Tonix Pharmaceuticals Holding Corp. · NASDAQ:TNXP

Tonix Pharmaceuticals — Investor Presentation (November 2018)

99 slides from Tonix Pharmaceuticals's investor presentation, Nov 1, 2018

1. Slide 1: Investor Presentation

   © 2018 Tonix Pharmaceuticals Holding Corp. November 2018 Version P0143 11 - 1 - 18 (Doc 0406) Investor Presentation

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

   © 2018 Tonix Pharmaceuticals Holding Corp. 2 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” as defined by the Private Securities Litigat

3. Slide 3: Tonix Pharmaceuticals

   © 2018 Tonix Pharmaceuticals Holding Corp. 3 Tonix Pharmaceuticals Who we are: • A clinical stage pharmaceutical company dedicated to developing innovative treatments for patients and making meaningful contributions to society What we do: • Target therapeutics with high need for improvement − Condit

4. Slide 4: Tonmya lead program; FDA Breakthrough Therapy in PTSD

   © 2018 Tonix Pharmaceuticals Holding Corp. 4 Tonmya ®1 – lead program; FDA Breakthrough Therapy in Posttraumatic Stress Disorder (PTSD) – Bedtime treatment in Phase 3 Development • Results from 2 efficacy studies improve the new Phase 3 study design • Preliminary acceptance of new design features re

5. Slide 5: Lead Program: TNX-102 SL Product Concept

   © 2018 Tonix Pharmaceuticals Holding Corp. 5 Lead Program: TNX - 102 SL – Product Concept Sleep disturbances are associated with a constellation of disorders • Considered co - morbid or a key symptom in these disorders • Believed to have a role in the onset, progression and severity of these disorde

6. Slide 6: Candidates in Development

   © 2018 Tonix Pharmaceuticals Holding Corp. 6 Candidates in Development Preclinical Phase 2 NDA 1 /BLA 2 Market Pipeline Product Indication/ Description Phase 3 Tonmya Bedtime Treatment for PTSD Daytime Treatment for PTSD TNX - 601 Novel polymorph and salt discovered and characterized; Preliminary hu

7. Slide 7: Tonmya for the Treatment of PTSD

   © 2018 Tonix Pharmaceuticals Holding Corp. 7 Tonmya for the Treatment of PTSD Breakthrough Therapy (BT) designation from the FDA • Expedited development and accelerated approval are expected One Phase 2 study completed and one Phase 3 study stopped early due to inadequate separation from placebo (un

8. Slide 8: Breakthrough Therapy Designation

   © 2018 Tonix Pharmaceuticals Holding Corp. 8 Breakthrough Therapy Designation FDA granted Tonmya Breakthrough Therapy designation – reported December 19, 2016 • PTSD is a serious condition • Tonmya has potential advantages over existing therapies in military - related PTSD Benefits of Breakthrough T

9. Slide 9: No Recognized Abuse Potential in Clinical Studies

   © 2018 Tonix Pharmaceuticals Holding Corp. 9 No Recognized Abuse Potential in Clinical Studies Active ingredient is cyclobenzaprine, which is structurally related to tricyclic antidepressants • Cyclobenzaprine interacts with receptors that regulate sleep quality: 5 - HT 2A, a 1 - adrenergic and hist

10. Slide 10: TNX-102 SL Intellectual Property – U.S. Protection until 2034

    © 2018 Tonix Pharmaceuticals Holding Corp. 10 TNX - 102 SL Intellectual Property – U.S. Protection until 2034 Composition of matter (eutectic) : Protection expected to 2034 • United States Patent and Trademark Office (USPTO) issued U.S. Patent No. 9,636,408 in May 2017 and U.S. Patent No. 9,956,188

11. Slide 11: Sublingual Formulation is Designed for Bedtime Administration

    © 2018 Tonix Pharmaceuticals Holding Corp. 11 TNX - 102 SL: Sublingual Formulation is Designed for Bedtime Administration TNX - 102 SL: Proprietary sublingual formulation of cyclobenzaprine (CBP) with transmucosal absorption • Innovation by design with patent protected CBP/mannitol eutectic • Rapid

12. Slide 12: Proprietary Cyclobenzaprine Eutectic Mixture Stabilizes Sublingual Tablet

    © 2018 Tonix Pharmaceuticals Holding Corp. 12 Proprietary Cyclobenzaprine Hydrochloride Eutectic Mixture Stabilizes Sublingual Tablet Formulation Base particle (K 2 HPO 4 ) Base particle (K 2 HPO 4 ) Base particle (K 2 HPO 4 ) Eutectic formulation 1 ANGSTRO - TECHNOLOGY™ Cyclobenzaprine - HCl (CBP -

13. Slide 13: Novel Mechanism Targets Sleep Quality for Recovery from PTSD

    © 2018 Tonix Pharmaceuticals Holding Corp. 13 Tonmya: Novel Mechanism Targets Sleep Quality for Recovery from PTSD PTSD is a disorder of recovery • Most people exposed to extreme trauma recover over a few weeks • In PTSD, recovery process impeded due to insufficient sleep - dependent memory processi

