Slides
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Corporate Presentation April 2025
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2 Safe Harbor Statement Disclaimers Except for historical information, all the statements, expectations and assumptions contained in this presentation are forward- looking statements. These forward-looking statements may include information concerning possible or projected future business operations. Actual results might differ materially from those explicit or implicit in the forward-looking statements. Important factors that could cause actual results to differ materially include: risks related to our business strategy, including the prioritization and development of product candidates; risks of our clinical trials, including, but not limited to, the timing, delays, costs, design, initiation, enrollment, and results of such trials; any delays in regulatory review and approval of product candidates in development; reliance on third parties, including Orion Corporation, our manufacturers and CROs; risks regarding the formulation, production, marketing, customer acceptance and clinical utility of our product candidates; the potential advantages of our product candidates; our estimates regarding the potential market opportunity for our product candidates; intellectual property risks; our competitive position; risks related to our continued listing on Nasdaq; our ability to maintain our culture and recruit, integrate and retain qualified personnel and advisors, including on our Scientific Advisory Boards and Board of Directors; volatility and uncertainty in the global economy and financial markets in light of the possibility of pandemics, global financial and geopolitical uncertainties, including in the Middle East and the Russian invasion of and war against the country of Ukraine; changes in legal, regulatory and legislative environments in the markets in which we operate and the impact of these changes on our ability to obtain regulatory approval for our products; and other risks and uncertainties set forth from time to time in our SEC filings. Tenax Therapeutics assumes no obligation and does not intend to update these forward-looking statements except as required by law. This presentation shall not constitute an offer to sell or the solicitation of an offer to buy any securities of the Company.
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3 The Tenax Mission Our mission is to transform the lives of patients with cardiovascular and pulmonary diseases by developing innovative therapies that address high unmet medical need. We are dedicated to advancing science and improving patient outcomes through cutting-edge research.
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4 Execution Led by a Highly Experienced Team Management Team Chris Giordano - President & CEO, Board Director Previous President of IQVIA Biotech 25+ years of clinical trial expertise Stuart Rich, MD - CMO, Board Director Globally recognized expert in Pulmonary Hypertension 40+ Years clinical experience in PH and HF Former FDA CardioRenal Advisory Panel Member Doug Randall - Chief Business Officer Experienced BD and Commercial expert 40+ years BD commercial roles, including founder Doug Hay, PhD - EVP, Regulatory Experienced senior pharmaceutical regulatory expert 35+ years regulatory experience, including founder Gerry Proehl - Chairman President, CEO and Chairman, Dermata Therapeutics Previously CEO, Santarus Michael Davidson, MD CEO, New Amsterdam Pharma Previously CSO, Corvidia Therapeutics June Almenoff, MD Previously President and CMO, Furiex Pharmaceuticals Declan Doogan, MD CMO, Juvenescence Previously Head of Global Drug Development, Pfizer Previously Chairman/Co-Founder, Biohaven Pharmaceuticals Robyn Hunter CFO, Sotio Biotech Previously CFO, Fortress Biotech Board of Directors
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5 Executive Summary: TNX-103 (Oral Levosimendan) 1. Mechanism of Action • Small molecule NCE with a unique dual mechanism of action, exerting strong vasodilatory effects on venous beds via K+ATP channel activation, while simultaneously enhancing cardiac contractility through calcium sensitization of troponin C 2. Compelling Clinical Data • The only treatment to produce favorable hemodynamic changes and improve exercise tolerance for PH- HFpEF patients, showing statistically significant 6MWD increases and reduction in PCWP across all exercise stages in the Phase 2 HELP trial • OLE portion of the Phase 2 trial showed that patients who transitioned from IV to oral levosimendan in a 6-week period experienced improvements in 6MWD (+7 meters), BNP/NT-proBNP and KCCQ scores, suggesting the oral formulation with an optimized PK profile is potentially a more effective chronic therapy 3. Clear Regulatory Path Forward • Large safety database with >2.2M patient exposures via IV administration for Acute HF ex-US • Phase 3 program design aligned with the FDA helps de-risk the potential approval pathway for TNX-103 4. Intellectual Property • U.S. patent protection for multiple methods of use out to end of 2040 + potential for continuations 5. Commercial Opportunity • Potential to be the first approved therapy for patients suffering from PH-HFpEF globally (~2.2 million US patients projected 2030) • Addressable market opportunity estimated to be at least $10B See Market Opportunity slide for additional details regarding projected addressable market opportunity.
