Tonix Pharmaceuticals Holding Corp. · NASDAQ:TNXP

Tonix Pharmaceuticals — Controversies in Fibromyalgia 2025

35 slides from Tonix Pharmaceuticals's conference presentation, Mar 3, 2025

  1. Slide 1: Controversies in Fibromyalgia 2025

    Controversies in Fibromyalgia 2025 Transmucosal Sublingual Cyclobenzaprine (TNX-102 SL) Treatment of Fibromyalgia at Bedtime to Target Non-Restorative Sleep Showed Durable Pain Reduction in Two Double-Blind Randomized Phase 3 Studies March 3, 2025 NASDAQ: TNXP Version P06048 March 3, 2025 (Doc 1564)

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

    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 Litigation Reform Act of 1995. These statements may be i

  3. Slide 3: TNX-102 SL (Cyclobenzaprine HCl Sublingual Tablets)

    TNX-102 SL (Cyclobenzaprine HCl Sublingual Tablets)1 CNS PORTFOLIO • Non-opioid analgesic designed for long-term daily bedtime use in fibromyalgia patients ‒ Targets non-restorative sleep ‒ Potent binding and antagonist activities at the serotonin-5-HT2A, α1-adrenergic, histaminergic-H1, and muscari

  4. Slide 4: Poor Sleep and Pain have Bi-directional Reinforcing Effects

    Poor Sleep and Pain have Bi-directional Reinforcing Effects1 CNS PORTFOLIO • Harvey Moldofsky – recognition of unrefreshing/non-restorative sleep in fibromyalgia • Poor sleep and pain form a vicious cycle in driving fibromyalgia decompensation • Can’t sleep → worse pain / In pain → can’t sleep • Poo

  5. Slide 5: Fibromyalgia: Unrefreshing Sleep and Cyclobenzaprine Treatment

    Fibromyalgia: Unrefreshing Sleep and Cyclobenzaprine Treatment CNS PORTFOLIO • Non-restorative sleep1,2 ‒ Harvey Moldofsky – recognition of unrefreshing/non-restorative sleep:  Symptom  Potential causative or potentiating factor • Cyclobenzaprine3,9 ‒ With amitriptyline one of the earliest drugs s

  6. Slide 6: Neither Cyclobenzaprine nor Amitriptyline Have Durable Activity on Pain in Fibromyalgia

    Neither Cyclobenzaprine nor Amitriptyline Have Durable (> 1 month) Activity on Pain in Fibromyalgia1 CNS PORTFOLIO Study: Change in visual analog scale • Double-blind randomized • Three Arms • n=208 • 6 months Bedtime Dosing2: First 3 months: • Cyclobenzaprine 20 mg • Amitriptyline 25 mg Last 3 mont

  7. Slide 7: Oral Tertiary Amine Tricyclics Are Prodrugs for Active Secondary Amine Tricyclics

    Oral Tertiary Amine Tricyclics (TATs) Are Prodrugs for Active Secondary Amine Tricyclics (SATs) in Depression CNS PORTFOLIO Tertiary Amine Tricyclics Amitriptyline Imipramine Clomipramine Doxepin • Dynamic PK profiles with shorter half-lives1 • Short-term utility for bedtime dosing to target nonrest

  8. Slide 8: Cyclobenzaprine is a Tertiary Amine Tricyclic Not Developed as an Antidepressant

    Cyclobenzaprine is a Tertiary Amine Tricyclic That was Not Developed as an Antidepressant CNS PORTFOLIO Cyclobenzaprine (CBP) NorCyclobenzaprine (norCBP) Tricyclic nucleus “First-pass” hepatic metabolism Amino- alkyl tail CH3 Demethylation Tertiary Amine Tricyclic (TAT) Seconary Amine Tricyclic (SAT

  9. Slide 9: Cyclobenzaprine HCl is 66,000 Times More Water Soluble than Amitriptyline HCl

    Cyclobenzaprine HCl is 66,000 Times More Water Soluble than Amitriptyline HCl CNS PORTFOLIO Single bond Double bond 2e- 2e- 2e- 2e- 2e- 2e- 2e- Antiaromaticity Solubility 664,000 mg/L3 10 mg/L1,2 CH 3 in Water: CH3 N N CH 3 CH 3 Amitriptyline Cyclobenzaprine Double Bond in Central Seven Member Ring

