Tonix Pharmaceuticals Holding Corp. · NASDAQ:TNXP
Tonix Pharmaceuticals — Investor Presentation (January 2015)
66 slides from Tonix Pharmaceuticals's investor presentation, Jan 12, 2015
Slide 1: Tonix Pharmaceuticals
TONIX PHARMACEUTICALS NASDAQ: TNXP January 2015 ‘© 2015 Tons Pharmaceuticals Holding Corp.
Slide 2: Safe harbor statement
Safe harbor statement 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 Litigation Reform Act of 1995. These statements may be identified by the use of
Slide 3: New approaches to treating CNS disorders
New approaches to treating CNS disorders First-in-class medicines for common disorders of the central nervous system (CNS) Innovative treatment paradigms Late stage candidates Large unmet medical needs Entering 2015 with three clinical development programs . a TNX-102 SL Episodic Tension-Type Headac
Slide 4: Pipeline led by TNX-102 SL for fibromyalgia
Pipeline led by TNX-102 SL for fibromyalgia Fibromyalgia Start Phase 3 trial 2015 Lrvx102 5 | sealoaie ‘Stress Disorder Start Phase 2 tr ‘Start Phase 2 trial 2015 Episodic Tension- TNX-201 Type Headache TNX-102 SL (cyclobenzaprine HCI sublingual tablet) 2.8 mg and TNX-201 ((R)-isometheptene mucate)
Slide 5: Fibromyalgia market opportunity
Fibromyalgi ja marke’ opportunity Tonix is pursuing a different approach: roars Tonix “Lawrence etal Arthritis Rheum 20065826-35; Vincent et al Arthritis Care Res 201365:786-792. * Estimates based on information from publicly-avallable sources 'SNRI = Serotonin Norepinephrine Reuptate Inhibitor © Co
Slide 6: Sleep quality is a new target for fibromyalgia therapy
Sleep quality is a new target for fibromyalgia therapy Restorative sleep improves pain and other fibromyalgia symptoms >90% of fibromyalgia patients complain of poor sleep quality* Sleep quality improvement is not a feature of approved medications Phase 2a study with low-dose cyclobenzaprine (CBP) c
Slide 7: BESTFIT Phase 2b trial in fibromyalgia
BESTFIT Phase 2b trial in fibromyalgia BESTFIT = BEdtime Sublingual TNX-102 SL as Fibromyalgia Intervention Therapy Randomized, double-blind, placebo-controlled trial 2010 American College of Rheumatology diagnostic criteria for fibromyalgia 205 participants were randomized 1:1 at 17 USS. sites One
Slide 8: TNX-102 SL improved pain in fibromyalgia
TNX-102 SL improved pain in fibromyalgia in the BESTFIT study Outcome Measure at Week 12 _Intent-to-Treat Population’ pvalue Method Daily Pain Diary, NRS Mean Change** hee pari Daily Pain Diary, NRS Proportion Achieving 30% Improvement* 0.033 LR Clinic NRS 7-day pain recall Mean Change 0.029 MMRM FI
Slide 9: TNX-102 SL improved sleep quality in fibromyalgia
TNX-102 SL improved sleep quality in fibromyalgia in the BESTFIT study Outcome Measure at Week 12 pvalue Method Daily Sleep Quality Diary, NRS Mean Change” <0,001 MMRM i x 0.005 MMRM PROMIS Sleep Disturbance T-score Change Aen Wea FIQ-R Sleep Quality Item Mean Change <0.001 MMRM ‘PROMS = Patent Repo
Slide 10: TNX-102 SL broadly improved fibromyalgia symptoms
TNX-102 SL broadly improved fibromyalgia symptoms in the BESTFIT study Outcome Measure at Week 12 Intent-to-Treat Population pvalue Method Patient Global Impression of Change Responder Analysis" 0.025 LR FIQ-R Total Score Mean Change* ene pa FIQ-R Symptom Domain Mean Change 0.004 MMRM FIQ-R Function
Slide 11: TNX-102 SL was well-tolerated in the BESTFIT Study
TNX-102 SL was well-tolerated in the BESTFIT Study No serious adverse events (SAE) reported ‘Systemic adverse events reported by TNX-102SL Placebo Total at least 3.0% of the total study population (N=103) (N=101) (N=204) ‘Somnolence 19 69 44 Dry Mouth 39 40 39 Back Pain 49 30 39 Most frequent local
Slide 12: Registration program for TNX-102 SL in fibromyalgia
Registration program for TNX-102 SL in fibromyalgia Phase 2b BESTFIT study confirmed activity and tolerability Statistically-significant improvements across key fibromyalgia symptoms were observed Systemic tolerability similar to placebo 2.8 mg daily dose confirmed for future development Phase 3 pro
Slide 13: 30% improvement is considered moderate or clinically significant response
30% improvement is considered moderate or clinically significant response Pain rated from Drug 1 0-10 A few strong least to worst responders Baseline (10 Subjects) 30% response (moderate/ clinically significant) j q Non-responder X prug2 Several significant responders Moore RA, et al. Ann Rheum Dis.