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6 (1): Circulation. 2022;146:e73–e88. DOI: 10.1161/CIR.000000000000107 (2): Ameri, Pietro et al. “A roadmap for therapeutic discovery in pulmonary hypertension associated with left heart failure. A sci entific statement of the Heart Failure Association (HFA) of the ESC and the ESC Working Group on Pulmonary Circulation & Right Ventricular Function.” European journal of heart failure vol. 26,4 (2024): 707- 729. doi:10.1002/ejhf.3236 (3): Borlaug, B, Sharma, K, Shah, S. et al. Heart Failure With Preserved Ejection Fraction: JACC Scientific Statement. JACC. 2023 May, 81 (18) 1810–1834. https://doi.org/10.1016/j.jacc.2023.01.049 PH-HFpEF Recently Highlighted as a Large Unmet Medical Need by all Major Global Cardiovascular Medical Associations: AHA, ACC, ESC “Heart failure (HF) with preserved ejection fraction (HFpEF) is one of the leading causes of pulmonary hypertension (PH) in the world …Despite this recognition, no evidence-based therapies exist for PH attributable to HFpEF (PH-HFpEF).”(1) 1 “PH-LHF is one of the most common causes of PH. There are no specific treatments for PH-LHF, despite the high number of drugs tested so far.”(2) 2 “Despite recent advances in the understanding of its pathophysiological effects on the heart, lungs, and extracardiac tissues, and introduction of new, easily implemented approaches to diagnosis, HFpEF remains under-recognized in everyday practice.”(3) 3
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7 PH-HFpEF Development Competitive Landscape Ongoing Ongoing(1) Ongoing(2) Tenax Merck AstraZeneca OngoingTectonic Phase 1 Phase 2 Phase 3Product TNX-103 Sotatercept TX-45 AZD3427 Company Indication PH-HFpEF Cpc-PH-HFpEF PH-HFpEF PH-HFpEF (1): Clinicaltrials.gov .NCT04945460 CADENCE Study (2): Clinicaltrials.gov NCT05737940 RePHIRE Study (3): Tectonic Therapeutic Press releases Mar 26, 2024 (Tectonic Therapeutic Initiates Phase 1B Study for TX45 in PH-HFpEF) &, Nov 07,2024(First subject dosed with TX000045 (“TX45”) in APEX Phase 2 clinical trial in early October) PH-HFpEF Market Opportunity and Competitive Landscape Ongoing(3)
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8 Confidential Growth in US HF Prevalence Drives PH-HFpEF Prevalence 6,700,000 8,500,000 2020 2030 EF≤40% EF41-50% EF ≥50% PH in ~50-80% ~3.5M patients ~1.2M patients ~3.8M patients 2,200,000 - 3,700,000 PH-HFpEF patients in US In 2030 Estimated US HF Prevalence EF% Distribution Estimated US PH-HFpEF Prevalence in 2030 1) Martin, Seth S., et al. "2024 heart disease and stroke statistics: a report of US and global data from the American Heart Association." Circulation 149.8 (2024): e347-e913. 2) Bozkurt, Biykem, et al. "Heart failure epidemiology and outcomes statistics: a report of the Heart Failure Society of America." (2023). 3) Vaduganathan, Muthiah, et al. "Potential implications of expanded US Food and Drug Administration labeling for sacubitril/valsartan in the US."JAMA cardiology 6.12 (2021): 1415-1423 4) .Lai, Yen‐Chun, Longfei Wang, and Mark T. Gladwin. "Insights into the pulmonary vascular complications of heart failure with preserved ejection fraction." The Journal of physiology 597.4 (2019): 1143-1156 5) Guazzi, Marco. "Pulmonary hypertension in heart failure preserved ejection fraction: prevalence, pathophysiology, and clinical perspectives." Circulation: Heart Failure 7.2 (2014): 367-377 6) Lam, Carolyn SP, et al. "Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study."Journal of the American College of Cardiology53.13 (2009): 1119-1126 (1) (2,3)(1,2) (4,5,6) PH-HFpEF Market Opportunity and Competitive Landscape
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PH-HFpEF Pathophysiology & Levosimendan MoA
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10 Pulmonary Hypertension with Heart Failure with Preserved Ejection Fraction (PH-HFpEF) Three fundamental abnormalities 1. The left ventricle has reduced compliance (i.e. “stiffness”) which limits its ability to fill with blood normally 2. Chronic sympathetic nervous system (SNS) activation results in excessive venous return (stressed blood volume) which produces elevated filling pressure in the heart 3. Chronic elevation in pulmonary venous pressure leads to elevation in the pulmonary arterial pressure (pulmonary hypertension). PH-HFpEF Pathophysiology
