Tonix Pharmaceuticals Announces Enrollment Initiated in Mass General Brigham Phase 2 Investigator-Initiated Study of TNX-1900 (Intranasal Potentiated Oxytocin) for Bone Health in Children with Autism Spectrum Disorder Ch

TONIX PHARMACEUTICALS HOLDING CORP. 8-K

Tonix Pharmaceuticals

Announces Enrollment Initiated in Mass General Brigham Phase 2 Investigator-Initiated Study of TNX-1900 (Intranasal

Potentiated Oxytocin) for Bone Health in Children with Autism Spectrum Disorder

Children with Autism Spectrum Disorder are at Risk

for Low Bone Density

Preliminary Data Suggest that the Administration

of Oxytocin May Favorably Impact Bone Formation and Strength

Recent Meta-Analysis Reported that Plasma Oxytocin

Levels Tend to be Lower in Children with Autism Spectrum Disorder than Controls1

CHATHAM, N.J., November

13, 2023 - Tonix Pharmaceuticals Holding Corp. (Nasdaq: TNXP) (Tonix or the Company), a biopharmaceutical company with

marketed products and a pipeline of development candidates, today announced that

the first participant was enrolled in an investigator-initiated Phase 2 study of TNX-1900 (intranasal potentiated oxytocin) for

improving bone health in children with autism spectrum disorder (ASD), named the BOX study, at Massachusetts General Hospital (MGH). The

aim of this Department of Defense-funded study is to investigate the efficacy and safety of TNX-1900 as a novel therapeutic agent to increase

bone density and improve bone structure and strength in children with ASD. Tonix is providing active drug and placebo for the BOX study

as part of a drug donation agreement with MGH. MGH is the sponsor of the trial, which is being conducted under an investigator-initiated

investigational new drug (IND) application.

in ASD is a serious problem," said Seth Lederman, M.D., Chief Executive Officer of Tonix Pharmaceuticals. "Intranasal potentiated

oxytocin is a potential treatment option that addresses the biology of bone loss specific to ASD which is different from osteoporosis

in post-menopausal women. Intranasal oxytocin has a long history of being tested for the treatment of ASD, but results have been inconsistent.

Tonix's magnesium-potentiated intranasal oxytocin is designed to improve consistency in clinical effects, because it reduces the

high-dose' inhibition seen in the inverted U' dose response in animals."2

Misra, M.D., MPH, Chief, Division of Pediatric Endocrinology, Department of Pediatrics, Mass General for Children, and principal investigator

of the study said, "The childhood and adolescent years are critical for bone mass accrual towards achievement of peak bone mass,

a key determinant of future bone health and fracture risk. Preliminary data show that over a four-year period, children with ASD fail

to catch-up with typically developing children for bone health measures despite optimizing calcium and vitamin D intake3. The

difference between these groups often becomes more drastic over time."

Elizabeth A. Lawson, M.D.,

M.M.Sc., Director, Interdisciplinary Oxytocin Research Program in the Neuroendocrine Unit, Department of Medicine, MGH, who is a co-investigator

on the study continued, "Preclinical studies indicate that, in addition to its known central prosocial effects,4 oxytocin

is an important mediator of bone homeostasis, promoting bone formation over resorption.5-7 Pilot data indicate strong associations

between low levels of oxytocin and worse bone health in both sexes and across clinical populations, supporting the critical role of oxytocin

in bone metabolism."8-11

studies and some clinical trials have shown prosocial effects of oxytocin in individuals with autism," reported Ann Neumeyer, M.D.,

Medical Director of Lurie Center for Autism, Department of Pediatrics and Neurology, Mass General for Children and also a co-investigator.

"This research study will further investigate effects of oxytocin on social impairment associated with autism as a secondary outcome."12

Dr. Lederman continued,

"Given the increasing prevalence of ASD in children and its association with impaired bone health, lower oxytocin levels in those

with ASD than neurotypical controls, and preclinical data showing that oxytocin can favorably impact bone health, a study examining the

role of oxytocin in improving bone health in children with ASD is both timely and essential."

Phase 2 investigator-initiated BOX study is a randomized, placebo-controlled study to evaluate the effects of twice daily administration

of TNX-1900 on bone measures in children with ASD. Study subjects, ages six to 18 years old, will be randomized 1:1 to receive TNX-1900

twice per day or placebo for 12 months in the double-blind phase, followed by a six-month open label phase during which all study subjects

will receive TNX-1900 twice daily. The primary endpoint is the difference between TNX-1900 compared to placebo groups in 12-month change

in whole body less head bone mineral density Z-scores. A Z-score compares one's bone density to the average bone density of age

and gender matched controls.

TNX-1900 (intranasal potentiated oxytocin)

is a proprietary formulation of oxytocin in development as a candidate for prevention of chronic migraine and other conditions. In 2020,

TNX-1900 was acquired from Trigemina, Inc. who had licensed the technology underlying the composition and method from Stanford University.