Slide 14: Illustration of mean pain vs. responder analyses
Illustration of mean pain vs. responder analyses with hypothetical drugs 1 and 2 30% Responder Rate (RR) indicates how many patients have 230% (clinically meaningful) improvement in pain score Drug 1 Mean Pain A 30% RR A few strong responders 50% | Wenee + Mean pain A is significant + 30% Ris not li
Slide 15: TNX-102 SL had a significant effect on 30% response rate
TNX-102 SL had a significant effect on 30% response rate but not mean pain in BESTFIT) Week 12 Change from Baseline in Mean Pain NRS 30% Responder Rate Based on Pain NRS (pre-specified primary) (pre-specified primary) o 40 2 £ a ° i 3 Ea 2 20 S 0.95 0.97 3 5 4 ? 1.39 o & . 1S ® Ee Pe P=086 o ~ TON x
Slide 16: Reversal of the central pain syndrome may reveal the original cause
Reversal of the central pain syndrome may reveal the original cause Back pain Fibromyalgia Back pain remains “ Pain centralization © Copyright 2015 Tonix Pharmaceuticals Fibromyalgia treated | | TONIX: PHARMACEUTICALS |
Slide 17: Central sensitization contributes to hyperalgesia and allodynia
Central sensitization contributes to hyperalgesia and allodynia ¢ Nociception and touch pathways are normally separate ¢ Central sensitization amplifies response to pain and reduces inhibition of pain As Nociceptor 2 1 Hyperalgesia Allodynia Inhibitory synapses Low-Threshold Mechanoceptor TONIX Wool
Slide 18: Conditioning of peripheral and visceral nerves can lead to central sensitization
Conditioning of the peripheral and) visceral nerves can lead to central sensitization and dermatome hypersensitivity Sustained stimulation of myofascial HN trigger points induces central sensitization and referred pain Stimulation of viscera (eg, acid reflux in esophagus) leads to * central sensitiz
Slide 19: Review of fibromyalgia endpoints reflects dissatisfaction with current treatments
Review of fibromyalgia endpoints reflects dissatisfaction with current treatments + Fibromyalgia is one of 16 conditions chosen by FDA's Patient-Focused Drug Development program - Solicit patient input to determine meaningful clinical endpoints What relevant clinical endpoints demonstrate Fibromyalg
Slide 20: Phase 2 trial of TNX-102 SL for PTSD is recruiting
Phase 2 trial of TNX-102 SL for PTSD is recruiting Candidate Indication ([[Precinical ] Phase] Phase2__/ Phase3__] NDA] Market Fibromyalgia Post-Traumatic EEE) sess Decree Episodic Tension- TNX-201 Type Headache aula * Recruitment begin in December 2014, ‘TNX-102 SL (cyciobenzaprine HCI sublingual t
Slide 21: PTSD: A Significant and Growing Public Health Problem
PTSD: A Significant and| Growing Public Health Problem Post-traumatic stress disorder is a chronic, debilitating condition High incidence among soldiers and veterans, but experiencing any trauma can lead to PTSD Associated with suicide and unpredictable, violent behaviors Patients desperate despite
Slide 22: Rationale for Developing TNX-102 SL for PTSD
Rationale for Developing TNX-102 SL for PTSD Overlap between PTSD and fibromyalgia ~50% of fibromyalgia or PTSD patients meet criteria for the other disorder Patients experience disturbed sleep Widespread pain is considered “co-morbid” with PTSD. Opioid, benzodiazepine, other sedative-hypnotic drug
Slide 23: Sleep Quality is a New Target for PTSD Therapy
Sleep Quality is a New Target for PTSD Therapy Poor sleep quality after trauma is linked to onset of PTSD 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” Correlated with depression,
Slide 24: TNX-102 SL acts on neurotransmitter systems
