PTSD Awareness Day October 26, 2016 Welcome & Introduction€¦ · Growing economic and social burden to care for veterans with PTSD. Health care costs associated with PTSD for OEF/OIF

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PTSD Awareness DayOctober 26, 2016

Welcome & IntroductionSeth Lederman, MD

Version P0035 10-24-16

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Certain statements in this presentation regarding strategic plans, expectations andobjectives for future operations or results are “forward-looking statements” as defined bythe Private Securities Litigation Reform Act of 1995. These statements may be identifiedby the use of forward-looking words such as “anticipate,” “believe,” “forecast,” “estimate”and “intend,” among others. These forward-looking statements are based on Tonix’scurrent expectations and actual results could differ materially. There are a number offactors that could cause actual events to differ materially from those indicated by suchforward-looking statements. These factors include, but are not limited to, substantialcompetition; our need for additional financing; uncertainties of patent protection andlitigation; uncertainties of government or third party payor reimbursement; limitedresearch and development efforts and dependence upon third parties; and risks relatedto failure to obtain U.S. Food and Drug Administration clearances or approvals andnoncompliance with its regulations. As with any pharmaceutical under development,there are significant risks in the development, regulatory approval and commercializationof new products. The forward-looking statements in this presentation are made as of thedate of this presentation, even if subsequently made available by the Company on itswebsite or otherwise. Tonix does not undertake an obligation to update or revise anyforward-looking statement, except as required by law. Investors should read the riskfactors set forth in the Annual Report on Form 10-K for the year ended December 31,2015, as filed with the Securities and Exchange Commission (the “SEC”) on March 3,2016, and future periodic reports filed with the SEC on or after the date hereof. All of theCompany's forward-looking statements are expressly qualified by all such risk factors andother cautionary statements.

Safe Harbor Statement

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Presenters Introductions and Disclosures

• Seth Lederman, MD– Tonix Pharmaceuticals President & CEO

• Jonathan Davidson, MD– Emeritus Professor, Duke University

• Thomas Mellman, MD– Professor, Howard University

• Gregory Sullivan, MD– Tonix Pharmaceuticals Chief Medical Officer

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Tonix Pharmaceuticals at a glance

• Primary focus- PTSD Phase 3 clinical program– Planning to start Phase 3 in Q1 2017– Targeting interim analysis topline 2H2017

• Discontinued fibromyalgia development– Narrowly missed primary endpoint in first Phase 3 study

(September 2016) – Strong effects on sleep quality measures– Redirected resources to PTSD

Posttraumatic Stress Disorder (PTSD) –TNX-102 SL* Phase 2 trial reported data in May 2016

*TNX-102 SL is an Investigational New Drug and has not been approved for any indication.

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Management Team

Seth Lederman, MDPresident & CEO

Jessica MorrisEVP, Operations

Bruce Daugherty, PhD, MBAChief Scientific OfficerGregory Sullivan, MDChief Medical Officer

Bradley Saenger, CPAChief Financial Officer

http://www.fusilev.com/index.html

http://www.fusilev.com/index.html

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Board of Directors

Seth Lederman, MDChairman

Ernest Mario, PhDALZA, Glaxo, Reliant Pharma

John RhodesNYSERDA, NRDC, Booz Allen Hamilton

Samuel Saks, MDJazz Pharma, ALZA, Johnson & Johnson

Charles MatherBTIG, Janney, Jefferies, Cowen, Smith Barney

Stuart DavidsonLabrador Ventures, Alkermes, Combion

Patrick GraceApollo Philanthropy, WR Grace, Chemed

Donald Landry, MD, PhDChair of Medicine, Columbia University

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PTSD milestones – recent and upcoming

TNX-102 SL – PTSD Dec. 2015 Entered into Collaborative Research and Development Agreement

(CRADA) with the United States Army Medical Materiel Development Activity (USAMMDA)

May 2016 Report results from AtEase study Aug. 2016 End-of-Phase 2 meeting with FDA

- Proposed Phase 3 clinical and NDA plan accepted- Breakthrough Therapy Designation Request can be submitted for review

