Tonix Pharmaceuticals : TNX-102 SL for Fibromyalgia and Long COVID

TNX-102 SL

Fibromyalgia, Long COVID, and Acute Stress Disorder

NASDAQ: TNXP

Version P0540 March 13, 2023 (Doc 1399)

© 2024 Tonix Pharmaceuticals Holding Corp.

Tonmya (TNX-102 SL)*

Cyclobenzaprine HCl (Protectic®)

Non-opiate analgesic

A unique, sublingual formulation of cyclobenzaprine designed for bedtime dosing with sublingual delivery and transmucosal absorption, bypassing 1st pass metabolism

Potent binding and antagonist activities at the serotonergic-5-HT2A,adrenergic-α1,histaminergic-H1, and muscarinic-M1 cholinergic receptors to facilitate restorative sleep

Innovative and proprietary PROTECTIC® Rapid drug exposure following once nightly sublingual administration

Differentiators:

Relative to Oral Cyclobenzaprine

• Lower daytime exposure
• Avoids first-pass metabolism
• Reduces risk of pharmacological interference from major metabolite

Relative to Standard of Care

• Potential for better tolerability while maintaining efficacy
• Not scheduled, without recognized abuse potential

Patents Issued

Indications Most Recently Pursued

Fibromyalgia

Status: Two potential pivotal Phase 3 studies completed

• Positive Phase 3 study (RELIEF) completed
• Second Phase 3 study (RALLY) missed primary endpoint
• Positive confirmatory Phase 3 study (RESILIENT) completed

Next Steps: Type B Pre-NDA meeting with FDA scheduled for 2Q 2024

Fibromyalgia-Type Long COVID

Status: Phase 2

• Phase 2 study (PREVAIL) completed
• Topline results reported 3Q 2023

Next Steps: Meeting with FDA regarding primary endpoint

Acute Stress Reaction/ Acute Stress Disorder

• Phase 2 ready investigator-initiated study
• Department of Defense funded/ UNC will perform study Next Steps: Expect to start Phase 2 in 1Q 2024

*TNX-102 SL has not been approved for any indication.

© 2024 Tonix Pharmaceuticals Holding Corp.

About Fibromyalgia

Fibromyalgia is a chronic pain disorderresulting from amplified sensory and pain signaling within the CNS1

Fibromyalgia is a syndromecomprised of the symptoms: chronic widespread pain, nonrestorative sleep, and fatigue

Fatigue

Multisite	Non-Restorative Sleep
pain

Fibromyalgia is considered a chronic overlapping pain condition (COPC)

• the only COPC with any FDA-approved drugs3

Fibromyalgia is the prototypic nociplastic syndrome

1American Chronic Pain Association (www.theacpa.org, 2019)

3CFS/ME = chronic fatigue syndrome/myalgic encephalomyelitis

3The three drugs with FDA approval for the treatment of fibromyalgia: Pregabalin (Lyrica®); Duloxetine (Cymbalta®); Milnacipran (Savella®)

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© 2024 Tonix Pharmaceuticals Holding Corp.

Fibromyalgia is a Large, Underserved and Dissatisfied population

• ~10 million U.S. adults are affected - predominantly women1,2
• • Debilitating and life altering condition
  • Significant economic cost
• Patients are dissatisfied, despite three FDA approved drugs3,4
• • Average patient has 20 physician office visits per year2
  • Typical for patients to rotate between drugs3
  • Polypharmacy (multiple drugs at the same time) common3
  • Estimated that >22 million prescriptions are issued for the treatment of fibromyalgia (on- and off- label usage) each year5,6
• Prescription opiate use declining because of availability
• • Unknown number of patients using 'street drugs'
• No new Rx product since 2009

1American College of Rheumatology (www.ACRPatientInfo.org accessed May 7, 2019) - prevalence rate of 2-4% for U.S. adult population (~250 million)

2Vincent A, et al. Arthritis Care Res (Hoboken). 2013 65(5):786-92. doi: 10.1002; diagnosed prevalence rate was 1.1% of adult population or 50% of the prevalent population

3Robinson RL, et al. Pain Med. 2012 13(10):1366-76. doi: 10.1111; ; 85% received drug treatment

4The three drugs with FDA approval for the treatment of fibromyalgia: Pregabalin (Lyrica); Duloxetine (Cymbalta); Milnacipran (Savella)

5Product sales derived from IMS MIDAS; IMS NDTIused to factor usage for fibromyalgia; data accessed April 2015.

6Market research by Frost & Sullivan, commissioned by Tonix, 2011

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© 2024 Tonix Pharmaceuticals Holding Corp.

Poor Sleep and Pain have Bi-directional Reinforcing Effects1

• Poor sleep and pain form a vicious cyclein driving fibromyalgia decompensation
• • Can't sleep → worse pain / In pain → can't sleep
  • Poor sleep and pain contribute to persistence, chronicity and severity
  • Syndrome includes symptoms of fatigue and brain fog
• Treating sleep disturbance in fibromyalgia has the potential to break the vicious cycle
• • Potential to remove an obstacle to recovery
  • Using the right medicine is important - some sedative/hypnotics don't work1,2

Fatigue PAIN

BAD	Brain Fog
SLEEP

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1Moldofsky H, et al. J Rheumatol. 1996;23:529-533.	5
2Grönbald M, et al. Clin Rheumatol. 1993;12(2):186-191	© 2024 Tonix Pharmaceuticals Holding Corp.