14. Slide 14: Proposed Mechanism of Action of Tonmya in PTSD

    © 2018 Tonix Pharmaceuticals Holding Corp. 14 Proposed Mechanism of Action of Tonmya in the Treatment of PTSD: The Effects of Nocturnal Neuroreceptor Blockade on Sleep Cyclobenzaprine is a functional antagonist at serotonergic 5 - HT 2A receptors , noradrenergic 1 receptors , and histaminergic H 1 r

15. Slide 15: Focus on Nocturnal 5-HT2A Receptor Blockade

    © 2018 Tonix Pharmaceuticals Holding Corp. 15 • Generally, serotonin (5 - HT) activity promotes the awake state and inhibits REM sleep; whereas once in REM sleep, the 5 - HT system is normally quiescent • Extinction learning is critical to recovery from trauma, and such new learning is consolidated

16. Slide 16: Fear Extinction Memory Consolidation and P-Waves

    © 2018 Tonix Pharmaceuticals Holding Corp. 16 Fear Extinction Memory Consolidation: The Proposed Role of P - Waves, REM Sleep, and Serotonergic Neuroreceptor Activity Serotonergic projections from the dorsal raphe nuclei pons Site of release of phasic waves called pontine or P - waves P - wave activ

17. Slide 17: Overview of Posttraumatic Stress Disorder (PTSD)

    © 2018 Tonix Pharmaceuticals Holding Corp. 17 Overview of Posttraumatic Stress Disorder (PTSD) PSTD is a chronic disabling disorder in response to experiencing traumatic event(s) Symptoms of PTSD fall into four clusters: 1. Intrusion (aversive memories, nightmares, flashbacks) 2. Avoidance (avoiding

18. Slide 18: Impact of PTSD on People

    © 2018 Tonix Pharmaceuticals Holding Corp. 18 Impact of PTSD on People Consequences: • Impaired daily function and substantial interference with work and social interactions • Reckless or destructive behavior • Increased health care utilization and greater medical morbidity PTSD as a risk factor for

19. Slide 19: PTSD: U.S. Prevalence and Index Traumas

    © 2018 Tonix Pharmaceuticals Holding Corp. 19 PTSD: U.S. Prevalence and Index Traumas PTSD is a chronic response to traumatic event(s) • A majority of people will experience a traumatic event at some point in their lifetime 1 • 20% of women and 8% of men in the U.S. who experience significant trauma

20. Slide 20: PTSD Prevalence and Market Characteristics

    © 2018 Tonix Pharmaceuticals Holding Corp. 20 PTSD Prevalence and Market Characteristics 1 Goldstein et al., 2016 (civilians) 2 Veterans: VA/DOD Clinical Practice Guidelines for the Managements of PTSD and Acute Stress Disorder, 2017, page 15 (619,493 v et s diagnosed with PTSD in VA for 2016) 3 IMS

21. Slide 21: What Drug Classes are Used to Treat PTSD?

    © 2018 Tonix Pharmaceuticals Holding Corp. 21 What Drug Classes are Used to Treat PTSD? * TRx = Total prescriptions 1 VA/DoD Clinical Practice Guideline for the Management of Post - Traumatic Stress, Version 2, 2010 2 IMS Consulting, Market Sizing & Treatment Dynamics: “Post - Traumatic Stress Disor

22. Slide 22: PTSD: Not Well-Served by Approved Treatments

    © 2018 Tonix Pharmaceuticals Holding Corp. 22 PTSD: Not Well - Served by Approved Treatments FDA - approved SSRIs, paroxetine and sertraline, are indicated as a treatment for PTSD • Neither drug has shown efficacy in military - related PTSD • Majority of male PTSD patients unresponsive or intolerant

23. Slide 23: Why Initially Target Military-Related PTSD?

    © 2018 Tonix Pharmaceuticals Holding Corp. 23 Why Initially Targeted Military - Related PTSD? 1 Friedman et al., J Clin Psychiatry 2007; 68:711 2 Zoloft Package Insert, August, 2014 3 Paxil Package Insert, June, 2014 4 Fava et al., Psychother Psychosom 84:72 - 81, 2015 Military - related PTSD not we

24. Slide 24: Prevalence of PTSD Among Civilians and Veterans

    © 2018 Tonix Pharmaceuticals Holding Corp. 24 Prevalence of PTSD Among Civilians and Veterans 1 Goldstein et al., 2016 ; 2 Norris, PTSD Res Quar . 2013; 3 Analysis of VA Health Care Utilization among Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn Veterans, from 1st Qtr F

25. Slide 25: Growing Economic and Social Burden of Veterans with PTSD

    © 2018 Tonix Pharmaceuticals Holding Corp. 25 Growing Economic and Social Burden to Care for Veterans with PTSD Health care costs associated with PTSD for OEF/OIF/OND veterans: Direct costs Indirect costs 1 CBO Report 2012; 2 Tanielan , Invisible Wounds of War . 2005; 3 Analysis of VA Health Care Ut