Q1 2017 Target commencement of Phase 3 study in military-related PTSD 2H 2017 Topline data from interim analysis of Phase 3 study in ~180

military-related PTSD patients


8 History of PTSD in the 21st century

VCyclobenzaprine and the potential efficacy of TNX-102 SL

IVThe current treatment landscape

III Sleep and PTSD

IIThe neurobiology

of PTSD

IPTSD in the

21st century

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References to PTSD have appeared in literature for more than 1,000 years1

1Stein D, Friedman M, Blanco C, eds. Post-traumatic Stress Disorder. 1st ed. John Wiley & Sons, Ltd.; 2011

The Iliad Homer

ca 8th Century BC

Henry IV, Part I William Shakespeare

ca AD 1598

The Red Badge of Courage Stephen Crane

Published AD 1895

Terms referring to PTSD as:

“…soldier’s heart…”

“…shell shock…”

“…traumatic neurosis…”

“…combat fatigue…”

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The classification of PTSD has evolved over time1

Recognition of PTSD in the Diagnostic and Statistical Manual of Mental Disorders (DSM)

DSM-I1952

Gross Stress Reaction“Stress response to an exceptional physical or mental stress”

DSM-II1968

Omitted

DSM-III1980

DSM-IV1994

PTSD classified as an Anxiety Disorder

DSM-52013

PTSD classified as a Trauma- and Stressor-Related Disorder2

1950 1960 1970 1980 1990 2000 2010

1Andreasen, N.C. Annals of the New York Academy of Sciences. 2010; 2American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing

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The “A” stressor criteria refined and now excludes criterion for individual’s response to the event

Avoidance separated from negative cognitions and mood

Reckless and self-destructive behavior added

The DSM-5 (2013) introduced significant changes to the diagnostic criteria for PTSD

Diagnostic Criteria for PTSD (DSM-5)

A. Exposure to actual or threatened death, serious injury or sexual violence1. Directly experienced2. Witness in person3. Indirectly (close family member or friend)4. Repeated or extreme exposure (e.g. first responders)

B. Presence of one (or more) intrusion symptoms

C. Persistent avoidance of stimuli associated with traumatic event

D. Negative alterations in cognitions and mood

E. Marked alterations in arousal and reactivity

F. Duration of disturbance (Criteria B-E) is more than 1 month

G. Disturbance causes clinically significant distress or impairment

H. Disturbance not attributable to physiological effects of a substance or medication

American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.

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Evolving cultural and professional perceptions

Abnormal response to normal trauma

Normal response to abnormal trauma

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High prevalence of PTSD among combat veterans

Prevalence of PTSD

1Kessler, Arch Gen Psych 2005; 2Norris, PTSD Res Quar. 2013;3Tanielan, Invisible wounds of war. 2005; 4CBO Report 2012; 5http://www.nimh.nih.gov/health/topics/post-traumatic-stress-disorder-ptsd/index.shtml

10-21%Operation Enduring Freedom

(OEF; Afghanistan) / Operation Iraqi Freedom

(OIF) veterans3,4

2-8%General population1

19-31%Vietnam veterans2

8.6 million American adults affected5

Women more likely to develop than men5

Susceptibility may run in families5

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PTSD Prevalence and Market Characteristics

Undiagnosed6,788,000 79%

Rx510,000

6%

No Rx128,000

2%

Rx872,000

10%

No Rx 288,000

3%

1Kessler, et al., 2005; ; Prevalence rate of 3.5% applied to U.S. Census estimate of 247 million U.S. adult (>18) population in 2015 (www.census.gov/quickfacts/table/PST045215/00)2IMS Consulting, Market Sizing & Treatment Dynamics: Posttraumatic Stress Disorder (PTSD) Patients", 2016 3Bowe and Rosenheck, 2015 ((638,451 veterans diagnosed with PTSD in the VA in fiscal year 2012 across all medical centers)4Bernardy et al., 2012 (80% of veterans diagnosed with PTSD had at least one medication from the Clinical Practice Guidelines)

Veterans Treated in VA3,4

Civilians Population2

Diagnosed populationLarge population (~1.8 million)Majority receive drug treatment

Civilians: ~75%2

Veterans: ~80%4

Prevalent Population (U.S.) ~8.6 million1

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Growing economic and social burden to care for veterans with PTSD

Health care costs associated with PTSD for OEF/OIF veterans:

Direct costs Indirect costs

1CBO Report 2012; 2Tanielan, Invisible Wounds of War. 2005

$6,000-10,000per patient per year for

OEF/OIF Veterans1

> 2 million soldiers deployed since

October 20011

$2-3 billionestimated yearly cost

to society2

Families, social care agencies, schools,

employers, welfare system2


16 Neurobiology of PTSD



IIThe neurobiology

of PTSD

IPTSD in the

21st century

III Sleep and PTSD

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What is fear1?