S|_acts on neurotransmitter systems sleep physiology Serotonin and Norepinephrine Antagonist and Reuptake Inhibitor (SNARI) Blocks serotonin and norepinephrine reuptake Selectively blocks serotonin 2A and a-1 adrenergic receptors O scons Bi Norepinephrine Cyeiobensapcine TAX-102 SL (eclobenzaprine A
Slide 25: Trazodone and prazosin compared with TNX-102 SL
Trazodone blocks serotonin reuptake and 2A receptors Prazosin blocks a-1 adrenergic receptors TNX-102 SL © serotonin Norepinepnrine Cyclobenzaprine TNX-102 SL. (eyciobenzaprine HCI sublingual tabled) 28 mg isan Investigational New Drug and isnot approved for any indication PHARMACEUTICALS 25 © Copyr
Slide 26: PTSD program with TNX-102 SL
PTSD program with TNX-102 SL Fibromyalgia program informs development of TNX-102 SL in PTSD Safety data from fibromyalgia studies are potentially supportive for PTSD program Efficacy data support potential for activity in PTSD Improvements in several outcomes analyses of BESTFIT that relate to PTSD
Slide 27: AtEase Phase 2 trial of TNX-102 SL in PTSD
_ 8 "AtEase” Phase 2 trial of TNX 102 SL in PTSD ‘TNX-102 SL at bedtime once-daily Randomized, double-blind, placebo-controlled trial in military-related PTSD 28mg N=220; i h . Clinical sit Ree -220; approximately 25 US. dinical sites Sto ini) Primary efficacy endpoint: Difference in Clinician-Admin
Slide 28: TNX-201 in development for episodic tension-type headache
TNX-201 in development for episodic tension-type headache Candidate Indication Precinicel Phase i Phase?) Phase3__] NDA | Market | TNX-102SL | ae 102 Post-Traumatic X-2 Episodic Tension- TNX-201 Type TNX-102 SL (cyclobenzaprine HCI sublingual tablet) 2.8 mg and TNX-201 ((R)-isometheptene mucate) ‘a7
Slide 29: Episodic tension-type headache affects millions of US adults
“Episodic tension-type headache (ETH) 75 million adults in the U.S. experience frequent episodic tension-type headaches* Constant band of pressure on the back/sides of head; “squeezed in a vice” feeling “Frequent” = one to 15 headaches per month over a three-month period Approximately 60% receive tr
Slide 30: TNX-201 in clinical development for ETTH
TNX-201 in clinical development for ETTH TNX-201 is (R)-isometheptene mucate Tonix is developing TNX-201 for ETTH Phase 2 study to begin in 2Q 2015 Racemic isometheptene mucate is a mixture of (R) and (S) isomers Had been widely prescribed for many decades in the U.S. as: a single-agent medicine (pr
Slide 31: Phase 1 study of TNX-201 completed
Phase 1 study of TNX-201 completed Phase 1 study in healthy volunteers Single ascending dose study (N=45) — three cohorts of 15 subjects Randomized to TNX-201, racemic isometheptene mucate, or placebo (3:1:1 ratio, resp.) TNX-201 TNX-201 TNX-201 Rac. Isometh. 35mg 7omg 140mg 70 mg Placebo (N=9) (N=9
Slide 32: Phase 2 trial of TNX-201 in ETTH
in2Q a Randomized, double-blind, placebo-controlled tral in 140 mg episodic tension-type headache N=150; approximately 10 US. clinical sites Primary efficacy endpoint: Number of subjects who report “pain free” at two hours following one dose of study medication (upon first ETTH episode experienced)
Slide 33: Migraine vs. episodic tension-type headache
igraine Lasts 4 hours to 3 days * Localized to left or right + Pulsating quality + Aggravated by routine activity + Nausea and light/sound sensitivity * May or may not be accompanied by aura ‘Cephalalgia. 2012: 23(0)'820-808, © Copyright 2015 Tonix Pharmaceuticals 2) Episodic Tension-Type Headache (
Slide 34: ETTH is the most common type of headache
a ETTH Is the most common ty 2 0 jeadache Global prevalence of ETTH A review of 107 publications on the epidemiology of headache + Regional differences exist (higher in Europe, lower in Asia) One-Year Prevalence for Global Population 60% 2 47% 4 = 40% 38% g c 2 § 20% @ 10% 0% + en All Headaches ETTH