26. Slide 26: Phase 2 P201/AtEase Study in Military-Related PTSD

    © 2018 Tonix Pharmaceuticals Holding Corp. 26 Phase 2 P201/AtEase 1 Study in Military - Related PTSD • Randomized, double - blind, placebo - controlled trial in military - related PTSD • Efficacy analysis from 231 * patients; 24 U.S. clinical sites • Enrolled patients with baseline CAPS - 5 2 ≥ 29 •

27. Slide 27: P201/AtEase Study

    © 2018 Tonix Pharmaceuticals Holding Corp. 27 P201/AtEase Study P201 was a large adequate well - controlled Phase 2 study in military - related PTSD • Primary endpoint (Week 12 CAPS - 5) did not separate from placebo for TNX - 102 SL 2.8 mg • No safety or tolerability issue discovered • Retrospectiv

28. Slide 28: P201/AtEase Summary of Primary and Secondary Analyses

    © 2018 Tonix Pharmaceuticals Holding Corp. 28 P201/AtEase Study – Summary of Primary and Secondary Analyses (Week 12)

29. Slide 29: P301/HONOR Study Discontinued Due to High Placebo Response

    © 2018 Tonix Pharmaceuticals Holding Corp. 29 P301/HONOR 1 Study – Evidence of Efficacy at Week 4 Discontinued Due to High Placebo Response at Week 12 Primary e ndpoint CAPS - 5 2 : • Mean change from baseline at W eek 12 (Tonmya 5.6 mg vs. placebo ) Unblinded interim analysis at 274 randomized part

30. Slide 30: P301/HONOR Primary Analysis in mITT Population

    © 2018 Tonix Pharmaceuticals Holding Corp. 30 P301/HONOR Study - Primary Analysis in mITT Population In P301 study both TNX - 102 SL and placebo - treated groups improved but the greater improvement on TNX - 102 SL compared with placebo diminished over time • TNX - 102 SL did not separate from place

31. Slide 31: P301/HONOR Study Stopped After Interim Analysis

    © 2018 Tonix Pharmaceuticals Holding Corp. 31 P301/HONOR Study Stopped After Interim Analysis (July 2018) P301 was a large adequate well - controlled Phase 3 study in military - related PTSD • Separation on primary endpoint at Week 12 did not cross pre - specified study continuation threshold at Wee

32. Slide 32: Differences Between P201 and P301 Studies

    © 2018 Tonix Pharmaceuticals Holding Corp. 32 Differences Between P201/AtEase and P301/HONOR Studies Design Phase 2 and 3 studies were very similar – both studied military related PTSD at multiple sites in the US • CAPS - 5 ≥ 33 entry criteria used in Phase 3 BDI - II= Beck Depression Inventory - II

33. Slide 33: P201 and P301 Demographics and Characteristics

    © 2018 Tonix Pharmaceuticals Holding Corp. 33 P201/AtEase and P301/HONOR Demographics and Characteristics The striking difference between P201 and P301 was time since trauma • Phase 2 P201 study recruited many participants from the surge in Iraq who were mostly <9 years since trauma

34. Slide 34: Retrospective Comparison of Time Since Trauma

    © 2018 Tonix Pharmaceuticals Holding Corp. 34 Retrospective Comparison of Time Since Trauma in P201/AtEase versus P301/HONOR (Tonmya 5.6 mg Groups) P301 study was initiated approximately two years later than Phase 2 P201 • The median time since trauma in Phase 3 was 9.5 years compared to the median

35. Slide 35: Primary Outcome in Phase 3 and ≤9 Years Subgroups

    © 2018 Tonix Pharmaceuticals Holding Corp. Primary Outcome (CAPS - 5) in Phase 3 ( mITT ) and ≤9 Years Time Since Trauma (TST) Subgroups P301 modified intent to treat ( mITT ) population P301 TST ≤9 yrs ** p=0.004, * p=0.039, # p=0.069, TNX - 102 SL 5.6 mg group v. placebo, using MMRM with MI ~50% m

36. Slide 36: PTSD Treatment Response in Phase 2 and Phase 3

    © 2018 Tonix Pharmaceuticals Holding Corp. P201 Baseline CAPS - 5 ≥33 (majority TST 1 ≤9 yr ) **p<0.01, *p=0.017, TNX - 102 SL 5.6 mg group v. placebo, using mixed model repeated measures (MMRM) with multiple imputation (MI) P301 TST ≤9 yr ** p=0.004, * p=0.039, # p=0.069 TNX - 102 SL 5.6 mg group v

37. Slide 37: Sustained Remission in Phase 2 and Phase 3 Studies

    © 2018 Tonix Pharmaceuticals Holding Corp. 37 Sustained Remission in Phase 2 and Phase 3 Studies: Retrospective Analyses of P201 Entry CAPS - 5 ≥33 and P301 ≤9 Years Since Trauma Subgroups Remission is a clinical state that is essentially asymptomatic In order to confirm remission: • Determined rate

38. Slide 38: Sustained Remission in P201 With and Without Oral AEs

    © 2018 Tonix Pharmaceuticals Holding Corp. 38 Sustained Remission in P201/AtEase Study Retrospective Analyses of Phase 2 Subgroups with and without Oral AE’s (ON/OT/NT) Oral numbness (ON), oral tingling (OT) and noticeable taste (NT) are local administration site reactions that are potentially unbli

