Tonix Pharmaceuticals Holding Corp. · NASDAQ:TNXP

Tonix Pharmaceuticals — Technical Presentation (June 2023)

42 slides from Tonix Pharmaceuticals's technical presentation, Jun 13, 2023

1. Slide 1: TNX-1700 Gastric and Colorectal Cancers

   © 2023 Tonix Pharmaceuticals Holding Corp. © 2023 Tonix Pharmaceuticals Holding Corp. TNX - 1700 Gastric and Colorectal Cancers NASDAQ: TNXP Version P0451 June 13 , 2023 (Doc 1243)

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

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

3. Slide 3: Table of Contents

   © 2023 Tonix Pharmaceuticals Holding Corp. 3 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO Table of Contents Slide Contents Section No. 3 Tumor microenvironment, MDSCs 2 About TNX - 1700 (hTFF2 - HSA 1 ) 1 12 Murine AOM/DSS 3 model, mTFF2 - MSA 4 Chemoprevention Studies 2 16 Domain

4. Slide 4: TNX-1700 Tumor Microenvironment, MDSCs

   © 2023 Tonix Pharmaceuticals Holding Corp. © 2023 Tonix Pharmaceuticals Holding Corp. TNX - 1700 (hTFF2 - HSA) fusion protein) Tumor Microenvironment, MDSCs

5. Slide 5: TNX-1700: Gastric and Colorectal Cancers Recombinant Trefoil Factor 2 Fusion Protein

   © 2023 Tonix Pharmaceuticals Holding Corp. 5 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO Patents Filed TNX - 1700*: Gastric and Colorectal Cancers Recombinant Trefoil Factor 2 (hTFF2) Fusion Protein Potential New Cancer Treatment • mTNX - 1700 (mTFF2) has effects on cancer by alt

6. Slide 6: Colorectal Cancer (CRC) is Common and Lethal

   © 2023 Tonix Pharmaceuticals Holding Corp. 6 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO Colorectal Cancer (CRC) is Common and Lethal • ~150,000 new cases each year in the US • ~53,000 expected to die • 3 rd most leading cause of cancer death in women • 2 nd most in men • Steady

7. Slide 7: TNX-1700 (hTFF2-HSA): A Potential Treatment for Gastric and Colorectal Cancers

   © 2023 Tonix Pharmaceuticals Holding Corp. 7 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO TNX - 1700 (hTFF2 - HSA): A Potential Treatment for Gastric and Colorectal Cancers Pre - IND Candidate Targeted as a treatment for cancer • Particularly for gastric and colorectal cancer • Me

8. Slide 8: Cancers Create Toxic, Immunosuppressive Tumor Microenvironments (TME)

   © 2023 Tonix Pharmaceuticals Holding Corp. 8 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO Cancers Create Toxic, Immunosuppressive Tumor Microenvironments (TME) • Tumors are surrounded by endothelial and stroma cells, and invading immune cells, both innate and adaptive 1,2 • Comple

9. Slide 9: MDSCs Are a Major Treatment Target

   © 2023 Tonix Pharmaceuticals Holding Corp. 9 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO MDSCs Are a Major Treatment Target • Levels of MDSCs tend to correlate with tumor stage, patient survival, and metastatic burden and may predict poor response to certain cancer treatments 1 •

10. Slide 10: Trefoil Family Factor (rTFF2) and Cancer Biology

    © 2023 Tonix Pharmaceuticals Holding Corp. 10 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO Trefoil Family Factor 2 (rTFF2) and Cancer Biology • TFF2 is a small secreted protein ‒ Encoded by the TFF2 gene in humans ‒ Expressed in gastrointestinal mucosa where it functions to protec

11. Slide 11: TFF2 Signals Through CXCR4

    © 2023 Tonix Pharmaceuticals Holding Corp. 11 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO TFF2 Signals Through CXCR4 • Importantly, TFF2 activates CXCR4 and may therefore modulate immune and tumorigenic responses, specifically by reducing the expansion or migration of immunosuppr

12. Slide 12: Chemokines Direct Immune Cell Production and Migration

    © 2023 Tonix Pharmaceuticals Holding Corp. 12 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO Chemokines Direct Immune Cell Production and Migration • Immune cells constantly migrate from the blood into and out of lymphoid organs, processes known as homing and egress 1,2 • Homing and

13. Slide 13: Chemoprevention Studies Murine AOM/DSS Model, mTFF2-MSA

    © 2023 Tonix Pharmaceuticals Holding Corp. © 2023 Tonix Pharmaceuticals Holding Corp. Chemoprevention Studies Murine AOM/DSS Model, mTFF2 - MSA

14. Slide 14: AOM/DSS induces Colorectal Cancer in a Mouse Model

    © 2023 Tonix Pharmaceuticals Holding Corp. 14 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO AOM/DSS induces Colorectal Cancer in a Mouse Model • The azoxymethane/dextran sodium sulfate (AOM/DSS) model is the most commonly used model of chemically - induced colon carcinogenesis • Tu