Slide 35: US prevalence of ETTH
ETTH is the most type of US Prevalence of ETTH Episodic tension-type headaches account for approximately: + 63% of all headaches * 80% of all non-migraine headaches + “Non-migraine” consists primarily of ETTH; >70% female One-Year Prevalence for U.S. Adult Population (18-65) P 60% 3 60% oC 4 8 40% d
Slide 36: Non-migraine headaches lead to 9.2 million visits
Non-migraine headaches lead| to 9.2 million emergency room or office visits Patients with non-migraine headache (primarily ETTH) seek medical attention Care-Seeking For Non-Migraine Headache e 8 7.6 «Migraine @Non-Migraine = £ a 2 ra oa 2 a ° 5 2 € 5 r4 Emergency Room’ Office Visits” sys ecm pat TON
Slide 37: Butalbital combinations are the only prescription medications approved for ETTH
Butalbital combinations are the only prescription medications approved for ETTH Butalbital combinations are used extensively to treat headaches Total of 8.2 Million Butalbital Combination Prescriptions 3.5 Million for Non-Migraine Headache 8.2 58 : : 2 6 2 Other uses F ee ™ Migraine é a m Non-Migrai
Slide 38: OTC products dominate but prescription market is still sizable
OTC products dominate but prescription market is still sizable (~10 M TRx) Treatment Patterns From Two Perspectives Patient Survey: (captures OTC & Rx) Opioids and Triptans (estimated) Drug Mentions in NSAIDs, Office Visits? Acetominophen (captures Rx) Estimated 10 M TRx for Target Segment 0% 20% 40
Slide 39: Annual cost of health care for migraine and headache exceeds $4B
Annual cost of health care for migraine and headache in the U.S. exceeds $4B Costs for different treatment settings in 2010 dollars? Annual Health Care Cost by Setting $3200 $700 Millions of Dollars N i—] i] i] $375 at > a= Outpatient ER Inpatient + Prescription costs are not included in these amoun
Slide 40: Public health attention to headache has increased in the past decade
Public health attention to headache has increased in the past decade + 2004 Lifting the Burden initiated The global campaign against headache involving WHO and 3 international headache NGOs * 2014 + 2007 Principal results Eurolight Project initiated of Eurolight project published European Union-leve
Slide 41: All FDA-approved medications for ETTH contain butalbital
All of the FDA-approved medications for ETT) contain butalbital Butalbital is a DEA schedule III substance due to its abuse potential and its extended use is not recommended Butalbit Trade % of Butalbital combination name 100% aie Fioricet x oe - 3 Certain ‘6 prescription a products Ss exempted from
Slide 42: Racemic isometheptene combination prescriptions had been commonly written
Racemic isometheptene combination (RIG) prescriptions had been commonly written Number of RIC prescriptions peaked at 2.5 million Usage of RIC Prescriptions for All Diagnoses 3 o § 244 4243 250 245 245 495 8 bie’ ao * ™ Other oc és oF = Non-Migraine (eg, ETTH) Lo &£ 2 £ a Migraine 3 z Or 1995 1996 1
Slide 43: Migraine and ETTH can exist together in mixed headache syndromes
Migraine and ETTH can exist toget! in mixed headache synd Migraine * Spectrum of presentations * Milder attacks are similar to ETTH * Episodic migraine has features distinct from ETTH (aura, light and noise sensitivity, GI disturbance) TONIX: Blumenfeld A, et al. Curr Pain Headache Rep. 2010; 14(6):
Slide 44: Pathophysiology of migraine and ETTH