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11 HFpEF and PH-HFpEF Share Two Underlying Physiological Features that are the Critical Targets for Treatments PH-HFpEF Pathophysiology This pathophysiology predicts that pulmonary vasodilators (PAH drugs) are doomed to fail in PH-HFpEF as these agents drive even more blood into the left ventricle Excessive venous return from chronic SNS activation as a maladaptive response Volume Overload Multifactorial in nature, difficult to measure, increases with aging Left Ventricle Stiffness Therapeutic Targets
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12 This patient has excessive blood in her veins: lowering elevated venous pressure is the objective PH-HFpEF Pathophysiology
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13 Anesthesiology 2004; 100:434–9 35% of circulating blood is in the systemic veins 30% of circulating blood is in the splanchnic vascular reservoir 35% of circulating blood is in the systemic arteries Reviving the Fundamental Role of the Splanchnic Circulation PH-HFpEF Pathophysiology
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14 Overview: Pathophysiology of PH with HFpEF The Venous Circulation is a Source of the Problem PH-HFpEF Pathophysiology Fudim M, Kaye DM, Borlaug BA, et.al.Venous Tone and Stressed Blood Volume in Heart Failure: JACC Review Topic of the Week. J Am Coll Cardiol. 2022 May 10;79(18):1858-1869.. EXCESSIVE VENOUS RETURN/VOLUME INCREASED CENTRAL VENOUS PRESSURE INCREASED PULMONARY VENOUS PRESSURE PULMONARY HYPERTENSION TNX-103 MOA addresses the underlying pathophysiology PH-HFpEF has recently been described to follow this course:
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15 Mechanism of Action Levosimendan is a Potent Venodilator • Strong vasodilatory action on the pulmonary vasculature via K+ATP channel activation • Downregulation of potassium channels is a hallmark of pulmonary hypertension • Strong vasodilatory action on the splanchnic vasculature • Key to its beneficial effect in PH-HFpEF Effects on Isolated Human Portal Vein Mondéjar-Parreño G, et.al. Potassium (K+) channels in the pulmonary vasculature: Implications in pulmonary hypertension Physiological, pathophysiological and pharmacological regulation. Pharmacol Ther. 2021 Sep;225:107835. 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 pharmacology 52.2 (2000): 213-217. Levosimendan
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16 TNX-103: Oral Levosimendan Mechanism of Action in PH-HFpEF is Unique Levosimendan is the only drug that is a K+ATP channel activator and calcium sensitizer(1) 01 Strong vasodilatory effects on venous beds(2) and causes a marked reduction in CVP and PCWP 02 Backed by recent clinical science demonstrating reducing elevated CVP and PCWP are critical targets for left heart failure(3) 03 (1): Rich, Stuart, Burkhoff, Daniel, Pollesello, Piero, Papp, Zoltan. “Levosimendan-induced venodilation is mediated by opening of potassium channels.” ESC Heart Failure. 10.1002 (2021) (2): Brener, Michael I., et al. "Changes in stressed blood volume with levosimendan in pulmonary hypertension from heart failure with preserved ejection fraction: insights regarding mechanism of action from the HELP trial." Journal of Cardiac Failure 27.9 (2021): 1023-1026 (3): Fudim, Marat, et al. "Splanchnic Nerve Block for Chronic Heart Failure." Heart Failure 8.9 (2020): 742-752. Mechanism of Action
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Phase 2 HELP Results
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18 Proof of Concept: The HELP Study IV levosimendan Phase 2 trial design Open label lead-in phase to evaluate the effects of IV levosimendan on hemodynamics at rest and exercise after 24 hours Patients with an initial response were enrolled into randomized, double blinded treatment with once weekly infusions of IV levosimendan for 6 weeks Patients return after 6 weeks for final assessment of 6-minute walk and a hemodynamic study Phase 2 HELP Trial