39. Slide 39: Tonmya Dose-Effect in Military-Related PTSD

    © 2018 Tonix Pharmaceuticals Holding Corp. 39 Tonmya Dose - Effect in Military - Related PTSD 1 1 Phase 2 P201/AtEase study: Retrospective analysis of Tonmya 5.6 mg on CAPS - 5 ≥33 (high - moderate) subgroup. Primary analysis of P 201/AtEase was on Tonmya 2.8 mg in participants with entry CAPS - 5 ≥

40. Slide 40: Treatment Response in ≤9 and >9 Years Since Trauma

    © 2018 Tonix Pharmaceuticals Holding Corp. 40 Retrospective Analysis of Treatment Response in ≤9 & >9 Years since Trauma in P301/HONOR Study The ≤ 9 years since trauma group in P301 replicated results from P201 • Retrospective analysis of P201 showed Tonmya 5.6 mg treatment group difference over pla

41. Slide 41: ≤9 Years Subgroup on Key Secondary Endpoints

    © 2018 Tonix Pharmaceuticals Holding Corp. 41 Retrospective Analyses of ≤9 Years Since Trauma Subgroup on Key Secondary Endpoints in P301/HONOR Study Key secondary endpoints showed strong treatment effects • CGI - I, PGIC and PROMIS SD were pre - specified secondary analyses • Supports CAPS - 5 resu

42. Slide 42: Adverse Events in P201 and P301 Studies

    © 2018 Tonix Pharmaceuticals Holding Corp. 42 Adverse Events (AEs) in P201/AtEase and P301/HONOR Studies No serious and unexpected AEs in P201 or P301 • Systemic AEs comparable between studies and also consistent with those described in approved cyclobenzaprine product labeling • Similar severity an

43. Slide 43: Time Since Trauma – Review of Published Studies

    © 2018 Tonix Pharmaceuticals Holding Corp. 43 Time Since Trauma – Review of Published Studies Published studies of prazosin suggested effects in military - PTSD prior to 9 years • Loss of treatment effect >9 years Paroxetine and sertraline studies supporting FDA approval were conducted on PTSD > 9 y

44. Slide 44: Time Since Trauma – Remitting and Persistent Phases of PTSD

    © 2018 Tonix Pharmaceuticals Holding Corp. 44 Time Since Trauma – Remitting and Persistent Phases of PTSD Kessler et al 1 studied remission in PTSD with and without therapy • Identified remitting and persistent phase of PTSD – with transition at approximately 6 years post trauma • Supported by other

45. Slide 45: Summary of Clinical Experience with Tonmya in PTSD

    © 2018 Tonix Pharmaceuticals Holding Corp. 45 Summary of Clinical Experience with Tonmya/ TNX - 102 SL in PTSD Median time since trauma (TST) in TNX - 102 SL 5.6 mg group in the P301/HONOR study (9.5 years) was longer than P201/AtEase study (6 years) • Both studied military - related PTSD • Time has

46. Slide 46: New Phase 3 P302 Study – To Start 1Q 2019

    © 2018 Tonix Pharmaceuticals Holding Corp. 46 New Phase 3 P302 Study – To Start 1Q 2019 Civilian and Military - Related PTSD, ≤9 Years Time since Trauma Primary e ndpoint CAPS - 5 1 : • Mean change from baseline at W eek 4 (Tonmya 5.6 mg vs. placebo ) Key Secondary e ndpoint s include: • CAPS - 5 m

47. Slide 47: Commercialization Options

    © 2018 Tonix Pharmaceuticals Holding Corp. 47 Commercialization Options Tonix is exploring a variety of options to commercialize TNX - 102 SL, including commercializing on our own or partnering all or some indications in specific regions of the world Tonix has participated in numerous partnering mee

48. Slide 48: Multi-Functional Mechanism Involves Antagonism at 3 Receptors

    © 2018 Tonix Pharmaceuticals Holding Corp. 48 TNX - 102 SL – Multi - Functional Mechanism Involves Antagonism at 3 Neuronal Receptors Active ingredient, cyclobenzaprine, interacts with 3 receptors • Antagonist at 5 - HT 2A receptors • Similar activity to trazodone and Nuplazid ® ( pimivanserin ) • A

49. Slide 49: Cyclobenzaprine is a Multi-Functional Drug

    © 2018 Tonix Pharmaceuticals Holding Corp. 49 Untreated Effects of TNX - 102 Cyclobenzaprine is a multi - functional drug - SNARI - inhibits serotonin and norepinephrine reuptake - blocks serotonin 5 - HT 2A and norepinephrine a 1 receptors SNARI = S erotonin and N orepinephrine receptor A ntagonist

50. Slide 50: Tonmya, Trazodone and Prazosin Comparison

    © 2018 Tonix Pharmaceuticals Holding Corp. 50 Tonmya Trazodone Trazodone (disordered sleep ), prazosin (night terrors) - Trazodone inhibits serotonin 5HT 2A receptors and serotonin reuptake (SARI) - Prazosin blocks norepinephrine a 1 receptors Prazosin SARI – S erotonin Receptor A ntagonist & R eupt

