Tenax Therapeutics, Inc. · NASDAQ:TENX
Tenax Therapeutics — CVCT 2021
24 slides from Tenax Therapeutics's conference presentation, 2021
Slide 1: Reducing stressed blood volume with levosimendan
Reducing stressed blood volume with levosimendan presenting data from Hemodynamic Evaluation of Levosimendan in PH-HFpEF Stuart Rich, MD Professor Emeritus of Medicine-Cardiology Northwestern University Feinberg School of Medicine
Slide 2: Disclosures
Disclosures: • Chief Medical Officer, Tenax Therapeutics • Tenax has the license for levosimendan in North America
Slide 3: Background: PH-HFpEF
Background: PH-HFpEF • HFpEF affects ~50% of all patients with HF • Approximately 70% of patients with HFpEF have PH, and ~30% have RVD • PH-HFpEF represents a more severe phenotype • Higher risk of death compared to HFpEF without PH • Poorer outcomes compared to WHO Group 1 PH, with no treatments e
Slide 4: Background: Levosimendan
Background: Levosimendan • Inotropic properties due to Ca++ sensitization of troponin C • K+ATP channel activator • Direct vasodilatory action of vascular smooth muscle • Selectivity for different arterial and venous circulations • Potential for mitochondrial protection from ischemia- reperfusion in
Slide 5: Why the K+ ATP activator properties of levosimendan are important in pulmonary hypertension
Why the K+ ATP activator properties of levosimendan are important in pulmonary hypertension • Downregulation of K+ channel activity is considered the hallmark of pulmonary hypertension • K+ channels control PASMCs and PAECs • K+ channels regulate pulmonary venous tone • Downregulation of K+ channels
Slide 6: Levosimendan has Vasodilating Effects on Human Portal Vein
Levosimendan has Vasodilating Effects on Human Portal Vein NE preconditioned Portal Vein Levosimendan KATP Activator Pataricza, János, et al. "Comparison of the vasorelaxing effect of cromakalim and the new inodilator, levosimendan, in human isolated portal vein." Journal of pharmacy and pharmacolog
Slide 7: Levosimendan and Active Metabolite OR-1896: sustained efficacy over 7 days
Levosimendan and Active Metabolite OR-1896: similar effects provide sustained efficacy over 7 days • Levosimendan currently only for intravenous use. • Approved for ADHF in the ICU. • Administered as a 24-hour infusion. Kivikko et al. Int J Clin Pharm & Ther 2002;40:465
Slide 8: Changes in cardiac output and PCWP over time from levosimendan
Changes in cardiac output and PCWP over time from levosimendan Lilleberg et al. Eur J Heart Fail 2007;9(1):75-82
Slide 9: Mechanistic Rationale for Levosimendan in PH-HFpEF – Inotrope or Vasodilator?
Mechanistic Rationale for Levosimendan in PH-HFpEF – Inotrope or Vasodilator? Pulmonary Right Heart Left Heart Vasculature Poor LV Increased Relaxation Problem RV Pulmonary and Reduced Failure Congestion & Cardiac Pressure Output Levosimendan Ca++ K-ATP Ca++ MOA Sensitizer Channel Sensitizer Activat
Slide 10: HELP Study
HELP Study Hemodynamic Evaluation of Levosimendan in PH-HFpEF • WHO Group 2 PH-HFpEF (EF≥40%) • NYHA class II-III symptoms • PCWP≥20 and mPAP≥35 mmHg • Two phases to the trial • Phase 1: Open label assessment (exercise RHC) of 24-hour infusion of levosimendan • Phase 2: Randomized double-blinded 6 w
Slide 11: HELP Study
HELP Study Hemodynamic Evaluation of Levosimendan in PH-HFpEF Phase 1 Rest and Ex PCWP≥20+ 24Hr Rest and Ex Ex PCWP Hemos Randomization mPAP≥35? IV LEVO Hemos ≥4 mmHg and 6MW No No Withdrawal Withdrawal Phase 2 IV Placebo once weekly x 6 weeks Rest and Ex Randomization Hemodynamics and 6MW IV LEVO
Slide 12: HELP Study Trial Endpoints
HELP Study Trial Endpoints • Primary Change in PCWP at 25 W exercise at 6 weeks • Secondary • Change in 6-minute walk distance • Change in CVP, PCWP, mPAP, CI, PVR at rest and with exercise