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19 Overview of PH-HFpEF Hemodynamics Exercise Hemodynamics Confirm the Diagnosis Marc A. Pfeffer, Amil M. Shah, Barry A. Borlaug. “Heart Failure with Preserved Ejection Fraction in Perspective.” Circulation Research 124 (2019): 1598-1617 Phase 2 HELP Trial No known treatment has been able to prevent the increase in PCWP during exercise The increase in PCWP during exercise is the defining impairment of PH-HFpEF
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20 IV Levosimendan Improves CVP and PCWP at Rest and with Exercise in PH-HFpEF Patients: Pronounced Changes Burkhoff D, Rich S, et. al. Levosimendan Improves Hemodynamics and Exercise Tolerance in PH-HFpEF. JACC Heart Fail. 2021; 9:360-370 PCWP Improvement CVP Improvement 44 pts 44 pts P value: <0.05 Phase 2 HELP Results 85% of the patients enrolled responded with a robust decrease (≥4mm Hg) in exercise PCWP P value: <0.05
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21 p=0.6615 † p=0.0017 † Rest Rest † Tested in a mixed effect model using treatments as factors and position as a random effect p=0.0475† 35 pts Significant PCWP Improvement Versus Placebo IV Levosimendan effect on PCWP across 3 positions: significant improvement Phase 2 HELP Results After 6 weeks, placebo patients experienced no change, while pressure in IV levosimendan-treated patients markedly improved in 3 positions as assessed by right heart cath
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22 HELP Study: Six-Minute Walk Distance IV Levosimendan Improves Exercise Capacity in PH-HFpEF Patients after 6 Weeks 29-meter improvement in 6-minute walk distance Dr Barry Borlaug, Mayo Clinic: “…this is the first medicine that has actually improved 6-minute walk distance in any patient population with HFpEF…” - 37 patients met hemodynamic criteria and were randomized; of these, 2 patients dropped out due to palpitations and COVID-19 infection. Both were in the placebo arm. - Burkhoff D, Rich S, et. al. Levosimendan Improves Hemodynamics and Exercise Tolerance in PH-HFpEF. JACC Heart Fail. 2021; 9:360-370 - https://www.medscape.com/viewarticle/938671 (Borlaug quote) 33 pts Phase 2 HELP Results
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23 Phase 2 HELP Results HELP Study Supports Targeting PCWP in PH-HFpEF Targeting PVR in PH-HFpEF has not proven successful 1) Burkhoff, Daniel, et al. "Levosimendan improves hemodynamics and exercise tolerance in PH-HFpEF: results of the randomized placebo-controlled HELP trial."Heart Failure 9.5 (2021): 360-370. 2) Koller, B., et al. "Pilot study of endothelin receptor blockade in heart failure with diastolic dysfunction and pulmonary hypertension (BADDHY-Trial)." Heart, Lung and Circulation26.5 (2017): 433-441 3) Mascherbauer, Julia, et al. "Evaluation of the pharmacoDYNAMIC effects of riociguat in subjects with pulmonary hypertension and heart failure with preserved ejection fraction: study protocol for a randomized controlled trial." Wiener Klinische Wochenschrift 128 (2016): 882-889. 4) Vachiéry, Jean-Luc, et al. "Macitentan in pulmonary hypertension due to left ventricular dysfunction."European Respiratory Journal51.2 (2018) 5) Hoeper, et al. "Tadalafil for treatment of combined postcapillary and precapillary pulmonary hypertension in patients with heart failure and preserved ejection fraction: a randomized controlled phase 3 study."Circulation 150.8 (2024): 600-610. 6) Hoendermis, et al. "Effects of sildenafil on invasive haemodynamics and exercise capacity in heart failure patients with preserved ejection fraction and pulmonary hypertension: a randomized controlled trial." European heart journal36.38 (2015): 2565-2573. Acute (24-h) Effects of Open-Label Levosimendan (N = 44) (1) Comparison of PCWP and PVR Effects Observed in HELP Study ∆24 h (95% CI) Legs Down Legs Up 25 W PCWP, mm Hg -4.9 (-7.0 to -2.9)* -5.3 (-7.3 to -3.3)* - 3.9 (-6.0 to - 0.9)* PVR, WU -0.1 (-0.6 to 0.3) 0.2 (-0.3 to 0.7) 0.0 (-0.4 to 0.5) Values are mean ± SD, unless otherwise indicated.