51. Slide 51: Opportunities to Expand to Other Indications

    © 2018 Tonix Pharmaceuticals Holding Corp. 51 v Opportunities to Expand to Other Indications Growing recognition that there are many disorders where sleep disturbances may have a role in the pathophysiology (cardiovascular, metabolic, neurologic) • Homeostatic role of sleep quality in several disord

52. Slide 52: Bedtime Treatment for Multiple Potential Indications

    © 2018 Tonix Pharmaceuticals Holding Corp. 52 TNX - 102 SL – Bedtime Treatment for Multiple Potential Indications Ma nagement of Fibromyalgia (FM) – chronic pain condition • TNX - 102 SL studied at low dose (2.8 mg) – half the dose being developed for PTSD – did not separate from placebo on primary

53. Slide 53: What is Agitation in Alzheimer's Disease?

    © 2018 Tonix Pharmaceuticals Holding Corp. 53 What is Agitation in Alzheimer’s Disease? Agitation is one of the most distressing and debilitating of the behavioral complications of Alzheimer’s disease • Includes emotional lability, restlessness, irritability and aggression 1 Link between disturbed s

54. Slide 54: Consequences of Agitation in Alzheimer's Disease

    © 2018 Tonix Pharmaceuticals Holding Corp. 54 Consequences of Agitation in Alzheimer’s Disease Outcomes • Agitation is associated with significant poor outcomes for Alzheimer’s patients and challenges for their caregivers Common reason for institutionalization • Development of agitation, or its wors

55. Slide 55: Agitation in Alzheimer's – Additional Indication for TNX-102 SL

    © 2018 Tonix Pharmaceuticals Holding Corp. 55 Agitation in Alzheimer’s Disease – Additional Indication Being Developed for TNX - 102 SL FDA designated Fast Track development program Significant unmet need • No FDA approved drugs for the treatment of agitation in Alzheimer’s Mechanism of improving sl

56. Slide 56: Regulatory Status and Registration Strategy for Alzheimer's Agitation

    © 2018 Tonix Pharmaceuticals Holding Corp. 56 TNX - 102 SL for Agitation in Alzheimer’s – Regulatory Status and Registration Strategy FDA confirmed no additional study is needed prior to IND submission • Pre - IND meeting established open dialogue with the FDA on pivotal clinical study design and ef

57. Slide 57: Scientific Rationale for Agitation in Alzheimer's Disease

    © 2018 Tonix Pharmaceuticals Holding Corp. 57 Scientific Rationale for Developing TNX - 102 SL for Agitation in Alzheimer’s Disease Connection between Sleep Disturbance and Agitation • Agitation in Alzheimer’s Disease is associated with sleep disturbance 1,2 • Evidence that improving sleep could imp

58. Slide 58: Potentially Addresses Challenges in Treating Alzheimer's Agitation

    © 2018 Tonix Pharmaceuticals Holding Corp. 58 TNX - 102 SL Potentially Addresses Some of the Challenges in Treating Agitation in Alzheimer’s Sublingual route of administration (no swallowing) • Swallowing can be an issue for a significant number of Alzheimer’s patients Low dose taken daily at bedtim

59. Slide 59: Protective Barriers in the Central and Peripheral Nervous Systems

    © 2018 Tonix Pharmaceuticals Holding Corp. 59 Protective Barriers in the Central and Peripheral Nervous Systems Glial cells are cells that reside in the central nervous system and can provide protective barriers between the central and peripheral nervous systems 1,2 Blood – Brain Barrier: supplies n

60. Slide 60: During Wakefulness, Proteins Accumulate in Extracellular Space

    © 2018 Tonix Pharmaceuticals Holding Corp. 60 During Wakefulness, Proteins Linked to Neuronal Death and Neurodegeneration Accumulate in the Brain’s Extracellular Space AQP4 = A quaporin - 4 CSF = Cerebrospinal Fluid ISF = Interstitial Fluid 1. Papadopoulos MC, et al. Nat Rev Neurosci . 2013;14(4):26

61. Slide 61: During Sleep, CSF–Brain Barrier Is More Permeable

    © 2018 Tonix Pharmaceuticals Holding Corp. 61 During Sleep, the CSF – Brain Barrier Is More Permeable, Allowing Debris to Clear Aβ = β - amyloid CSF = Cerebrospinal Fluid 1. Bellesi M, et al. BMC Biol. 2015;13:66. 2. Xie L, et al. Science. 2013;342(6156):373 - 377. Permeability of CSF – brain barrie

62. Slide 62: Sleep–Wake Cycles Alter Permeability of the CSF–Brain Barrier

    © 2018 Tonix Pharmaceuticals Holding Corp. 62 Sleep – Wake Cycles Alter Permeability of the CSF – Brain Barrier Fluid exchange at the CSF – brain barrier allows for clearance of toxic proteins called β – amyloids (A β ). 1 Glial cells in the brain work to facilitate this fluid exchange. 2 Sleep – wa