Fibromyalgia Program Status
Tonmya *
(TNX-102 SL)	Fibromyalgia	Positive 2nd Phase 3 Topline Results Reported 4Q'23
Cyclobenzaprine Protectic®

Sublingual Tablets

Positive Phase 3 study (RELIEF) reported - December 20201

Second Phase 3 study (RALLY) missed primary endpoint - July 2021

Positive 2nd (confirmatory) Phase 3 study (RESILIENT) reported - December 2023

Next Steps:

• Type B Pre-NDA meeting scheduled with FDA in 2Q'24
• NDA filing expected 2H'24
• FDA decision on NDA approval expected 2H'25

*Tonmya is conditionally accepted by the U.S. Food and Drug Administration (FDA) as the tradename for TNX-102 SL for the management of fibromyalgia. Tonmya has not been approved for any indication.

1Lederman S, et al. Arthritis Care Res (Hoboken). 2023 Nov;75(11):2359-2368. doi: 10.1002.

© 2024 Tonix Pharmaceuticals Holding Corp.

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Tonmya (TNX-102 SL): Phase 3 RESILIENT Study Design

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

Primary Endpoint:

• Change from baseline to Week 14 (TNX-102 SL vs. placebo) in weekly averages of daily diary average pain severity score
• Primary Endpoint, p-value = 0.00005

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TNX-102 SL once-daily at bedtime

5.6 mg (2 x 2.8 mg tablets)*

Placebo once-daily at bedtime

14 weeks

*Two-weekrun-in at 2.8 mg dose at bedtime

followed by 12 weeks at 5.6 mg dose

ClinicalTrials.gov Identifier: NCT05273749

Study Title: A Phase 3 Study to Evaluate the Efficacy and Safety of TNX-102 SL Taken Daily in Patients With Fibromyalgia (RESILIENT)

Trial ID: TNY-CY-F307 ('RESILIENT')

1Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Häuser W, Katz RL, Mease PJ, Russell AS, Russell IJ, Walitt B. 2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria. Semin Arthritis Rheum. 2016; 46(3):319-329.

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© 2024 Tonix Pharmaceuticals Holding Corp.

RESILIENT Summary of Endpoints

Endpoint	P-value	Effect Size (ES)
Primary Endpoint
Daily Diary Pain ratings	p = 0.00005	ES = 0.38
Key Secondary Endpoints
Patient Global Impression of Change (PGIC), responders	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 Disturbance instrument	p = 0.0000001	ES = 0.50
PROMIS Fatigue instrument	p = 0.00009	ES = 0.37
Diary Sleep Quality ratings	p = 0.0007	ES = 0.32

*In order of statistical serial gate-keeping hierarchy (or, "waterfall") to control overall Type 1 error **Statistical significance met

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© 2024 Tonix Pharmaceuticals Holding Corp.

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)
Score	-0.2
-0.4
Pain	-0.6
	*
in NRS	-0.8
-1
Change
-1.2		***
-1.4			***
(SE)
-1.6
LS Mean				***
-1.8				***			**
				***	***			**
-2					***	**	**	***	***	*p<0.01; **p<0.001; ***p<0.0001
	-2.2
	0	1	2	3	4	5	6	7	8	9	10	11	12	13	14

Week of Study

Week 14 LS mean (SE) change from baseline for TNX-102 SL -1.82 (0.12) and for placebo -1.16 (0.12); LSMD from placebo -0.65 (0.16); p=0.00005#

#Based on Mixed Model Repeated Measures with Multiple Imputation, with fixed categorical effects of treatment, center, study week, and treatment by study week interaction, as well as baseline value and baseline value-by-study week interaction. Abbreviations: LS, least squares; LSMD, least squares mean difference; NRS, numerical rating scale; SE, standard error

© 2024 Tonix Pharmaceuticals Holding Corp.

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RESILIENT Continuous Pain Responder Graph

	100						Placebo		TNX-102 SL
	90
				30% Responders#
	80				(45.9% vs 27.1%)
				p < 0.001
of Subjects	70
60
50								50%
Percent	40
						Responders#
30							(22.5% vs. 13.3%)
	20							p = 0.011
	10
	0
	≥ 0	≥ 10%	≥ 20%	≥ 30%	≥ 40%	≥ 50%	≥ 60%	≥ 70%	≥ 80%	≥ 90%	≥ 100%
					Percentage Redution in Pain

#Analyses: Pearson's Chi Squared test for equality of proportions

Abbreviations: CI, confidence interval; DIP, difference in proportions ^pre-specified analyses but not key secondary analyses

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© 2024 Tonix Pharmaceuticals Holding Corp.