*p < 0.05 comparedwith baseline. PCWP ¼ pulmonary capillary wedge pressure; PVR ¼ pulmonary vascular resistance; SVR ¼ systemic vascular resistance. Multicenter Trials of Pulmonary Vasodilators in PH-HFpEF Patients Drug Multicenter Trial PCWP/PAWP Change vs Placebo PVR Change vs Placebo 6MWD Change vs Placebo Safety Conclusion Bosentan BADDHY (2) Not Reported Not Reported No Difference Questionable- study stopped early Ineffective Macitentan MELODY (3) No Difference No difference No Difference Questionable- fluid retention Ineffective Riociguat DYNAMIC (4) No Difference Decreased No Difference Questionable- increased dropouts for AEs in drug arm Ineffective Tadalafil PASSION (5) Not Reported Not Reported No Difference Questionable-all-cause death was higher (HR, 5.10 [95% CI, 1.10–23.69]; P=0.04 Ineffective Sildenafil Hoendermis et al (6) Reduction in favor of placebo No Difference No Difference No concerns Ineffective
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K-ATP Channel Effects on Pulmonary Vasculature May Have Disease Modifying Implications
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25 Pulmonary Vascular Remodeling in PH is Associated with Downregulation of K-ATP Channels Mechanism of Action
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26 Altered K-ATP/Potassium Channel Signaling is Associated with Pulmonary Vasculopathies Mandegar M, Yuan JX. Role of K+ channels in pulmonary hypertension. Vascul Pharmacol. 2002 Jan;38(1):25-3 Mechanism of Action
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27 Pulmonary Hypertension with HFpEF Has a Distinct Pathology Circulation. 2018;137:1796–1810 • Involvement of the pulmonary arteries, pulmonary veins, and arteriole/venule interface. • Triggered via the increased pressure within the left atrium and/or pulmonary veins. • The signaling pathway is uncertain. Mechanism of Action
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Rationale for TNX-103 Dose Selection & HELP OLE
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29 Levosimendan and its Active Metabolite: Non-Protein Bound Plasma Concentrations A 24-hour IV infusion: 0.2 µg/kg/min (vs. 0.1 µg/kg/min used in HELP) Kivikko et al. Int J Clin Pharm & Ther 2002;40:465 Rationale for Oral Dose Selection
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30 Rationale for TNX-103 Dose Regimen in PH-HFpEF Patients Objective: Select optimal oral daily dose that would achieve steady state of OR1896 levels Strategies: Identify the oral daily dose that provides similar systemic exposure to the weekly IV infusion, and provides higher steady state concentrations of OR1896, across a range of patient weights • Consider the efficacy and safety results from legacy oral dosing studies: • Poder et al (MAD study) • PERSIST study (HFrEF) • REFALS study (ALS) • Test a dose range of 1-4mg/day in IV to Oral Transition Study, including comparative PK Answer: 2-3mg daily oral dosing achieves our objective Note: A substantial amount of controlled clinical trial data with oral levosimendan was available to Tenax prior to our transition of patients from the IV to oral form in the HELP OLE Rationale for Oral Dose Selection
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31 Specific Features: IV to Oral Transition Substudy Goals: • Determine safety and tolerability of the transition of patients receiving weekly infusions of levosimendan to an oral dose • Determine the dose of oral levosimendan that maintains the efficacy in patients receiving weekly infusions • Determine the pharmacokinetics of oral levosimendan in this population Design: • Amendment to the OLE trial (not a new clinical trial, not a separate protocol) • No placebo or control group Clinical Data Phase 2 HELP OLE
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32 Patients in the Open Label Extension Stage of HELP Transitioned Safely from IV to Oral Levosimendan Previous IV Infusion Week 0 (Office) Week 2 (Home) Week 4 (Home) Week 6 (Office) 0.10 µg/kg/min 1mg QD (1mg total daily dose) Morning 1mg BID (2mg total daily dose) Every 12 hrs. 1mg TID (3mg total daily dose) Every 8 hrs. Patient evaluated for further titration 6 Week Transition Period Clinical Data Phase 2 HELP OLE