63. Slide 63: Alzheimer's Agitation – Competitive Landscape of Drugs in Development

    © 2018 Tonix Pharmaceuticals Holding Corp. 63 Agitation in Alzheimer’s – Competitive Landscape of Select Drugs in Development Competitive landscape • 5HT 2A Antagonists/inverse agonists • Nelotanserin ( Axovant ) • Atypical Antip sychotics (also have 5HT 2A antagonism) • Rexulti ® brexpiprazole (Ots

64. Slide 64: Candidates in Development

    © 2018 Tonix Pharmaceuticals Holding Corp. 64 Candidates in Development Preclinical Phase 2 NDA 1 /BLA 2 Market Pipeline Product Indication/ Description Phase 3 Tonmya Bedtime Treatment for PTSD 3 Daytime Treatment for PTSD TNX - 601 Novel polymorph and salt discovered and characterized; Preliminary

65. Slide 65: TNX-601 (Tianeptine Oxalate): Potential Clinical Candidate for PTSD

    © 2018 Tonix Pharmaceuticals Holding Corp. 65 TNX - 601 ( Tianeptine Oxalate): A Potential Clinical Candidate for PTSD Pre - IND Candidate Targeted as a 1 st line monotherapy for PTSD: oral formulation for daytime dosing x Leverages expertise in PTSD (clinical and regulatory experience, market analy

66. Slide 66: Structural Comparison: TNX-102 and TNX-601

    © 2018 Tonix Pharmaceuticals Holding Corp. 66 Structural Comparison: TNX - 102 and TNX - 601 Cyclobenzaprine and tianeptine share structural similarities with classic tricyclic antidepressants (TCAs) and to each other, but each has unique pharmacological properties • Tianeptine has a 3 - chlorodiben

67. Slide 67: TNX-801: Smallpox-Preventing Vaccine Candidate

    © 2018 Tonix Pharmaceuticals Holding Corp. 67 TNX - 801 (Synthesized Live Horsepox Virus): A Smallpox - Preventing Vaccine Candidate Pre - IND Stage Potential improvement over current biodefense tools against smallpox ✓ Leverages Tonix’s government affairs effort ✓ Collaboration with Professor David

68. Slide 68: TNX-801 Synthesis and Relation to Modern Vaccines

    © 2018 Tonix Pharmaceuticals Holding Corp. 68 TNX - 801 (Synthesized Live Horsepox Virus): A Smallpox - Preventing Vaccine Candidate Synthesis 1 from sequence of a 1976 Mongolian isolate 2 In mice, TNX - 801 behaved like attenuated vaccinia virus • Vaccinia is the term used to classify the live poxv

69. Slide 69: ACAM2000 is a Live Vaccinia Virus Vaccine

    © 2018 Tonix Pharmaceuticals Holding Corp. 69 ACAM2000 is sold to the U.S. Strategic National Stockpiles 1 • Sold by Emergent BioSolutions • Sanofi divested ACAM2000 to Emergent BioSolutions in 2017 for $97.5 M upfront plus milestones • ACAM2000 was developed by Acambis which was acquired by Sanofi

70. Slide 70: HPXV and its Relationship to Other Orthopoxviruses

    70 © 2018 Tonix Pharmaceuticals Holding Corp. HSPV074 – fragmented homolog of VACV I4L (ribonucleotide reductase) HSPV200 – 216 kDa protein probably regulates T - cell activation with homologs still present in variola , cowpox, and monkeypox viruses HPXV and its Relationship to Other Orthopoxviruses

71. Slide 71: HPXV Sequence and Synthesis

    71 © 2018 Tonix Pharmaceuticals Holding Corp. Sequence: GenBank entry DQ792504; DNA: GeneArt Genome Assembly (212 kbp ) by Synthesis of Fragments and Construction of Telomeres Noyce, RS, Lederman S, Evans DH. PLoS ONE. 2018; 13(1): e0188453 https://doi.org/10.1371/journal.pone.0188453

72. Slide 72: HPXV Produces Small Plaques Like Cowpox

    72 © 2018 Tonix Pharmaceuticals Holding Corp. HPXV Produces Small Plaques that are More Like Cowpox Than Vaccinia (VACV) Noyce, RS, Lederman S, Evans DH. PLoS ONE. 2018; 13(1): e0188453 https://doi.org/10.1371/journal.pone.0188453

73. Slide 73: Production of Cell-Associated and Extracellular Virus

    73 © 2018 Tonix Pharmaceuticals Holding Corp. Cell - associated virus Virus in the media Production of Cell - Associated and Extracellular Virus Noyce, RS, Lederman S, Evans DH. PLoS ONE. 2018; 13(1): e0188453 https://doi.org/10.1371/journal.pone.0188453

74. Slide 74: HPXV Growth Characteristics

    74 © 2018 Tonix Pharmaceuticals Holding Corp. HPXV Growth Characteristics Noyce, RS, Lederman S, Evans DH. PLoS ONE. 2018; 13(1): e0188453 https://doi.org/10.1371/journal.pone.0188453