15. Slide 15: Transgenic Overexpression of mTFF2 Reduces Tumorigenesis via Suppression of MDSCs

    © 2023 Tonix Pharmaceuticals Holding Corp. 15 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO Transgenic Overexpression of mTFF2 Reduces Tumorigenesis via Suppression of MDSCs Dubeykovskaya Z, et al. Nat Commun . 2016 7:1 - 11 MDSC number Colon appearance Tumor burden * p <0.05, ** p

16. Slide 16: Adenoviral Delivery of mTFF2-CTP-Flag Reduces Tumorigenesis via Suppression of MDSCs

    © 2023 Tonix Pharmaceuticals Holding Corp. 16 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO Adenoviral Delivery of mTFF2 - CTP - Flag Reduces Tumorigenesis via Suppression of MDSCs Colon appearance Tumor burden MDSC number * p <0.05 Dubeykovskaya et al, Cancer Gene Ther 26:48 - 57

17. Slide 17: TNX-1700 Structure Domains, CXCR4 Interaction

    © 2023 Tonix Pharmaceuticals Holding Corp. © 2023 Tonix Pharmaceuticals Holding Corp. TNX - 1700 Structure Domains, CXCR4 Interaction

18. Slide 18: TFF2 Contains Trefoil Domains, Each Containing Conserved Residues

    © 2023 Tonix Pharmaceuticals Holding Corp. 18 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO TFF2 Contains 2 Trefoil Domains, Each Containing 5 Conserved Residues Carr et., PNAS (1994) Crystal structure Simplified view (top) Rotate Rotate Space - filling model (side) Domain 1 Domain

19. Slide 19: Chimeric rTFF2 Domain Swaps

    © 2023 Tonix Pharmaceuticals Holding Corp. 19 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO Chimeric rTFF2 Domain (D) Swaps Key TFF2 Domains (D) DI DII TFF2 Ligand Binding Domains (LBD) LBDI LBDII Wild type = DI/II DI/I DII/II DII/I

20. Slide 20: Chimeric rTFF2 Ligand Binding Domain Swaps

    © 2023 Tonix Pharmaceuticals Holding Corp. 20 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO Wild type = LBDI/II LBDI/I LBDII/II LBDII/I Key TFF2 Domains (D) DI DII TFF2 Ligand Binding Domains (LBD) LBDI LBDII Chimeric rTFF2 Ligand Binding Domain (LBD) Swaps

21. Slide 21: TNX-1700 Protein Design Albumin Fusion Proteins, Pharmacokinetics

    © 2023 Tonix Pharmaceuticals Holding Corp. © 2023 Tonix Pharmaceuticals Holding Corp. TNX - 1700 Protein Design Albumin Fusion Proteins, Pharmacokinetics

22. Slide 22: Strategies for Half-Life Extension: Albumin Fusion

    © 2023 Tonix Pharmaceuticals Holding Corp. 22 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO Strategies for Half - Life Extension: Albumin Fusion • Albumin ‒ Most abundant plasma protein ‒ Involved in transport of nutrients in the body ‒ Interaction with cellular receptors Gp18, Gp3

23. Slide 23: hTFF2-HSA Fusion Protein

    © 2023 Tonix Pharmaceuticals Holding Corp. 23 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO hTFF2 - HSA Fusion Protein hTFF2 Human Serum Albumin Predicted Mw ~ 78,000 daltons

24. Slide 24: SDS-PAGE of hTFF2-HSA Fusion Proteins

    © 2023 Tonix Pharmaceuticals Holding Corp. 24 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO SDS - PAGE of hTF2 - HSA Fusion Proteins Lane 1: Marker Lane 2: TFF2 - HSA [WT] Lane 3: TFF2 - HSA [DI/I] Lane 4: TFF2 - HSA [DII/I] Lane 5: TFF2 - HSA [DII/II] Lane 6: TFF2 - HSA [LBDI/I] L

25. Slide 25: Pharmacokinetic Analysis of mTNX-1700 (mTFF2-MSA) in Mice

    © 2023 Tonix Pharmaceuticals Holding Corp. 25 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO Pharmacokinetic Analysis of mTNX - 1700 (mTTF2 - MSA) in Mice Concentration, mg/mL

26. Slide 26: Therapeutic Studies Synergy with PD-1 Blockade Colorectal Cancer

    © 2023 Tonix Pharmaceuticals Holding Corp. © 2023 Tonix Pharmaceuticals Holding Corp. Therapeutic Studies Synergy with PD - 1 Blockade Colorectal Cancer (CRC) MC38 and CT26.wt Murine Models

27. Slide 27: Schematic of Syngeneic MC38 CRC Tumor Model

    © 2023 Tonix Pharmaceuticals Holding Corp. 27 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO Schematic of Syngeneic MC38 CRC Tumor Model Daugherty et al., AACR Poster. 2023. MDSC - targeted TFF2 - MSA suppresses tumor growth and increases survival in anti - PD - 1 treated MC38 and C

