with higher disease burden to de-risk the levosimendan development program. Further publications and presentations are expected in 2026 and early 2027.

Management Comments

• The neutral LEVEL result was not due to an ineffective drug, but to a protocol design flaw: the inclusion of too many patients who walked too far at baseline, with little room to improve. LEVEL-2 will not face this obstacle.
• The degree to which a patients limitation at baseline determines the effect of this treatment (in 6MWD) is now clear.
• LEVEL-2 is substantially de-risked thanks to these insights.
• Oral levosimendan is safe and well-tolerated, with 1 mg BID/TID providing PK concentrations expected.
• Targeting volume overload with K-ATP channel activation has direct effects on NT-proBNP and RVSP, two prespecified endpoints.
• Treatment effect seen in HELP study validated.
• Successful trial execution by sites and clinical development team.

Industry Context

StockSavvy.ai notes that the PH-HFpEF space remains challenging, with a high unmet need. The results from Tenax Therapeutics' LEVEL trial, while not meeting the primary endpoint, align with industry trends where specific patient sub-populations show greater benefit from novel therapies. The focus on biomarker improvement (NT-proBNP, RVSP) and refined patient selection strategies is a common approach in developing treatments for complex cardiovascular conditions.

Comparison to Industry Standards

• The magnitude of NT-proBNP reduction (49%) is noted as the largest to date in a Heart Failure with Preserved Ejection Fraction (HFpEF) Randomized Controlled Trial (RCT).
• The observed treatment effect in patients with baseline 6MWD < 333m (+26.3m LS Mean Difference) is comparable to improvements seen in other PH and PH-HFpEF studies like HELP (IV levosimendan, median 282m baseline 6MWD) and CADENCE (sotatercept, median 259m baseline 6MWD).
• The reduction in RVSP aligns with findings in other pulmonary arterial hypertension (PAH) studies, such as SERAPHIN (macitentan), SUPER-1 (sildenafil), PHIRST (tadalafil), and TRIUMPH-1 (treprostinil), which also showed benefits in lower baseline 6MWD cohorts.
• The improvement in 6MWD in the sicker patient population is also consistent with positive results from SGLT2 inhibitors (dapagliflozin in PRESERVED-HF) and other HFpEF therapies.

Stakeholder Impact

• Shareholders: The mixed results may lead to short-term stock price volatility. The clear path forward for LEVEL-2 could provide long-term confidence if successful.
• Patients: The trial identified a sub-population that may benefit significantly from levosimendan, offering hope for improved exercise capacity and reduced cardiac stress.
• Healthcare Providers: The data provides insights into patient selection for PH-HFpEF treatment and highlights the potential of levosimendan in specific patient groups.

Next Steps

• Strategically reshape the LEVEL-2 trial based on learnings from LEVEL, focusing on patient selection.
• Publish primary paper and additional publications.
• Present findings at upcoming conferences such as HFSA, AHA, CVCT, and THT.

Key Dates

Recommendation

The primary endpoint miss is a significant negative, but the clear biomarker improvements and the identification of a responsive patient subgroup for future trials provide a basis for holding the stock. The de-risking of the LEVEL-2 program is a positive development, but further clinical success is required for a more bullish outlook.

Keywords

PH-HFpEF, Levosimendan, LEVEL Trial, Clinical Trial Results, Heart Failure, Pulmonary Hypertension, Biomarkers, NT-proBNP