  10. Slide 10: Cyclobenzaprine is More Water Soluble Than Amitriptyline Because it is More Polar

    Cyclobenzaprine is More Water Soluble Than Amitriptyline Because it is More Polar Equal distribution of electrons  non-polar Unequal distribution of electrons  partial polarity1,2 Hydrophobic ᵟ+ ᵟ+ ᵟ- H H H H H H Hydrophobic ᵟ+ ᵟ+ Hydrophobic ᵟ+ ᵟ+ ᵟ+ ᵟ+ ᵟ- ᵟ- ᵟ+ ᵟ- ᵟ+ ᵟ+ ᵟ- Amitriptyline Cycloben

  11. Slide 11: Cyclobenzaprine's Solubility in Water is Driven by the Avoidance of Antiaromaticity

    Cyclobenzaprine’s Solubility in Water is Driven by the Avoidance of Antiaromaticity CNS PORTFOLIO • Cyclobenzaprine in solution reduces antiaromaticity by bending more or flattening more • A range of conformations increase polarity between maximum curvature (exocyclic alkene) or maximum flatness (ar

  12. Slide 12: Oral Cyclobenzaprine Undergoes First-Pass Metabolism

    Oral Cyclobenzaprine Undergoes First-Pass Metabolism CNS PORTFOLIO CBP undergoes “first pass” hepatic metabolism and is CBP administered as a ~50% converted to the CBP and norCBP enter swallowed oral dose persistent active metabolite the brain norCyclobenzaprine (norCBP) CBP < norCBP tongue H3C N H3

  13. Slide 13: Oral Cyclobenzaprine: Simulated Day Steady-State Blood Levels

    Oral Cyclobenzaprine: Simulated Day 20 Steady-State Blood Levels: Secondary Amine Tricyclic norCBP Accumulates CNS PORTFOLIO Cyclobenzaprine (CBP) NorCyclobenzaprine (norCBP) Bedtime dosing – blood levels Accumulates with oral peak ~5 hours after dosing and dosing – little diurnal then rapidly fall

  14. Slide 14: Cyclobenzaprine Binding Affinities for Receptors and Transporters

    Cyclobenzaprine Binding Affinities* for Receptors and Transporters CNS PORTFOLIO H1 5-HT2A α1A α1B M1 SERT NET Cyclobenzaprine (CBP) 1.3 5.2 5.6 9.1 7.9 29 35 norCyclobenzaprine 5.6 13 34 11 30 91 2.6 (norCBP) CBP/norCBP Activity Antagonist Inhibitor CBP: more active (lower Ki) at the key receptors

  15. Slide 15: Formulation with Basic Excipient Increases Transmucosal Absorption

    Formulation with Basic Excipient Increases Transmucosal Absorption of Sublingual Cyclobenzaprine1 CNS PORTFOLIO Concentration gradient increases diffusion of free base across oral mucosa (Le Chatelier’s Principle) Low pH (acidic) High pH (basic) Base (K2HPO4) CBP-HCl CBP-HCl + +f + + + + + + + + + +

  16. Slide 16: TNX-102 SL: Proprietary Eutectic Formulation

    TNX-102 SL: Proprietary Eutectic Formulation CNS PORTFOLIO Proprietary cyclobenzaprine HCl eutectic composition stabilizes sublingual tablet formulation Eutectic Cyclobenzaprine-HCl formulation1 (CBP-HCl) Mannitol (inactive) Base particle Base particle (K2HPO4) (K2HPO4) Base particle Cyclobenzaprine

  17. Slide 17: Cyclobenzaprine in Crystals: Poised to Dissolve

    Cyclobenzaprine in Crystals: Poised to Dissolve Planar rings stack better to form more Puckered shape doesn’t stack well forming stable crystals  lower solubility unstable crystals  higher solubility Flexible single bond allows for the Avoidance of antiaromaticity prevents planar planar alignment