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33 BNP or NT-proBNP (Collected per Institutional Standard) 33 -4 -46 -47 -147 -258 -277 -320-350 -300 -250 -200 -150 -100 -50 0 50 100 pg/dL Change in BNP 367 255 146 -77 -616 -696 -1055 -1200 -1000 -800 -600 -400 -200 0 200 400 600 pg/dL Change in NT-proBNP Mean = 239.4 pg/dLMean = 133.3 pg/dL Clinical Data Phase 2 HELP OLE
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34 KCCQ Summary Scores Clinical Data Phase 2 HELP OLE mean Δ •TOTAL SYMPTOM +4.7 • Symptom Stability +9.4 • Symptom Frequency +3.1 • Symptom Burden +6.3 mean Δ •PHYSICAL LIMITATION +0.3 •SELF EFFICACY -2.3 •QUALITY OF LIFE +4.2 •SOCIAL LIMITATION +5.5 •OVERALL SUMMARY +3.7
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35 • 6MWD (exercise capacity) • Improved 7 meters during 6-week transition • BNP/NT-proBNP (measure of cardiac function) • Improved by 23% over IV • KCCQ (patient reported symptoms) • Improved in 6 of 7 different domains Conclusion: “The transition to oral levosimendan was well tolerated without safety concerns over a 6-8-week period in patients with PH-HFpEF who had been receiving IV levosimendan for more than 18 months. Oral levosimendan was also associated with … improvements in 6MWD, BNP/NTProBNP, and KCCQ scores.” Thenappan, Thenappan, et al. "The Transition From Chronic Intravenous To Oral Levosimendan Is Safe And Effective In Patients With Pulmonary Hypertension With Heart Failure And Preserved Ejection Fraction." Journal of Cardiac Failure 29.4 (2023): 714-715. Clinical Data Phase 2 HELP OLE 18 pts
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36 Efficacy Considerations for Oral Dose Regimen Oral Levosimendan causes a rapid and sustained reduction in NT-proBNP vs. Baseline (data from PERSIST Trial) Rationale for Oral Dose Selection 2000 2500 3000 3500 4000 4500 5000 5500 6000 6500 7000 Baseline D7 D30 D60 D90 D180 End of study PERSIST - Oral Levosimendan 1 mg QD and 1 mg BID mean NT-proBNP 1 mg/day 2 mg/day 32% Reduction in 7 Days 38% Reduction in 7 Days 1mg oral QD 1mg oral BID Return towards baseline Return towards baseline Treatment Stopped N=102 N=103 Mean NT-proBNP Time (days)
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37 Efficacy Considerations for Oral Dose Regimen Oral Levosimendan causes a sustained reduction in PCWP in Chronic Heart Failure Patients (data from PERSIST Trial) Jalanko, Mikko, et al. "Oral levosimendan improves filling pressure and systolic function during long-term treatment." Scandinavian cardiovascular journal 45.2 (2011): 91-97. Rationale for Oral Dose Selection
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Ongoing Phase 3 LEVEL Trial
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39 Phase 3 Clinical Program • Two trials, Δ6MWD primary endpoint, p≤0.05 • First Trial: 12-weeks acceptable • Second Trial: 26-weeks to show durability and extended safety • Tenax has the option of conducting the two trials serially or concurrently • Two trials will provide minimum safety database requirements • 300 PH-HFpEF patients followed for >6 months, and • 100 PH-HFpEF patients followed for >12 months Ongoing Pivotal Phase 3 LEVEL Trial and FDA Guidance Highly supportive guidance from FDA following submission of Tenax’s PH-HFpEF White Paper
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40 LEVosimendan to Improve Exercise Limitation in Patients With PH-HFpEF A Phase 3, Double-Blind, Randomized, Placebo-Controlled Study of Levosimendan in Pulmonary Hypertension Patients With Heart Failure With Preserved Left Ventricular Ejection Fraction (PH-HFpEF)
