Tonix Pharmaceuticals Holding Corp. · NASDAQ:TNXP

Tonix Pharmaceuticals — Investor Presentation (June 2023)

41 slides from Tonix Pharmaceuticals's investor presentation, Jun 5, 2023

1. Slide 1: TNX-601 ER & TNX-4300 Major Depressive Disorder

   © 2023 Tonix Pharmaceuticals Holding Corp. © 2023 Tonix Pharmaceuticals Holding Corp. TNX - 601 ER & TNX - 4300 Major Depressive Disorder NASDAQ: TNXP Version P0449 June 5, 2023 (Doc 1238)

2. Slide 2: Cautionary Note on Forward-Looking Statements

   © 2023 Tonix Pharmaceuticals Holding Corp. 2 © 2023 Tonix Pharmaceuticals Holding Corp. Cautionary Note on Forward - Looking Statements Certain statements in this presentation regarding strategic plans, expectations and objectives for future operations or results are “forward - looking statements” a

3. Slide 3: Major Depressive Disorder (MDD)

   © 2023 Tonix Pharmaceuticals Holding Corp. 3 © 2023 Tonix Pharmaceuticals Holding Corp. CNS PORTFOLIO Major Depressive Disorder (MDD) • Major depressive disorder (MDD) is a leading cause of disability worldwide, with 21 million adults in the US alone experiencing a depressive episode in 2020 1 • L i

4. Slide 4: High Unmet Need for New Classes of Antidepressants

   © 2023 Tonix Pharmaceuticals Holding Corp. 4 © 2023 Tonix Pharmaceuticals Holding Corp. CNS PORTFOLIO • The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, regarded as the largest antidepressant trial ever conducted, indicated approximately 30% of depressed patients fail to ac

5. Slide 5: TNX-601 ER: Depression Development Program

   © 2023 Tonix Pharmaceuticals Holding Corp. 5 © 2023 Tonix Pharmaceuticals Holding Corp. CNS PORTFOLIO PROFILE DEVELOPMENT PROGRAM Patents Issued TNX - 601 E R*: Depression Tianeptine Hemioxalate Extended - Release Tablets (39.4 mg) CNS PORTFOLIO • A novel, oral, extended - release once - daily table

6. Slide 6: TNX-601 ER Pharmacokinetics and Formulation

   © 2023 Tonix Pharmaceuticals Holding Corp. 6 © 2023 Tonix Pharmaceuticals Holding Corp. CNS PORTFOLIO TNX - 601 ER - Pharmacokinetics and Formulation 1 TNX - 601 ER 39.4 mg (fed) N=12 TNX - 601 ER 39.4 mg (fasted) N=12 TNX - 601 ER 39.4 mg (fed) N=12 TNX - 601 ER 39.4 mg (fasted) N=12 Table 1 Metabo

7. Slide 7: TNX-601 ER Phase 2 UPLIFT Study Design

   © 2023 Tonix Pharmaceuticals Holding Corp. 7 © 2023 Tonix Pharmaceuticals Holding Corp. CNS PORTFOLIO TNX - 601 ER - Phase 2 UPLIFT* Study Design General s tudy c haracteristics: • Randomized, double - blind, placebo - controlle d study in Major Depressive Disorder to evaluate monotherapy with TNX -

8. Slide 8: History of Tianeptine and TNX-601 ER

   © 2023 Tonix Pharmaceuticals Holding Corp. 8 © 2023 Tonix Pharmaceuticals Holding Corp. CNS PORTFOLIO History of Tianeptine and TNX - 601 ER CNS PORTFOLIO • Tianeptine sodium (amorphous) immediate release (IR) tablets have been available in Europe and many countries in Asia and Latin America for the

9. Slide 9: Proposed MOA of Tianeptine

   © 2023 Tonix Pharmaceuticals Holding Corp. 9 © 2023 Tonix Pharmaceuticals Holding Corp. CNS PORTFOLIO 1 Tartt et al., 2022. Molecular Psychiatry 27: 2689 – 2699. 2 Plaisant et al.,2003. Neuropharmacology 44: 801 – 809. 3 Slusarczyk et al., 2018. Int J Mol Sci 19: 1965. • In Table 1 (right), it is il

10. Slide 10: Clinical Trials of Tianeptine Sodium

    © 2023 Tonix Pharmaceuticals Holding Corp. 10 © 2023 Tonix Pharmaceuticals Holding Corp. CNS PORTFOLIO Clinical Trials of Tianeptine Sodium • Antidepressant efficacy confirmed in multicenter double - blind, placebo - controlled, randomized trials 1,2 • Enriched enrollment randomized withdrawal desig