75. Slide 75: Testing Vaccine Protective Activity of HPXV in Mice

    75 © 2018 Tonix Pharmaceuticals Holding Corp. Testing Vaccine Protective Activity of HPXV in Mice Model Noyce, RS, Lederman S, Evans DH. PLoS ONE. 2018; 13(1): e0188453 https://doi.org/10.1371/journal.pone.0188453

76. Slide 76: HPXV Less Virulent than Dryvax Clone, Protective Immunity

    76 © 2018 Tonix Pharmaceuticals Holding Corp. PBS VACV WR (5x10 3 PFU) Dryvax clone (10 7 PFU) HPXV (10 7 PFU) Challenge (10 6 PFU VAC strain WR) Biological Properties of HPXV: Less Virulent than a Dryvax Clone, but Produces Protective Immunity Noyce, RS, Lederman S, Evans DH. PLoS ONE. 2018; 13(1):

77. Slide 77: HPXV Vaccine Protection Observed at Low Doses

    77 © 2018 Tonix Pharmaceuticals Holding Corp. PBS HPXV (10 5 PFU) HPXV (10 6 PFU) HPXV (10 7 PFU) Challenge (10 6 PFU VAC strain WR) HPXV Vaccine Protection Activity Observed As Low As 10 5 PFU* *PFU = plaque forming units Noyce, RS, Lederman S, Evans DH. PLoS ONE. 2018; 13(1): e0188453 https://doi.

78. Slide 78: No Overt Clinical Sign in HPXV-Vaccinated Mice After Challenge

    78 © 2018 Tonix Pharmaceuticals Holding Corp. No challenge PBS ➔ VACV (10 6 PFU) VACV* (5x10 3 PFU) ➔ VACV (10 6 PFU) HPXV (10 5 PFU) ➔ VACV (10 6 PFU) HPXV (10 6 PFU) ➔ VACV (10 6 PFU) HPXV (10 7 PFU) ➔ VACV (10 6 PFU) * VACV (strain WR) No Overt Clinical Sign Observed in HPXV Vaccinated Mice After

79. Slide 79: HPXV May Have an Improved Safety Profile

    © 2018 Tonix Pharmaceuticals Holding Corp. 79 HPXV or TNX - 801 – May Have an Improved Safety Profile as a Smallpox Preventing Vaccine Horsepox is caused by HPXV and is characterized by mouth and skin eruptions HXPV isolate from the 1976 outbreak later sequenced Modern smallpox vaccines are associat

80. Slide 80: Improved Smallpox-Preventing Vaccine is Important and Necessary

    © 2018 Tonix Pharmaceuticals Holding Corp. 80 An Improved Smallpox - Preventing Vaccine is Important and Necessary for a Potential Public Health Issue Smallpox was eradicated as a result of global public health campaigns No cases of naturally - occurring smallpox have been reported since 1977 Accide

81. Slide 81: Current Needs to Vaccinate Against Smallpox

    © 2018 Tonix Pharmaceuticals Holding Corp. 81 Ongoing vaccination of U.S. troops • Troops in the Global Response Force Threat of smallpox re - introduction • Strategic National Stockpile & public health policy Re - emergence of monkey pox 1 • Believed to resurgent because of vaccinia - naïve populat

82. Slide 82: TNX-801: A Potential Medical Countermeasure

    © 2018 Tonix Pharmaceuticals Holding Corp. 82 TNX - 801: A Potential Medical Countermeasure 21st Century Cures Act (2016), Section 3086 • Encouraging treatments for agents that present a national security threat Medical countermeasures are drugs, biologics (vaccines) or devices intended to treat: •

83. Slide 83: TNX-801 Mechanism of Action and Possible Advantages

    © 2018 Tonix Pharmaceuticals Holding Corp. 83 Live virus vaccines stimulate cross - reactive immunity • Protects from possible infection with smallpox virus • Renders recipient “immune” • Provides indirect protection to non - immunized population “herd immunity” Potential safety improvement over exi

84. Slide 84: Evidence of Effectiveness for Smallpox Vaccine

    © 2018 Tonix Pharmaceuticals Holding Corp. 84 Given that smallpox is eradicated the only evidence of effectiveness for modern vaccines is from historical use when smallpox was endemic • Stimulates interest in the evolution of vaccinia Vaccinia stocks around the world diverged from Jenner’s 1798 vacc

85. Slide 85: ACAM2000 – Best Technology of its Time

    © 2018 Tonix Pharmaceuticals Holding Corp. 85 Single clone picked from “swarm” of Dryvax ® 1 • Some rationale for selection 2 Growth in serum free Vero cells • Eliminates risk of Bovine Spongiform Encephalopathy (BSE)/prion contamination – safety concerns in Wyeth’s Dryvax (grown in calf lymph) In 2

86. Slide 86: Rationale for Developing a Potentially Improved Smallpox Vaccine

    © 2018 Tonix Pharmaceuticals Holding Corp. 86 Toxicity concern of modern vaccinia (VACV) vaccines limit wildly administration • Not recommended for use, even in first responders • U.S. soldiers in the Global Response Force are immunized Modern VACV vaccination safety studied in 1081 VACV ( Dryvax [6