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41 Tenax’s PH-HFpEF Scientific Advisors Recognized World Experts in Pulmonary Hypertension and Heart Failure Sanjiv Shah, MD Professor of Medicine, Northwestern University Feinberg School of Medicine Director, Northwestern HFpEF Program, Bluhm Cardiovascular Institute Daniel Burkhoff, MD, PhD Director Heart Failure, Hemodynamics and MCS Research at the CRF Adjunct Associate Professor of Medicine, Columbia University Barry Borlaug, MD Professor of Medicine and Director, Circulatory Failure Research, Mayo Clinic Chair for Research, Division of Circulatory Failure Javed Butler, MD, MPH, MBA President of the Baylor Scott and White Research Institute Chair of Medicine, Chair of CV Research, Distinguished Professor of Medicine, University of Mississippi Ongoing Pivotal Phase 3 LEVEL Trial
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42 LEVEL Study Design 42 Primary Endpoint: change in 6MWD >90% power to detect a 25-meter change (SD=55 meters) at alpha 0.05 Ongoing Pivotal Phase 3 LEVEL Trial Levosimendan 2mg (Weeks 0-4) Placebo (Weeks 0-4) 0 2 4 6 8 10 12 Placebo (Weeks 5-12) 1mg oral capsule BID, titrated to 1mg TID week N=230 Open-label extension to 2 years Randomize Levosimendan 3mg (Weeks 5-12)
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43 LEVEL Trial Objectives 43 By the Numbers • 230 randomized patients • ~55 investigator sites, U.S. & Canada • Site initiation & enrollment: competitive • Enrollment commenced Q1 2024 Double Blind Phase • Randomized at a 1:1 ratio: 2mg/day (1 mg BID) Weeks 1-4; 3mg/day (1 mg TID) Weeks 5-12 • 6 MWT (Day 1, Week 4, 8, 12) and any unscheduled visit Primary Endpoint: • To evaluate the efficacy of TNX-103 (oral levosimendan) compared with placebo in subjects with PH- HFpEF as measured by the change in 6MWD (Day 1 to Week 12) Secondary Endpoints: • Change in KCCQ - Total Symptom Score (KCCQ-TSS) • Number of Clinical Worsening Events, e.g. death/hosp. due to PH/HF, ER visits requiring diuretics • Change in NT-proBNP • Improvement in NYHA Functional Class Ongoing Pivotal Phase 3 LEVEL Trial
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44 LEVEL Trial: Current Timelines The LEVEL Study Phase 3 PH-HFpEF TNX-103 2023 2024 2025 2026 H1 H2 H1 H2 H1 H2 H1 H2 Site Initiation Starts First Patient Enrolled Last Patient Enrolled Topline LEVEL Data Ongoing Pivotal Phase 3 LEVEL Trial
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PH-HFpEF Market Opportunity & Intellectual Property
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46 PH-HFpEF Market is Large and Growing PH-HFpEF Market Opportunity and Competitive Landscape 54% of Heart Failure Patients have EF ≥ 40% (2,3,4) 8.2M Heart Failure Patients(2) PH-HFpEF Prevalence in the U.S. (2030) 4.4M HFpEF Patients 2.2M PH-HFpEF Patients ~770K PH-HFpEF Patients Treated 50% of HFpEF Patients with PH (3,6,7) 35% Addressable Market x =>$15,000 Cost per Patient(1) >$10B Estimated Addressable Market x 2.1% 2030 – 2040 CAGR(2) = 2.7 Million PH-HFpEF Patients in 2040 1) Drugs.com. March 2023 Annual cost/patient branded for ANRI or SGLT2 inhibitors approved in HF. Assumes similar pricing for a PH-HFpEF drug 2) Tsao, Connie W., et al. "Heart disease and stroke statistics—2023 update: a report from the American Heart Association." Circulation 147.8 (2023): e93-e621. 3) Lai, Yen‐Chun, Longfei Wang, and Mark T. Gladwin. "Insights into the pulmonary vascular complications of heart failure with preserved ejection fraction." The Journal of physiology 597.4 (2019): 1143-1156. 4) Pfeffer, Marc A., Amil M. Shah, and Barry A. Borlaug. "Heart failure with preserved ejection fraction in perspective." Circulation research 124.11 (2019): 1598-1617. 5) Steinberg, Benjamin A., et al. "Trends in patients hospitalized with heart failure and preserved left ventricular ejection fraction: prevalence, therapies, and 6) Brittain, Evan L., et al. "Elucidating the Clinical Implications and Pathophysiology of Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction: A Call to Action: Circulation 146.7 (2022): e73-e88. 7) Guazzi, Marco. "Pulmonary hypertension in heart failure preserved ejection fraction: prevalence, pathophysiology, and clinical perspectives." Circulation: Heart Failure 7.2 (2014): 367-377 8) 2.1% CAGR from 2030-2040 is a Company calculation based on data published in the articles cited here.