11. Slide 11: Tianeptine's off-target activity

    © 2023 Tonix Pharmaceuticals Holding Corp. 11 © 2023 Tonix Pharmaceuticals Holding Corp. CNS PORTFOLIO Tianeptine's off - target activity • Because of low affinity binding and agonist activity on µ - opioid receptor 1 , there is the potential abuse liability of tianeptine drug substance when availab

12. Slide 12: Prescription Tianeptine has Low Incidence of Abuse

    © 2023 Tonix Pharmaceuticals Holding Corp. 12 © 2023 Tonix Pharmaceuticals Holding Corp. CNS PORTFOLIO Prescription Tianeptine has Low Incidence of Abuse • Tianeptine and its MC5 metabolite are weak opioid (µ - opioid) receptor (MOR) agonists 1 that present a potential abuse liability if illicitly m

13. Slide 13: TNX-601 ER Drug Product

    © 2023 Tonix Pharmaceuticals Holding Corp. 13 © 2023 Tonix Pharmaceuticals Holding Corp. CNS PORTFOLIO TNX - 601 ER Drug product • The only abuse - deterrent properties approved for the labels of certain marketed opioids are extended - release formulations with physiochemical barriers +/ - aversive

14. Slide 14: Summary: TNX-601 ER vs. Other Antidepressants

    © 2023 Tonix Pharmaceuticals Holding Corp. 14 © 2023 Tonix Pharmaceuticals Holding Corp. CNS PORTFOLIO Summary: TNX - 601 ER vs. Other Antidepressants • Given tianeptine’s unique metabolic pathway, which is independent of the hepatic P450 system, it is anticipated that, like tianeptine sodium, TNX -

15. Slide 15: Additional Potential Indications for TNX-601 ER

    © 2023 Tonix Pharmaceuticals Holding Corp. 15 © 2023 Tonix Pharmaceuticals Holding Corp. CNS PORTFOLIO Looking Forward: Additional Potential Indications for TNX - 601 ER • Neurodegenerative disorders ‒ Parkinson’s (and associated conditions, e.g. depression and psychosis) 1 ‒ Alzheimer’s (and associ

16. Slide 16: Tianeptine Sodium

    © 2023 Tonix Pharmaceuticals Holding Corp. 16 © 2023 Tonix Pharmaceuticals Holding Corp. CNS PORTFOLIO Tianeptine Sodium • Tianeptine discovered and patented by French Society of Medical Research in 1960s • Tianeptine first marketed in 1989 for the treatment of major depression by French pharmaceuti

17. Slide 17: Structural Comparison: Tricyclic and TNX

    © 2023 Tonix Pharmaceuticals Holding Corp. 17 © 2023 Tonix Pharmaceuticals Holding Corp. CNS PORTFOLIO Structural Comparison: Tricyclic and TNX - 601 Cyclobenzaprine and tianeptine share structural similarities with classic tricyclic antidepressants (TCAs) and to each other, but each has unique phar

18. Slide 18: Tianeptine is a PUFA Analogue

    © 2023 Tonix Pharmaceuticals Holding Corp. 18 © 2023 Tonix Pharmaceuticals Holding Corp. Tianeptine is a Polyunsaturated Fatty Acid (PUFA) Analogue PUFAs and PUFA - analogues • Polar acidic “head” and hydrophobic fatty acid “tail” Pharmacological modulation of PUFA signaling has therapeutic potentia

19. Slide 19: EPA and DHA are Examples of PUFAs

    © 2023 Tonix Pharmaceuticals Holding Corp. 19 © 2023 Tonix Pharmaceuticals Holding Corp. EPA and DHA are Examples of Polyunsaturated Fatty Acids (PUFAs) PUFAs 1 1 Bohannon et al., 2023. bioRxiv preprint 2 Wikipedia: https://en.wikipedia.org/wiki/Eicosapentaenoic_acid 3 Wikipedia: https://en.wikipedi

20. Slide 20: Racemic Tianeptine – Composed of Two Isomers

    © 2023 Tonix Pharmaceuticals Holding Corp. 20 © 2023 Tonix Pharmaceuticals Holding Corp. CNS PORTFOLIO TNX - 601 ER – Racemic Tianeptine – Composed of Two Isomers Racemic tianeptine : • Approved in Europe and ex - US • 1:1 mixture of 2 mirror r - image isomers 1,2 • Weak µ - o pioid receptor agonism

21. Slide 21: (S)-Tianeptine Increased Average Neurite Length

    © 2023 Tonix Pharmaceuticals Holding Corp. 21 © 2023 Tonix Pharmaceuticals Holding Corp. CNS PORTFOLIO Treatment with 0.1 and 0.32 µM (S) - Tianeptine Significantly I ncreased A verage N eurite L ength 1 PBS (S) - Tianeptine 0.1 µM (R) - Tianeptine 0.1 µM Neurite network dynamics tested in plated hu