87. Slide 87: Postulated Divergence of Historical Strains of Vaccinia

    © 2018 Tonix Pharmaceuticals Holding Corp. 87 Postulated Divergence of Historical Strains of Vaccinia Proposed Evolution of Vaccinia Vaccines NYCBH/European precursor stocks Horsepox - like ancestral strain Lister/Evans/USSR Dryvax ® IHD - J WR Copenhagen Tashkent RPXV TianTan Ankara LIVP IHD - J=In

88. Slide 88: Relationship to Smallpox Incidence and Eradication

    © 2018 Tonix Pharmaceuticals Holding Corp. 88 Relationship to Smallpox Incidence and Eradication Proposed Evolution of Vaccinia Vaccines TIME *Rough approximation (not data derived) 1977 Eradication SMALLPOX CASES IN US/EUROPE* ACAM2000™ 1798 1902 1931 2007 Dryvax ® swarm Mulford Vaccine Jenner’s Va

89. Slide 89: Evidence of Effectiveness of Smallpox Vaccines

    © 2018 Tonix Pharmaceuticals Holding Corp. 89 Theoretical effectiveness of modern vaccinia vaccines are based on extrapolation from older vaccines • Newer/modern vaccines were not widely used when smallpox was endemic MVA ( Modified Virus Ankara) which has large deletions also produces different T c

90. Slide 90: Possible Smallpox Prevention and Treatment Strategies

    © 2018 Tonix Pharmaceuticals Holding Corp. 90 Preventing Vaccine • Jenner’s vaccine, HPXV (upon licensure), Vaccinia Post - exposure vaccination 1 • Jenner’s vaccine Priming of the immune system • Imvamune ® (MVA) and DNA vaccines 2 Pharmacotherapy for infected or exposed individuals • Arestvyr ® /T

91. Slide 91: Viral Replication Proficiency, Immunogenicity and Safety

    © 2018 Tonix Pharmaceuticals Holding Corp. 91 Pox vaccines with low or no replication appear safer than vaccines replicate fast in human cells • Canarypox and Imvamune ® (Modified Virus Ankara/MVA) appear to have good tolerability • Relatively safe in immunocompromised hosts • Rapidly replicating mo

92. Slide 92: Manufacturing and Dosing Requirements

    © 2018 Tonix Pharmaceuticals Holding Corp. 92 TNX - 801 (HPXV) is expected to have similar scalability for mass production as ACAM2000 • TNX - 801 grows well in cell lines – immunity is expected after single administration (immunization) • Only a small dose (replicating live virus) is required for i

93. Slide 93: Rationale for Developing Improved Smallpox Vaccine Based on Jenner's Vaccine

    © 2018 Tonix Pharmaceuticals Holding Corp. 93 Vaccination protects against smallpox – both individuals and populations at risk • Use of Jenner’s vaccine resulted in eradication of smallpox Vaccination can protect AFTER smallpox infection • Vaccinia can be administered 1 - 3 days after infection Vacc

94. Slide 94: Potential for Use of HPXV as a Vector for Vaccines

    © 2018 Tonix Pharmaceuticals Holding Corp. 94 Potential for Use of HPXV as a Vector for Vaccines to Infectious Disease or Cancer Poxviruses like HPXV can be engineered to express foreign genes and are well recognized platforms for vaccine development • Large packaging capacity for exogenous DNA inse

95. Slide 95: Management Team

    © 2018 Tonix Pharmaceuticals Holding Corp. 95 Management Team Seth Lederman, MD President & CEO Jessica Morris Chief Operating Officer Gregory Sullivan, MD Chief Medical Officer Bradley Saenger, CPA Chief Financial Officer

96. Slide 96: Board of Directors

    © 2018 Tonix Pharmaceuticals Holding Corp. 96 Board of Directors Seth Lederman, MD Chairman Adeoye “Oye” Olukotun, MD Squibb, BMS, Mallinckrodt, Esperion John Rhodes Chair, NYS Public Service Commission, CEO, NYS Dept. of Public Service, Booz Allen Charles Mather BTIG, Janney, Jefferies, Cowen, Smit

97. Slide 97: Milestones – Recently Completed and Upcoming

    © 2018 Tonix Pharmaceuticals Holding Corp. 97 Milestones – Recently Completed and Upcoming □ July 201 8 Completed P301/HONOR study interim analysis - result did not support study continuation but strengthened new Phase 3 study □ August 201 8 Presentation of P301/HONOR study results at Military Healt

98. Slide 98: Summary

    © 2018 Tonix Pharmaceuticals Holding Corp. 98 Summary Phase 3 development of Breakthrough Therapy treatment for PTSD, including military - related PTSD • Major unmet need; ~11 million Americans affected • Benefited from FDA 505(b)(2) NDA approval requirement New indication in development for agitati

99. Slide 99: Thank you!

    © 2018 Tonix Pharmaceuticals Holding Corp. Thank you ! NASDAQ: TNXP

Tonix Pharmaceuticals Holding — Investor Presentation (November 2018) on 6ix