Stimulus

Phobia Panic

1Stahl SM, Grady MM. Stahl’s Illustrated Anxiety, Stress, and PTSD. New York, NY: Cambridge University Press; 2010.

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Fear conditioning can result in sustained activation of stress response1

• PTSD patients suffer from repeated/sustained stress through fear conditioning

• Loud noises (explosions), objects (weapons), and smells (burning rubber) can trigger fear response

1Stahl, SM. Stahl's Essential Psychopharmacology. 4th ed. Cambridge, United Kingdom: Cambridge University Press; 2013

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The sympathetic nervous system responds to fearful stimuli1

Pupils Dilate

Heart RateBlood Pressure

Respiratory Rate

Energy Mobilization

UrinationDefecation

Peristalsis

“Fight or Flight”

Sympathetic Nervous System

Mobilizes the body for activity

1Fundamental Neuroscience. 2nd ed. Academic Press, Elsevier Science; 2003.

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The healthy autonomic nervous system orchestrates balanced physiology1

Sympathetic Nervous System

Mobilizes the body for activity1

Parasympathetic Nervous System

Conserves energy1

Autonomic NervousSystem

Homeostasis

PTSD is decompensated hyper-sympathetic2

Sympathetic > > > Parasympathetic

CompensationHyper-sympathetic

DecompensationHypo-parasympathetic

1Fundamental Neuroscience. 2nd ed. Academic Press, Elsevier Science; 2003.2Stahl SM, Grady MM. Stahl’s Illustrated Anxiety, Stress, and PTSD. New York, NY: Cambridge University Press; 2010.

“Fight or

Flight”

“Rest &

Digest”

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Sustained stress can lead to stress sensitization1

Amygdala

Stress response returns to baseline when stressor is withdrawn

Amygdala Amygdala

Stress response remains active when extreme stressor is withdrawn

Stressor Extreme/Repeated

Normal Stress Resilience Stress Sensitization

PTSD

CompensationHyper-sympathetic

DecompensationHypo-parasympathetic

1Stahl SM, Grady MM. Stahl’s Illustrated Anxiety, Stress, and PTSD. New York, NY: Cambridge University Press; 2010.

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Consequences of autonomic decompensation

• Low/Absent parasympathetic tone– makes it difficult to re-integrate in civilian life and enjoy nurturing

interactions and relationships with families and friends

• Hyper sympathetic tone– better suited to deployment and may encourage re-enlisting,

particularly if employment in law enforcement is not an option


23 Sleep and PTSD



III Sleep and PTSD

IIThe neurobiology

of PTSD

IPTSD in the

21st century

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Sleep disturbances are a core feature of PTSD1

Sleep disturbances are a core feature of PTSD and a component of three of the four major symptom clusters:

1Germain A. Am J Psychiatry. 2013; 2American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.

Diagnostic Criteria for PTSD (DSM-5)2

B. Presence of one (or more) intrusion symptoms

C. Persistent avoidance of stimuli associated with traumatic event

D. Negative alterations in cognitions and mood

E. Marked alterations in arousal and reactivity

Nightmares Arousal/wakefulness Avoidance of Sleep

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Sleep disturbances in PTSD recognized by the VA1

1VA/DoD Clinical Practice Guideline for Management of Post-Traumatic Stress. 2010

“One of the most difficult symptoms to address in the immediate aftermath of exposure to a traumatic event is sleep disturbance”

“Theoretically, the more sleep impairment and trauma-related nightmares an individual continues to experience, the more likely he or she is to continue to experience the symptoms of [Acute Stress Disorder] ASD and/or subsequently develop PTSD”

“There is little evidence for the effectiveness of any sleep aids in the immediate aftermath of trauma.”

Sleep Disturbance in VA Guideline:

“Recommend adjunctive treatment with prazosin for sleep/nightmares.”