  18. Slide 18: TNX-102 SL: CBP Detected in Plasma Within Minutes Following Sublingual Administration

    TNX-102 SL: CBP Detected in Plasma Within Minutes Following Sublingual Administration CNS PORTFOLIO Plasma Concentration Versus Time of TNX-102 SL Compared to CBP-IR 2500 TNX-102 SL 2.8mg 2000 Concentration (ng/L) 1500 1000 CBP-IR 5mg 500 0 0 0.5 1.0 1.5 Time (h) 18 © 2025 Tonix Pharmaceuticals Hold

  19. Slide 19: TNX-102 SL: Transmucosal CBP Bypasses First-Pass Metabolism

    TNX-102 SL: Transmucosal CBP Bypasses First-Pass Metabolism CNS PORTFOLIO The sublingual tablet rapidly disintegrates, dissolves and releases solubilized CBP into the saliva adjacent to the mucosal membrane. TNX-102 SL is CBP enters the brain administered sublingually The base drives formation of CB

  20. Slide 20: Steady State Pharmacokinetics of Daily Sublingual TNX-102 SL at Bedtime

    Steady State Pharmacokinetics of Daily Sublingual TNX-102 SL (5.6 mg) at Bedtime CNS PORTFOLIO Steady State PK (after 20 days dosing) Sleep Time Awake Time 14000 CBP norCBP 12000 Concentration [pg/mL] 10000 8000 6000 With repeat daily dosing of 4000 TNX-102 SL, dynamic peak levels of CBP exceed 2000

  21. Slide 21: TNX-102 SL: Multi-Dose PK Differentiation from Simulated Oral Cyclobenzaprine

    TNX-102 SL: Multi-Dose PK Differentiation from Simulated Oral Cyclobenzaprine (CBP)-Immediate Release (IR) CNS PORTFOLIO Steady State PK (after 20 days dosing) Day 20 TNX-102 SL 5.6 mg v. Simulated Oral IR 10 mg Sleep Time Awake Time 14000 CBP 5.6 sl F106 (Measured) CBP 10.0 po (Simulated) 12000 nor

  22. Slide 22: TNX-102 SL (Cyclobenzaprine HCl Sublingual Tablets) 5.6 mg

    TNX-102 SL* (Cyclobenzaprine HCl Sublingual Tablets) 5.6 mg A unique, sublingual formulation of cyclobenzaprine (CBP) designed to optimize absorption and delivery • Non-opioid analgesic – Tertiary Amine Tricyclic (TAT) • Rapid drug exposure following once-nightly sublingual administration • Reductio

  23. Slide 23: Cyclobenzaprine as an Oral Product for Muscle Spasm and Investigational Sublingual Product

    Cyclobenzaprine (CBP) as an Oral Product for Muscle Spasm and Investigational Sublingual Product for Fibromyalgia CNS PORTFOLIO AMRIX® controlled Flexeril® release oral TNX-102 SL approved in 1977 CBP Postmarketing sublingual TNX-102 SL for the treatment approved for surveillance product NDA of musc

  24. Slide 24: TNX-102 SL (5.6 mg) Fibromyalgia Pivotal Clinical Trial Results

    TNX-102 SL (5.6 mg) Fibromyalgia Pivotal Clinical Trial Results CNS PORTFOLIO • Activity • First pivotal Phase 3 study (RELIEF) reported – December 20201 ‒ Statistically significant reduction in daily pain compared to placebo (p = 0.010) • Second Phase 3 study (RALLY) missed primary endpoint – July

  25. Slide 25: TNX-102 SL: RESILIENT Study Design

    TNX-102 SL: Phase 3 RESILIENT Study Design CNS PORTFOLIO General study characteristics: • Randomized, double-blind, multicenter, placebo-controlled study in fibromyalgia • 33 U.S. sites enrolled 457 participants with fibromyalgia as defined by 2016 Revisions to the 2010/2011 FM Diagnostic Criteria1

  26. Slide 26: RESILIENT Pre-Specified Primary Endpoint

    RESILIENT Pre-Specified Primary Endpoint CNS PORTFOLIO Summary1 • TNX-102 SL demonstrated statistically significant improvement in mean weekly pain scores over placebo at Week 14 • P-value of 0.00005 is highly statistically significant Additional Findings • Cohen’s d effect size 0.38 • All pre-speci