Slide 13: Patient disposition
Consented Patients N=60 Did not meet inclusion criteria N=16 Underwent 24-hour Levosimendan infusion N=44 Did not meet criteria for randomization N=7 Met PCWP Criteria for Randomization N=37 Placebo Infusion Levosimendan Infusion N=19 N=18 Dropout N=2 1 - COVID restrictions 1 - Palpitations Complete
Slide 14: Key Baseline Characteristics
Key Baseline Characteristics Characteristic N=44 Patients Age (years) 69.0 ± 9.1 Gender, n (% male) 17 (38.6) BMI (kg/m²) 35.1 ± 8.9 Medical History Atrial Fibrillation (history) 34 (77.3) HTN, n (%) 26 (59.1) CAD, n (%) 13 (29.5) CKD, n (%) 11 (25.0) Obstructive Sleep Apnea, n (%) 28 (63.6) COPD, n
Slide 15: Hemodynamics at Baseline
Hemodynamics at Baseline Characteristic Placebo Levo (n=19) (N = 18) Right atrial pressure (mmHg) 17 (5) 15 (5) Mean PA pressure (mmHg) 42 (11) 41 (9) PCWP (mmHg) 25 (7) 26 (5) Cardiac index (l/min/m2) 2.3 (0.6) 2.7 (1.0) PVR (WU) 4.1 (3.6) 2.7 (1.5) Mean values (SD) or % shown All p > 0.05
Slide 16: Baseline vs Post 24-Hour Levosimendan Infusion
Baseline vs Post 24-Hour Levosimendan Infusion All values between baseline and 24 hr LEVO infusion p<0.01 Burkhoff, Daniel, et al. “Levosimendan Improves Hemodynamics and Exercise Tolerance in PH-HFpEF: Results of the Randomized Placebo-Controlled HELP Trial" Journal of the American College of Cardi
Slide 17: Baseline vs post 24-hour Levosimendan Infusion on LV contractility
Baseline vs post 24-hour Levosimendan Infusion on LV contractility Rest Exercise 175 175 Baseline Baseline 150 24 Hr Levo 150 24 Hr Levo LV Pressure (mmHg) LV Pressure (mmHg) 125 125 100 100 75 75 50 50 25 25 0 0 0 25 50 75 100 125 150 0 25 50 75 100 125 150 LV Volume (ml) LV Volume (ml) (No signifi
Slide 18: PCWP Endpoint
PCWP Endpoint p=0.6615 † p=0.0017 † Rest Rest p=0.0475† Levosimendan effect on PCWP across positions significant vs placebo † Tested in a mixed effect model using treatments as factors and position as a random effect
Slide 19: CVP Endpoint
CVP Endpoint Baseline vs. 6 weeks * p<0.05
Slide 20: Weekly Levosimendan Dosing Improves Exercise Capacity in PH-HFpEF Patients
Weekly Levosimendan Dosing Improves Exercise Capacity in PH-HFpEF Patients Burkhoff, Daniel, et al. “Levosimendan Improves Hemodynamics and Exercise Tolerance in PH-HFpEF: Results of the Randomized Placebo-Controlled HELP Trial" Journal of the American College of Cardiology: Heart Failure Vol. x No.
Slide 21: Safety
Safety Placebo LEVO Characteristic (n=18) (n=19) Discontinued study drug 2 0 PICC Line Infection 0 2 Arrhythmia* 0 0 All p > 0.05 Worsening HF 1 2 Stroke 0 0 Syncope 0 0 SAE - Death 0 0 *comparison of 72 hr ambulatory ECG monitoring between baseline and week 5
Slide 22: Baseline vs 24-hour Levosimendan Infusion on Estimated Stressed Blood Volume
Baseline vs 24 hour Levosimendan Infusion on Estimated Stressed Blood Volume 6000 P < 0.001 at each timepont 5000 eSBV (ml/70 kg) 4000 3000 2000 Legs Down Legs Up 25 Watts 22
Slide 23: Baseline vs 6 weeks of Levosimendan on Estimated Stressed Blood Volume
Baseline vs 6 weeks of Levosimendan on Estimated Stressed Blood Volume Brener MI, Hamid NB, Sunagawa K, Borlaug BA, Shah SJ, Rich S, Burkhoff D. Changes in Stressed Blood Volume with Levosimendan in Pulmonary Hypertension from Heart Failure with Preserved Ejection Fraction: Insights Regarding Mechan
Slide 24: Conclusion
Conclusion • Levosimendan causes a significant fall in PCWP and CVP during rest and exercise in patients with PH-HFpEF • Long term (6 weeks) use of levosimendan produced a significant improvement in 6MW • The mechanism of action appears to be a reduction in stressed blood volume from splanchnic dila