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What is restorative sleep?

Restorative Sleep Hypothesis1: Sleep is an active, necessary state for processing emotionally charged memories, replenishing energy, and resetting homeostasis to circuitry in the brain

Homeostasis

Sleep DeprivationSleep Disturbances

Depression, Chronic Pain, Anxiety, and PTSD

1Germain A. Am J Psychiatry. 2013.

ENERGY

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Many PTSD patients suffer from dysregulation in REM and NREM sleep1

REM DisturbancesNightmaresBad dreams unrelated to traumatic eventsDisruptive behavior (acting out dreams)Sleep-disordered breathing

NREM DisturbancesInsomniaNocturnal panic attacksSleep terrors

Clinical observations of sleep complaints in PTSD found1:

Targeted treatment for nightmares and insomnia in PTSD patients found that all symptom domains in PTSD improved2,3

– Normalization of sleep disturbances has beneficial effects on daytime PTSD Symptoms2,3

Dyssomnia: symptom or contributing factor?1Germain A. Am J Psychiatry. 2013; 2Taylor F. et al. Biol Psychiatry. 2006. 3Raskin M. et al. Biol Psychiatry. 2007

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Hypothesis: Emotionally charged memories can form a mental abscess that is normally resorbed by restorative sleep

Restorative Sleep

Disturbed Sleep

If the memory is too painful, it awakens the PTSD sufferer and prevents processing and resorption

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Sleep quality is a new target in PTSD therapy

• PTSD patients complain of poor sleep quality as a core symptom– Distressing dreams (nightmares) are part of “re-experiencing”– Restless sleep is part of “hyper-arousal”

• Poor sleep quality after trauma is linked to onset of PTSD– Poor sleep correlates with depression, substance abuse and

suicide


30 The current treatment landscape



III TNX-102 SL in PTSD

IIThe neurobiology

of PTSD

IPTSD in the

21st century

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What Drug Classes are Used to Treat PTSD?

• Market highly fragmented, with benzodiazepines being the largest class (but contraindicated1)

• Multiple medications per patient (or “Polypharmacy”) is the norm• Approximately 55% of patients receive a benzodiazepine, and 53% receive an

SSRI• Selective serotonin reuptake inhibitors (SSRIs) are the only FDA approved drug class

* TRx = Total prescriptions1VA/DoD Clinical Practice Guideline for the Management of Post-Traumatic Stress, Version 2, 20102IMS Consulting, Market Sizing & Treatment Dynamics: Posttraumatic Stress Disorder (PTSD) Patients", 2016

Benzodiazepines2,844,792 TRx

SSRIs2,839,118 TRx

Anticonvulsants/Mood Stabilizers

Atypical Antipsychotics

Other Antidepressants

Serotonin and norepinephrine reuptake inhibitors

Non-benzodiazpepine Hypnotics

Adrenergic Agents Tricyclic AntidepressantsAll Others Estimated PTSD Market

Volume (Civilian Population Only)

~14.1 million TRx*2

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Pharmacotherapy: Standard of Care

1ISTSS Guidelines 2009; Foa, E. Pharmacotherapy for Adults; Guideline 6.

2VA/DoD Clinical Practice Guideline for Management of Post-Traumatic Stress. 2010

Two SSRI Antidepressants are FDA approved for the treatment of PTSD

• Nearly all guidelines recommend SSRIs or serotonin-norepinephrine reuptake inhibitors (SNRIs) at Grade A level of evidence– ISTSS Practice Guidelines 2009, “The best evidence

supports the use of SSRIs and SNRIs as first-line drugs…”1

– VA/DoD Guidelines 2010, “Strongly recommend SSRI or SNRI”2

• ISTSS for tricyclic antidepressants (TCAs) – level A• VA/DoD for TCAs – level B

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Interpreting Guidelines: Questions and challenges for military-related PTSD

Little supporting data for military-related PTSD treatments

• Reasons to doubt applicability of the results from non-VA/non-combat populations– Civilian PTSD is predominantly female, may be

associated with less nightmares• SSRI and SNRI drugs have performed

poorly in VA studies, yet remain first level recommended treatment– New drug studies are challenging because of

drop-outs, concomitant meds and suicidal symptoms

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Why Initially Target Military-Related PTSD?