Pathophysiology of migraine and ETTH Migraine Elta + May be a mild form of migraine or have distinct etiology + Believed to involve vasodilation trigeminahnerve Three branches of trigeminal nerve geminal nerye Migraine symptoms \ Nausea, aura, . | ight and sound sensitivity < X ‘Spinal tract TONDX P
Slide 45: Trigeminal nerve and headache mechanisms
Trigeminal Substance P nerve CGRP A Meningeal blood vessel Vasodilation Vasocanstriction Headache Treatment
Slide 46: Targets in the treatment of headache and pain
Targets in the treatment of headache and pain + Sodium channel,? Na(V); 7/18 - Nerve growth factor2 * Calcium channel alpha-2-delta (“gabapentinoids”)? + Serotonin receptors, 5-HTj,/p/-4 (“triptans”) ¢ Prostanoid receptors (EP2/EP,) 4 * Calcitonin gene-related peptide (CGRP) receptor* - NO receptor*
Slide 47: Racemic isometheptene has a long track record of use
Racemic isometheptene (MH slong track record of use = 2013: Tonix discovers TNX-201(R-isomer of IMH) and begins development + Developing science around TNX-201 * 1960s Drug Efficacy Study Implementation + 1930s (DESI) recommends IMH for tension IMH introduced and vascular headache, and for GI condit
Slide 48: Racemic IMH is a sympathomimetic amine
Racemic IMH Is a sympathomimetic amine Sympathomimetic activity presumed t ¢ Sympathomimetic action leads to vasoconstriction in cranial vessels — Common therapeutic strategy for vascular headaches New proprietary data points to a different mechanism Willems EW, et al. Naunyn Schmiedebergs Arch Phar
Slide 49: IMH isomers have different pharmacological activities
IMH isomers have different pharmacological activities ¢ Previously marketed isometheptene drugs were a mixture of two chemically distinct, mirror-image isomers R-isomer H S-isomer + Analgesic ia ical ia + Sympathomimetic + Binds to imidazoline-1 receptor + Inactive on adrenergic receptors TONIX: i ‘
Slide 50: R-IMH binds to the imidazoline-1 receptor
R-IMH binds to the imidazoline-1 receptor Binding of isometheptene isomers and racemic mixture to I,-R 100 20 [3H] Clonidine, % Initial Bound Data on file. Tonix Pharmaceuticals, 2015. © (S)-Isometheptene, Ki = 1100 nM © (R)-Isomethepene, Ki = 18 nM y Racemic Isometheptene, Ki = 42 nM o -10 9 8 7 6
Slide 51: R-IMH has reduced effects on blood pressure
R-IMH has reduced effects on blood pressure compared to S-IMH and racemic IMH ‘Comparison of the effects of isometheptene mucate (IMH), (R)-IMH, and (S)-IMH on blood pressure following IV administration in anesthetized rats at doses ranging from 0.03 to 10 mg/kg Diastolic arterial blood pressure, ch
Slide 52: Discovery of the imidazoline receptor
Discovery of the imidazoline receptor * Clonidine has been in clinical use for 40 years — High blood pressure, migraine, pain, psychiatric disorders — Use in pain limited by side effects — Primary activity—a, adrenergic agonist * Imidazoline receptor hypothesized in ‘80s when a, activity could not f
Slide 53: The imidazoline-1 receptor is a novel target for the treatment of pain
The imidazoline-1 receptor is a novel target for the treatment of pain Imidazoline I, Receptor (1,-R) Characteristics! + Transmembrane receptor + Distinct from a,AR and MAO receptor subtypes + No sequence similarity to GPCRs or ATP-sensitive K*+ channels + Shares similarities to ryanodine and cytoki
Slide 54: The imidazoline-1 receptor is a novel target for pain
The imidazoline-1 receptor is a novel target for the treatment of pain Imidazoline I, Receptor (1,-R) Drugs with I,-R Affinity orn | Tsaost | osm Clonidine Vv Vv Rilmenidine vv vv Moxonidine Vv Vv Dexmedetomidine Vv Vv v Isometheptene Isometheptene is a non-imidazoline, selective imidazoline-1 recep
Slide 55: Initial physician response to TNX-201