22. Slide 22: (R)-Tianeptine, not (S)-Tianeptine, Reduces Immobility in Forced Swim Test

    © 2023 Tonix Pharmaceuticals Holding Corp. 22 © 2023 Tonix Pharmaceuticals Holding Corp. CNS PORTFOLIO (R) - Tianeptine, but not (S) - Tianeptine Reduces Immobility in Murine Forced Swim Test (FST) 1 (S) - Tianeptine Study (R) - Tianeptine Study Racemic Tianeptine in FST Similar Acute Effects Report

23. Slide 23: Summary of CNS Abilities: Tianeptine and Isomers

    © 2023 Tonix Pharmaceuticals Holding Corp. 23 © 2023 Tonix Pharmaceuticals Holding Corp. CNS PORTFOLIO Summary of CNS Abilities: Tianeptine, (S) - & (R) - Isomers (R) - Tianeptine (S) - Tianeptine TNX - 4300 Racemic - Tianeptine + - + µ - Opioid Receptor - + + PPAR - β / δ - - - PPAR - α + + + PPAR

24. Slide 24: TNX-4300: Depression, Alzheimer's & Parkinson's Diseases

    © 2023 Tonix Pharmaceuticals Holding Corp. 24 © 2023 Tonix Pharmaceuticals Holding Corp. CNS PORTFOLIO PROFILE DEVELOPMENT PROGRAM Patents Issued TNX - 4300*: Depression, Alzheimer’s & Parkinson’s diseases Estianeptine (Single (S) - isomer of Tianeptine) CNS PORTFOLIO • Single isomer, oral treatment

25. Slide 25: PPAR Family: PPAR-β/δ

    © 2023 Tonix Pharmaceuticals Holding Corp. 25 © 2023 Tonix Pharmaceuticals Holding Corp. Peroxisome Proliferator Activated - Receptor (PPAR) Family: PPAR - β/δ Emw . Wikimedia Commons . February 10, 2010. Accessed March 31, 2022. https://commons.wikimedia.org/wiki/File:Protein_PPARA_PDB_1i7g.png Emw

26. Slide 26: PPAR-β/δ Protects Against Pathology in CNS Animal Models

    © 2023 Tonix Pharmaceuticals Holding Corp. 26 © 2023 Tonix Pharmaceuticals Holding Corp. PPAR - β / δ Protects Against Pathology in CNS Animal Models • PPAR - β /δ normally protects against pathophysiological processes in the nervous system 1 ‒ PPAR - β /δ also plays roles in neuronal development an

27. Slide 27: Peroxisome Proliferator-Activated Receptor Delta (PPAR-β/δ)

    © 2023 Tonix Pharmaceuticals Holding Corp. 27 © 2023 Tonix Pharmaceuticals Holding Corp. Peroxisome Proliferator - Activated Receptor Delta (PPAR - β/δ) BDNF=brain - derived neurotrophic factor 1 Woods et al., 2003. Brain Res. 975(1 - 2):10 - 21 2 Higashiyama et al., 2007. Histochem Cell Biol . 127(

28. Slide 28: PPAR-β/δ and BDNF Signaling

    © 2023 Tonix Pharmaceuticals Holding Corp. 28 © 2023 Tonix Pharmaceuticals Holding Corp. Peroxisome Proliferator - Activated Receptor Delta (PPAR - β/δ) BDNF = brain - derived neurotrophic factor CREB = cAMP response element binding protein mBDNF = mature BDNF 1 Ji et al., 2015. Int J Neuropsychopha

29. Slide 29: Tianeptine Helps Restore Stress-Related Hippocampal Remodeling

    © 2023 Tonix Pharmaceuticals Holding Corp. 29 © 2023 Tonix Pharmaceuticals Holding Corp. Tianeptine Helps Restore Stress - Related Hippocampal Remodeling Tianeptine activation of PPAR - β / δ regulates the expression of genes that stimulate dendrite arborization and reduce proinflammatory microglia

30. Slide 30: Tianeptine Restores Neuronal Connectivity and Neuroplasticity

    © 2023 Tonix Pharmaceuticals Holding Corp. 30 © 2023 Tonix Pharmaceuticals Holding Corp. Tianeptine Restores Neuronal Connectivity and Neuroplasticity in Animal Models Healthy Depressed Restored Decreased connectivity and neuroplasticity Restored connectivity and neuroplasticity + Stress + Tianeptin

31. Slide 31: (S)-Tianeptine Directly Affects Neuroplasticity vs Monoaminergic Antidepressants

    © 2023 Tonix Pharmaceuticals Holding Corp. 31 © 2023 Tonix Pharmaceuticals Holding Corp. While Monoaminergic Antidepressants Work at the Synapse, (S) - Tianeptine “Cuts in Line” to More Directly Affect Neuroplasticity Depressed Decreased connectivity and neuroplasticity Tianeptine + + mRNA ( eg , BD