28. Slide 28: Inhibition of Tumor Growth in the MC38 CRC Model

    © 2023 Tonix Pharmaceuticals Holding Corp. 28 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO Inhibition of Tumor Growth in the MC38 CRC Model Daugherty, op. cit **p<0.001 ****p<0.0001

29. Slide 29: Probability of Survival in the MC38 CRC Model

    © 2023 Tonix Pharmaceuticals Holding Corp. 29 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO Probability of Survival in the MC38 CRC Model Daugherty, op. cit

30. Slide 30: Inhibition of Tumor Growth in the CT26.wt CRC Model

    © 2023 Tonix Pharmaceuticals Holding Corp. 30 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO Inhibition of Tumor Growth in the CT26.wt CRC Model Days on Study Daugherty, op. cit

31. Slide 31: Probability of Survival in the CT26.wt CRC Model

    © 2023 Tonix Pharmaceuticals Holding Corp. 31 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO Probability of Survival in the CT26.wt CRC Model Days Daugherty, op. cit

32. Slide 32: Therapeutic Studies Synergy with PD-1 Blockade Gastric Cancer ACKP Murine Model

    © 2023 Tonix Pharmaceuticals Holding Corp. © 2023 Tonix Pharmaceuticals Holding Corp. Therapeutic Studies Synergy with PD - 1 Blockade Gastric Cancer ACKP Murine Model

33. Slide 33: mTNX-1700 Showed Synergy with anti-PD1 Antibody in Inhibition of ACKP Xenograft Growth

    © 2023 Tonix Pharmaceuticals Holding Corp. 33 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO mTNX - 1700 (mTFF2 - MSA) Showed Synergy with anti - PD1 Antibody in Inhibition of s.c. ACKP Xenograft Growth B. Tumor growth curve of s.c. implanted ACKP tumors in response to anti - PD1 an

34. Slide 34: mTNX-1700 Synergy in Orthotopic ACKP Xenograft Growth and Lung Metastasis

    © 2023 Tonix Pharmaceuticals Holding Corp. 34 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO mTNX - 1700 Showed Synergy w/ anti - PD1 Antibody in Inhibition of Orthotopic ACKP Xenograft Growth & Spontaneous Lung Metastasis Tumor Imaging PD1 Ab TFF2 - MSA Combo Vehicle Vehicle PD1 Ab

35. Slide 35: mTNX-1700 Reduced MDSC Accumulation in the Tumor and Bone Marrow

    © 2023 Tonix Pharmaceuticals Holding Corp. 35 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO mTNX - 1700 Reduced MDSC Accumulation in the Tumor and Biogenesis in the Bone Marrow A. HDC - GFP + CD11b + LY6G + cell percentage among CD45 + cells in TME. B. HDC - GFP + CD11b + LY6G + ce

36. Slide 36: mTNX-1700/Anti-PD1 Combination Increased Tumor-Infiltrating CD8+ T cells

    © 2023 Tonix Pharmaceuticals Holding Corp. 36 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO mTNX - 1700/Anti - PD1 Ab Combination Increased Tumor - Infiltrating CD8 + T cell Associated with a Better Effector Phenotype A . CD 8 + t cell percentage among CD 45 + cells in TME . B . Gr

37. Slide 37: Summary

    © 2023 Tonix Pharmaceuticals Holding Corp. © 2023 Tonix Pharmaceuticals Holding Corp. Summary

38. Slide 38: Conclusions

    © 2023 Tonix Pharmaceuticals Holding Corp. 38 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO Conclusions • TFF2 is a naturally occurring anti - inflammatory peptide that is a key part of the inflammatory reflex. • TFF2 is a partial agonist for CXCR4, upregulates ApoE and suppresses

39. Slide 39: Product Development

    © 2023 Tonix Pharmaceuticals Holding Corp. 39 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO Product Development • Progress ‒ Expression of TNX - 1700 (hTFF2 - HSA fusion protein) • Next Steps ‒ File the Investigational New Drug (IND) application in the US ‒ Scale - up and produce G

40. Slide 40: TNX-1700: Gastric and Colorectal Cancers Recombinant Trefoil Factor 2 Fusion Protein

    © 2023 Tonix Pharmaceuticals Holding Corp. 40 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO Patents Filed TNX - 1700*: Gastric and Colorectal Cancers Recombinant Trefoil Factor 2 (rTFF2) Fusion Protein Potential New Cancer Treatment • TNX - 1700 (rTFF2) has effects on cancer by alt

41. Slide 41: Thank You Appendix

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

42. Slide 42: AACR Presentations

    © 2023 Tonix Pharmaceuticals Holding Corp. 42 © 2023 Tonix Pharmaceuticals Holding Corp. IMMUNOLOGY PORTFOLIO AACR Presentations Presentation # 1 Title: MDSC - targeted TFF2 - MSA suppresses tumor growth and increases survival in anti - PD - 1 treated MC38 and CT26.wt murine color ectal cancer model

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