Initial physician response to TNX-201 * Based on the established use of racemic isometheptene, the single isomer, TNX-201, should have a superior safety profile* with similar efficacy compared to NSAIDs and Fioricet ¢ The likelihood of a non-habit forming nature and a low rebound risk, judging from
Slide 56: Future opportunities for TNX-201
Future opportunities for TNX-201 ¢ There are currently a limited number of MOAs used in treating headache pain * The MOA of TNX-201 on headache pain is novel, with the imidazole I, receptor representing a strong candidate TONIX: PHARMACEUTICALS - © Copyright 2015 Tonix Pharmaceuticals
Slide 57: Intellectual property
Intellectual property AILIP wholly-owned by Tonix without obligations to others TNX-102 SL TNX-201 Fibromyalgia, PTSD Headache Composition-of-matter (eutectic) Composition-of-matter (isomer) Patents filed Patents filed Protection expected to 2034 Protection expected to 2033 Pharmacokinetics (PK) Pat
Slide 58: Financial summary
Financial summary NASDAQ: TNXP Cash reported at September 30, 2014 $ 46.2 million Net cash used in operations in 3Q14 $ 49 million Shares outstanding’ 10.8 million +As of anuary 9, 2015 T o N IX i ‘ . PHARMACEUTICALS 59 © Copyright 2015 Tonix Pharmaceuticals
Slide 59: Seth Lederman, MD
Seth Lederman, MD TARGENT” i . . ol COWEN ATON™ Zolina® Chief Financial Officer PHARMA {rorinostar} capsules Chief Scientific Officer & MERCK @ MAP. GlaxoWellcome INSPIRE@ — @SEPRACOR © Copyright 2015 Tonix Pharmaceuticals
Slide 60: Milestones — recent and upcoming
Milestones — recent and upcoming TINX-102 SL - Fibromyalgia September 2014 — Reported top line results from Phase 2b BESTFIT study ‘f January 2015 - Reported on FDA acceptance of 30% responder analysis as primary endpoint @ 2Q2015-Begin Phase 3 program TNX-102 SL ~ Post-Traum: ‘June 2014— Received I
Slide 61: Tonix Pharmaceuticals contact details
TONIX PHARMACEUTICALS NASDAQ: TNXP 509 Madison Avenue New York, NY 10022 (212) 980-9155 www: pharma.com
Slide 62: Backup slides
BACKUP SLIDES PHARMACEUTICALS © Copyright 2015 Tonix Pharmaceuticals 62
Slide 63: Headache costs U.S. employers approximately $20B annually
Headache costs U.S. employers approximately $20B annually Costs due to missed work time and reduced performance while at work ¢ Headache is the most common pain condition causing lost productive time, costing employers $19.6B annually(2002 US $)! Lost productivity* Annual loss to employers in days/y
Slide 64: Medications used for treatment of ETTH
Medications used for treatment of ET TH A vast majority of people with episodic headache are treated with analgesics Current and Past Pain Medication Used for ETTH Listed in decreasing order of usage = -, im Acetaminophen otc 4 m Ibuprofen 5 @ OTC/Caf/Combo 3 93%| "Aspirin § _° Naproxen 8 m Total Rx
Slide 65: Rx medications used for treatment of ETTH
Rx medications used for treatment of ETTH Existing prescription therapies have low market penetration Current and Past Pain Medication Used for ETTH 4% 8 Baba | Triptan 3 ™ Butalbital compounds es | Opioid compounds e a £ 0% 1st Choice TONIX: Scher AI, et al. Cephalalgia. 2010; 30(3):321-328. PHARMA
Slide 66: Isometheptene prescriptions previously were commonly written
Isometheptene prescriptions previously were commonly written Number of Isometheptene prescriptions peaked at 2.5 million Usage of Isometheptene Combinations for all Diagnoses 3 2.44 2.43 250 2.45 2.45 potter? | Nor-Migraine Migraine 54 ce ae Isometheptene/_ 1.06 1.08 4.93} dichloralpher lili i jacet
Tonix Pharmaceuticals Holding — Investor Presentation (January 2015) on 6ix