TNX-1900 is a drug-device combination product, based on an intranasal actuator device that delivers oxytocin into the nasal cavity. Oxytocin

is a naturally occurring human peptide hormone that also acts as a neurotransmitter within the central nervous system (CNS). Oxytocin

has no recognized addiction potential. It has been observed that low oxytocin levels in the body are associated with increases in migraine

headache frequency, and that increased oxytocin levels are associated with fewer migraine headaches. Certain other chronic pain conditions

are also associated with decreased oxytocin levels. Migraine attacks are caused, in part, by the activity of pain-sensing trigeminal neurons

which, when activated, release calcitonin gene-related peptide (CGRP) which binds to receptors on other nerve cells and starts a cascade

of events that is believed to result in headache. Oxytocin when delivered via the nasal route, concentrates in the trigeminal system1

resulting in binding of oxytocin to receptors on neurons in the trigeminal system, inhibiting the release of CGRP and transmission of

pain signals returning from the site of CGRP release.2 Blocking CGRP release is a distinct mechanism compared with CGRP antagonist

and anti-CGRP antibody drugs, which block the binding of CGRP to its receptor. With TNX-1900, the addition of magnesium to the oxytocin

formulation enhances oxytocin receptor binding3 as well as oxytocin's inhibitory effects on trigeminal neurons and resultant

craniofacial analgesic effects, as demonstrated in animal models4. Intranasal oxytocin has been shown to be well tolerated

in several clinical trials in both adults and children5. Targeted nasal delivery results in low systemic exposure and lower

risk of non-CNS, off-target effects, which could potentially occur with systemic CGRP antagonists such as anti-CGRP antibodies6.

For example, CGRP has roles in dilating blood vessels in response to ischemia, including in the heart. The Company believes nasally-targeted

delivery of oxytocin could translate into selective blockade of CGRP release from neurons in the trigeminal ganglion and not throughout

the body, which could be a potential safety advantage over systemic CGRP inhibition. In addition, daily dosing is more rapidly reversible,

in contrast to monthly or quarterly dosing, as is the case with anti-CGRP antibodies, giving physicians and patients greater control.

In addition to chronic migraine, TNX-1900 will be developed for treatment of episodic migraine, binge eating disorder, and craniofacial

pain conditions. Tonix also has a license with the University of Geneva for the use of TNX-1900 in the treatment of insulin resistance

and related conditions.

TNX-2900 is another intranasal potentiated

oxytocin-based therapeutic candidate, being developed for the treatment of Prader-Willi syndrome, or PWS. The technology for TNX-2900

was licensed from the French National Institute of Health and Medical Research. PWS, an orphan condition, is a rare genetic disorder of

failure to thrive in infancy, associated with uncontrolled appetite later in childhood.

1. Yeomans DC, et al. Transl Psychiatry.

2. Tzabazis A, et al. Cephalalgia.

2016. 36(10):943-50.

3. Antoni FA and Chadio SE. Biochem

J. 1989. 257(2):611-4.

4. Cai Q, et al., Psychiatry Clin Neurosci.

2018. 72(3):140-151.

5. Yeomans, DC et al. 2017. US patent US2017368095

6. MaassenVanDenBrink A, et al. Trends

Pharmacol Sci. 2016. 37(9):779-788

Tonix Pharmaceuticals Holding Corp.*

Tonix is a biopharmaceutical company focused

on commercializing, developing, discovering and licensing therapeutics to treat and prevent human disease and alleviate suffering. Tonix

Medicines, our commercial subsidiary, markets Zembrace SymTouch (sumatriptan injection) 3 mg and Tosymra (sumatriptan nasal

spray) 10 mg under a transition services agreement with Upsher-Smith Laboratories, LLC from whom the products were acquired on June 30,

2023. Zembrace SymTouch and Tosymra are each indicated for the treatment of acute migraine with or without aura in adults. Tonix's

development portfolio is composed of central nervous system (CNS), rare disease, immunology and infectious disease product candidates.

Tonix's CNS development portfolio includes both small molecules and biologics to treat pain, neurologic, psychiatric and addiction

conditions. Tonix's lead development CNS candidate, TNX-102 SL (cyclobenzaprine HCl sublingual tablet), is in mid-Phase 3 development

for the management of fibromyalgia, having completed enrollment of a potentially confirmatory Phase 3 study in the third quarter of 2023,

with topline data expected in late December 2023. TNX-102 SL is also being developed to treat fibromyalgia-type Long COVID, a chronic

post-acute COVID-19 condition, and topline results were reported in the third quarter of 2023. TNX-1900 (intranasal potentiated oxytocin),

is in development as a preventive treatment in chronic migraine, and enrollment has completed in a Phase 2 proof-of-concept study with

topline data expected in early December 2023. TNX-1900 is also being studied in binge eating disorder, pediatric obesity and social anxiety