32. Slide 32: Potential Side Effects of Monoaminergic Antidepressants

    © 2023 Tonix Pharmaceuticals Holding Corp. 32 © 2023 Tonix Pharmaceuticals Holding Corp. Potential Side Effects of Monoaminergic Antidepressants Related to Neurotransmitter Modulation Gelenberg et al., 2010. Am J Psychiatry .167(suppl):1 - 152 Dry mouth Headaches Nausea Hypertension Weight gain Cons

33. Slide 33: Tianeptine Acts on Microglia in the Hippocampus

    © 2023 Tonix Pharmaceuticals Holding Corp. 33 © 2023 Tonix Pharmaceuticals Holding Corp. • Microglia are immune effector cells 1 • Under normal conditions, microglia regulate synaptic transmission, prune neuronal synapses, and assist in the formation of neural circuits 1,2 • When homeostasis is disr

34. Slide 34: PPAR Family Members: PPAR-γ

    © 2023 Tonix Pharmaceuticals Holding Corp. 34 © 2023 Tonix Pharmaceuticals Holding Corp. PPAR Family Members: PPAR - γ Emw . Wikimedia Commons . February 10, 2010. Accessed March 31, 2022. https://commons.wikimedia.org/wiki/File:Protein_PPARA_PDB_1i7g.png Emw . Wikimedia Commons . December 15, 2009.

35. Slide 35: PPAR-γ Restores Glucose-Sensing Ability in Type 2 Diabetes

    © 2023 Tonix Pharmaceuticals Holding Corp. 35 © 2023 Tonix Pharmaceuticals Holding Corp. Glucose metabolism • Insulin receptor substrate 1 (IRS - 1) • Insulin receptor substrate 2 (IRS - 2) • P85 subunit of PI3K • CAP Restore glucose - sensing ability PPAR - γ Restores Glucose - Sensing Ability in T

36. Slide 36: Diabetes Is a Risk Factor for Neurodegenerative Diseases

    © 2023 Tonix Pharmaceuticals Holding Corp. 36 © 2023 Tonix Pharmaceuticals Holding Corp. Diabetes Is a Risk Factor for Neurodegenerative Diseases Like Alzheimer’s Disease (AD) 1 - 3 AD is a neurodegenerative disease characterized by brain cell death largely attributed to amyloid plaques and neurofib

37. Slide 37: The Relationship Between Type 3 Diabetes and Alzheimer's

    © 2023 Tonix Pharmaceuticals Holding Corp. 37 © 2023 Tonix Pharmaceuticals Holding Corp. The Relationship Between Type 3 Diabetes and Alzheimer’s 1 - 3 3b ↑ GSK3B activation P P P P Tau phosphorylation ↓ Akt activation 2b 4a Insulin A β protein Tau Overloaded with insulin - degrading enzyme (IDE), c

38. Slide 38: Tianeptine Has Pro-cognitive Effects in Alzheimer's and Bipolar

    © 2023 Tonix Pharmaceuticals Holding Corp. 38 © 2023 Tonix Pharmaceuticals Holding Corp. Tianeptine Has Pro - cognitive Effects in Alzheimer’s and Bipolar After 12 months, patients with AD on tianeptine demonstrated improvements on most cognitive measurements 1 1 García - Alberca et al., 2022. J Alz

39. Slide 39: Observations that Relate Tianeptine's Action to PPAR Activation

    © 2023 Tonix Pharmaceuticals Holding Corp. 39 © 2023 Tonix Pharmaceuticals Holding Corp. CNS PORTFOLIO Observations that Relate Tianeptine’s Action to PPAR Activation • Tianeptine selectively activates PPAR - β / δ and PPAR - γ, but not PPAR - α 1 − Regulates PPAR - β / δ and PPAR - γ driven transcr

40. Slide 40: Observations that Relate Tianeptine's Action to µ-Opioid Receptors

    © 2023 Tonix Pharmaceuticals Holding Corp. 40 © 2023 Tonix Pharmaceuticals Holding Corp. CNS PORTFOLIO Observations that Relate Tianeptine’s Action to µ - Opioid Receptors • In 2014, tianeptine was reported to be a weak µ – opioid agonist 1 − K i = 383 nM and EC 50 = 194 nM 1 − Others have found eve

41. Slide 41: Thank You

    © 2023 Tonix Pharmaceuticals Holding Corp. © 2023 Tonix Pharmaceuticals Holding Corp. THANK YOU

Tonix Pharmaceuticals Holding — Investor Presentation (June 2023) on 6ix