Military-related PTSD is not well-served by FDA-approved therapies

• No clear treatment response observed in U.S. military population1

• Inconsistent treatment response observed in males2

• Important tolerability issues with SSRIs in this population3,4

1Friedman et al., J Clin Psychiatry 2007; 68:711, 2Zoloft Package Insert, August, 2014, 3Paxil Package Insert, June, 2014, 4Fava et al., Psychother Psychosom 84:72-81, 2015


35Cyclobenzaprine and the potential efficacy of TNX-102 SL in PTSD



III Sleep and PTSD

IIThe neurobiology

of PTSD

IPTSD in the

21st century

36


Cyclobenzaprine (CBP) is a potent analogue of the tricyclic antidepressant (TCA) amitriptyline (AMI)

• TCAs were developed before CNS receptors were identified or characterized

– Today it’s understood that each TCA has a unique signature of receptor interactions and activities1

• CBP was considered ~2x more potent than AMI in a 6 month dose-escalating fibromyalgia study1

Cyclobenzaprine Amitriptyline

Single BondCH3CH3

1Daugherty and Lederman, 20152Carrette S. 1994 Arth Rheum 37(1):32-40)

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Effects of CBP on Sleep

• Targeting sleep quality1,2

– Harness the effect of bedtime TNX-102 SL for a potential therapeutic effect in PTSD

• Active sleep improvement dose confirmed in fibromyalgia– Oral CBP studied in dose escalating Phase 2a study in

fibromyalgia3 and TNX-102 SL activity confirmed in Phase 2B study (BESTFIT)4 and a Phase 3 study (AFFIRM)5: consistent and durable activity improving sleep quality

– Bedtime dosing time for TNX-102 SL– Effects seen in 10-14 days in fibromyalgia

New paradigm: low dose CBP exposure during sleep

1Iglehart IW. Methods for treating or preventing fibromyalgia using very low doses of cyclobenzaprine. 22003, US Patent 6,541,523, 3Moldofsky et al, J. Rheum. 2011; 4Tonix Pharmaceuticals data; 5Tonix Pharmaceuticals data

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TNX-102 SL is a sublingual tablet formulation optimized for long-term use at bedtime

COMPARE:

TNX-102 capsules

GI absorption

* Absorption lag time (tlag) based on clinical pharmacokinetic data.

TNX-102 SL sublingual tablets

• Transmucosal absorption

• 10× faster absorption than capsule formulation*

Bedtime administration• Fast onset aligns exposure with sleeping period• Designed to optimize ease-of-use and compliance

Daytime tolerability• Low dose sublingual tablets: 5.6 mg daily at bedtime (compared to

15 or 30 mg/day dosing for relief of muscle spasms)• Developed for long-term use

BENEFITS OF SUBLINGUAL FORMULATION:

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Cyclobenzaprine is a…

Let’s take a closer look…

Serotonin 5HT2A receptorerotonin andS

ntagonist andA

nhibitorI

α1 adrenergic receptororepinephrineN

Serotonin Transporter (SERT)

Norepinephrine Transporter (NET)euptakeR

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Cyclobenzaprine: multi-functional receptor binding and activity

• TNX-102 SL binds to 5HT2a, α1, and H1 and is a functional antagonist at each receptor1

5-HT2A 5-HT2C H1 α1 adrenergicTNX-102 SL1

1Daugherty B and Lederman S, unpublished

Sleep quality SedativeAnxiolytic

Treating nightmares

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Summary

Military-related Posttraumatic Stress Disorder (PTSD) is a chronic debilitating disorder that has shown responsiveness to certain tricyclic antidepressants (TCAs): TNX-102 SL is a potent analogue of amitriptyline

Sleep quality is a new target for PTSD therapy: TNX-102 SL is designed for bedtime use. CBP is multifunctional agent that functions as an antagonist at:

– 5HT2A, α1 adrenergic, and H1 receptors

The pharmacodynamic profile and sublingual formulation of TNX-102 SL suggested that it may have therapeutic potential for military-related PTSD and related conditions

Documents

PTSD Awareness Day October 26, 2016 Welcome & Introduction€¦ · Growing economic and social burden to care for veterans with PTSD. Health care costs associated with PTSD for OEF/OIF