  27. Slide 27: RESILIENT Primary Outcome Measure

    RESILIENT Primary Outcome Measure Reduction in Widespread Pain Weekly Average of Daily Diary NRS Ratings of Average Pain Over Prior 24 Hours 0 Placebo (N=225) TNX-102 SL (N=231) -0.2 LS mean (SE) change in NRS pain score -0.4 -0.6 -0.8 * -1 -1.2 *** -1.4 *** -1.6 *** -1.8 *** *** *** ** *** ** -2 **

  28. Slide 28: Summary of Key Secondary Endpoints

    Summary of Key Secondary Endpoints CNS PORTFOLIO Endpoint1 P-value Effect Size2 Patient Global Impression of Change (PGIC) p = 0.00013 -- Fibromyalgia Impact Questionnaire – Symptoms Domain p = 0.000002 ES = 0.44 Fibromyalgia Impact Questionnaire – Function Domain p = 0.001 ES = 0.30 PROMIS Sleep Di

  29. Slide 29: Safety and Tolerability

    Safety and Tolerability CNS PORTFOLIO • Completion Rate (safety population): TNX-102 SL 81.0% and Placebo 79.2% • No new safety signals observed • Only systemic adverse events (AEs) at rate ≥ 3.0% (TNX-102 SL v. Placebo) ‒ COVID-19 (4.3% v. 3.1%), somnolence (3.0% v. 1.3%), and headache (3.0% v. 1.8

  30. Slide 30: RESILIENT Safety Summary

    RESILIENT Safety Summary CNS PORTFOLIO Treatment-Emergent Adverse Events (TEAEs) at Rate of ≥ 3% in Either Treatment Group System Organ Class TNX-102 SL Placebo Total* Preferred Term N=231 N=226 N=457 Systemic Adverse Events COVID-19 10 (4.3%) 7 (3.1%) 17 (3.7%) Somnolence 7 (3.0%) 3 (1.3%) 10 (2.2%

  31. Slide 31: RESILIENT Analysis by Sensory Adverse Events

    RESILIENT Analysis by Sensory Adverse Events (AEs) TNX-102 SL group divided for presence/absence of 3 sensory AEs CNS PORTFOLIO • AEs of oral numbness, oral tingling, and bitter aftertaste named ‘Sensory AEs’* F307 Primary Endpoint: Pain Reduction by Sensory AEs (Yes/No) Weekly Averages of Daily Dia

  32. Slide 32: TNX-102 SL Showed Activity on Pain, Sleep and Fatigue and was Generally Well Tolerated

    TNX-102 SL Showed Activity on Pain, Sleep and Fatigue and was Generally Well Tolerated in the RESILIENT Study1 CNS PORTFOLIO Drug TNX-102 SL (sublingual cyclobenzaprine)1 Class Tertiary Amine Tricyclic Mechanism Antagonist at 4 post-synaptic receptors2 Pain reduction (primary endpoint) + Fibromyalgi

  33. Slide 33: TNX-102 SL: Sublingual Formulation Designed for Long-Term Daily Administration at Bedtime

    TNX-102 SL: Sublingual Formulation is Designed for Long-Term Daily Administration at Bedtime and Transmucosal Absorption CNS PORTFOLIO • TNX-102 SL: Proprietary sublingual formulation of cyclobenzaprine (CBP) with transmucosal absorption ‒ Rapid systemic exposure of CBP – Tertiary Amine Tricyclic (T

  34. Slide 34: Summary and Conclusions

    Summary and Conclusions CNS PORTFOLIO • Neither oral cyclobenzaprine nor oral amitriptyline provide durable reduction in fibromyalgia pain ‒ Short-term (1 month), but not long-term (3 months) benefit ‒ Chasing loss-of-effect with higher and higher doses was of no benefit • TNX-102 SL (cyclobenzaprin

  35. Slide 35: Thank You

    THANK YOU © 2024 Tonix Pharmaceuticals Holding Corp.

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