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47 Global IP Strategy to Protect Rights to Levosimendan Use in PH-HFpEF United States: • US 11,213,524, issued January 4, 2022, expires November 14, 2039 (SC Formulation/Use) • US 11,607,412, issued March 21, 2023, expires December 15, 2040 (IV Use) • US 11,701,355, issued July 18, 2023, expires December 15, 2040 (Oral Use) • US 11,969,424, issued April 30, 2024, expires December 15, 2040 (Expanded dose & CV Drug combo use) • All patents have continuation applications pending Europe: • European Patent Application No. 20900848.1, filed July 14, 2022 (regional of PCT/US2020/065166) Japan/Canada/ New Zealand/Australia/Thailand/ Malaysia/Singapore: • Regional stage applications filed (PCT/US2020/065166) Other PCT Applications: • PCT/US2022/080708, filed November 30, 2022 (Combination use of levosimendan and SGLT-2 in HF) • PCT/US2022/082561, filed December 29, 2022 (Oral Levosimendan use in PH-HFpEF) Intellectual Property
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48 Tenax Investment Summary 1. Mechanism of Action • Small molecule NCE with a unique dual mechanism of action, exerting strong vasodilatory effects on venous beds via K+ATP channel activation, while simultaneously enhancing cardiac contractility through calcium sensitization of troponin C 2. Compelling Clinical Data • The only treatment to produce favorable hemodynamic changes and improve exercise tolerance for PH- HFpEF patients, showing statistically significant 6MWD increases and reduction in PCWP across all exercise stages in the Phase 2 HELP trial • OLE portion of the Phase 2 trial showed that patients who transitioned from IV to oral levosimendan in a 6-week period experienced improvements in 6MWD (+7 meters), BNP/NT-proBNP and KCCQ scores, suggesting the oral formulation with an optimized PK profile is potentially a more effective chronic therapy 3. Clear Regulatory Path Forward • Large safety database with >2.2M patient exposures via IV administration for Acute HF ex-US • Phase 3 program design aligned with the FDA helps de-risk the potential approval pathway for TNX-103 4. Intellectual Property • U.S. patent protection for multiple methods of use out to end of 2040 + potential for continuations 5. Commercial Opportunity • Potential to be the first approved therapy for patients suffering from PH-HFpEF globally (~2.2 million US patients projected 2030) • Addressable market opportunity estimated to be at least $10B See Market Opportunity slide for additional details regarding projected addressable market opportunity.
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TNX-201: Modified- Release Oral Imatinib (PAH: WHO Group 1)
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50 PAEC = pulmonary artery endothelial cell PASMC = pulmonary artery smooth muscle cell GF = growth factors BCR-Abl, PDGFR, c-Kit Imatinib Targets the Pathophysiology of PAH imatinib blocks and reverses GF
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51 Proof of Concept IMPRES Study Imatinib is Proven Effective in Treating PAH Phase 3 Clinical Trial: Imatinib Mesylate as Add-On Therapy for Pulmonary Arterial Hypertension: Results of the Randomized IMPRES Study Results: After 24 weeks, the mean placebo-corrected treatment effect on 6-minute walk distance was 32 meters (95% confidence interval, 12–52; P=0.002) Conclusions: Imatinib improved exercisecapacity and hemodynamics in patients with advanced PAH,but frequent dropout events prevented approval. Circulation. 2013;127:1128-1138. The primary endpoint was change in 6-minute walk distance
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52 Key Learnings from IMPRES Study Informed Phase 3 IMPROVE . Efficacy was established in PAH Avoid excessive dropouts, mostly related to early-onset side effects 01 02 03 04 Adequate dose is critical (400mg) to achieve clinical efficacy Gastrointestinal side effects are most the common, novel formulation to reduce PAH >400 mg Open-label Lead-in Modified Formulation IMPROVE
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Appendix
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54 Abbreviations and Acronyms 6MWD result of the 6MWT, a measurement in meters 6MWT 6-minute walk test, an assessment of exercise tolerance, specifically the distance one can walk in 6 min. CVP Central Venous Pressure HF Heart Failure HFpEF Heart Failure with preserved Ejection Fraction K-ATP ATP-sensitive potassium channels, which control the vascular tone (state of constriction and dilation) of the blood vessels KCCQ Kansas City Cardiomyopathy Questionnaire, a scale commonly used in assessing HF KCCQ-TSS KCCQ - Total Symptoms Score; a subscore of the KCCQ PAH Pulmonary Arterial Hypertension (Group 1 in WHO’s PH classification system) PCWP Pulmonary Capillary Wedge Pressure PH Pulmonary Hypertension PH-HFpEF Pulmonary Hypertension in the setting of heart failure with preserved ejection fraction, the most common form of Group 2 PH in WHO’s PH classification system PVR Pulmonary Vascular Resistance WHO World Health Organization, which established a PH classification including 5 categories, or “groups”