Tonix Pharmaceuticals is enrolling participants in a Phase 3 trial for fibromyalgia.
For more information, please visit www.thereliefstudy.com or www.clinicaltrials.gov (NCT04172831).

Pipeline
: TNX-102 SL for Fibromyalgia

TNX-102 SL* for Fibromyalgia

Fibromyalgia

Fibromyalgia is a pain disorder.

TNX-102 SL: Development for Bedtime Treatment of Fibromyalgia

Tonix is developing TNX-102 SL* as a potential treatment for the symptoms of Fibromyalgia. It is currently in Phase 3 clinical development. TNX-102 SL targets mechanisms which are associated with disturbed sleep. It is believed that increasing sleep quality in fibromyalgia may facilitate the body's adaptive ability to modulate the perception of pain.

What makes TNX-102 SL unique?

TNX-102 SL is a small, rapidly-disintegrating, under the tongue (sublingual) product candidate containing 2.8 mg of cyclobenzaprine HCl. The unique formulation has been designed to optimize the delivery and absorption of cyclobenzaprine for the therapeutic benefit of improving sleep quality, while minimizing the potential residual effects of oral formulations of cyclobenzaprine. The dose of TNX-102 SL being studied in fibromyalgia is two tablets, or 5.6 mg of cyclobenzaprine each night at bedtime.

Low drug exposure favors the recruitment of high affinity target receptors over lower affinity off-target receptors. Cyclobenzaprine has been shown to have high affinity for three relevant receptor sites (target sites) and is a functional antagonist at all three sites.1

  • Serotonin-2A (5-HT2A) receptor: antagonism is associated with an increase in restorative slow wave sleep (SWS) and a decrease in waking-after-sleep onset2
  • Alpha-1-adrenergic receptor: antagonism is associated with reducing trauma-related nightmares and sleep disturbances3
  • Histamine-1 receptor: antagonism is associated with a decrease in wakefulness and increase in restorative slow wave sleep (SWS) in preclinical studies4

As such, TNX-102 SL is believed to possess a trimodal mechanism of action which may be beneficial in addressing disorders in which sleep disturbances play a central role. In addition, TNX-102 SL is being developed for long-term use, in contrast to oral formulations of cyclobenzaprine which are only approved for 2-3 weeks of daily use. The proposed registration plan for TNX-102 SL for PTSD, agreed to by the FDA, does not require further assessment of abuse and drug dependency potential in clinical or nonclinical study.

Pharmacokinetic studies have shown that TNX-102 SL, after sublingual administration, is distinguished from oral formulations of cyclobenzaprine:

  • Active drug is more rapidly absorbed into the blood, a desired feature for administration at bedtime, when a more rapid onset of action is believed to be beneficial.
  • Sublingual administration avoids first-pass hepatic metabolism, and reduces the formation of the long-lived active metabolite, norcyclobenzaprine (nCBP).
    • In vitro studies have shown that nCBP is a norepinephrine-reuptake inhibitor (NRI),1 and the clinical pharmacology of NRIs indicate that they have a risk of being anxiogenic5 and are associated with 'CNS activating' side-effects (insomnia, sweating, palpitations, tachycardia),6,7 and may interfere with the desired pharmacological action of improved sleep quality. By avoiding first-pass metabolism, and reducing exposure to the long-lived active metabolite, nCBP, TNX-102 SL may mitigate the potential risk of pharmacological interference from nCBP.

Scientific Rationale for TNX-102 SL in Treating Fibromyalgia

Sleep disturbances are frequently experienced by fibromyalgia patients, and evidence suggests that these disturbances may have a role in the chronicity and exacerbation of fibromyalgia Therapies designed to treat sleep disturbances may therefore offer a unique approach to the overall treatment of fibromyalgia symptoms.

Results from earlier clinical trials have provided evidence that TNX-102 SL improves sleep quality in fibromyalgia, another disorder characterized by poor sleep quality.9

Development Status

Phase 3 clinical trials in fibromyalgia

Basis for Exclusivity

TNX-102 SL is covered by a number of issued and pending worldwide patents which cover the eutectic composition of matter, method of use, and pharmacokinetic profile. These patents are owned outright by Tonix Pharmaceuticals, and no obligations are owed to another party.

*TNX-102 SL  (cyclobenzaprine HCl sublingual tablets) is an investigational new drug and has not been approved for any indication.

Click here for Scientific Presentations on TNX-102 SL

  1. Daugherty B, Sullivan G, Gershell L, Lederman S. Serotonin receptor profiles of bedtime pharmacotherapies targeting posttraumatic stress disorder (PTSD) [abstract 728]. Biological Psychiatry. 2015;77(Supplement):271S-272S.
  2. Monti JM. Serotonin control of sleep-wake behavior. Sleep Med Rev. 2011;15(4):269-281.
  3. Hendrickson RC, Raskind MA. Noradrenergic dysregulation in the pathophysiology of PTSD. Exp Neurol. 2016;284(Pt B):181-195.
  4. Krystal AD, Richelson E, Roth T. Review of the histamine system and the clinical effects of H1 antagonists: basis for a new model for understanding the effects of insomnia medications. Sleep Med Rev. 2013;17(4):263-272.
  5. Blier P, Briley M. The noradrenergic symptom cluster: clinical expression and neuropharmacology. Neuropsychiatr Dis Treat. 2011;7(Suppl 1):15-20.
  6. Arnold LM, Hirsch I, Sanders P, Ellis A, Hughes B. Safety and efficacy of esreboxetine in patients with fibromyalgia: a fourteen-week, randomized, double-blind, placebo-controlled, multicenter clinical trial. Arthritis Rheum. 2012;64(7):2387-2397.
  7. Hajos M, Fleishaker JC, Filipiak-Reisner JK, Brown MT, Wong EH. The selective norepinephrine reuptake inhibitor antidepressant reboxetine: pharmacological and clinical profile. CNS Drug Rev. 2004;10(1):23-44.
  8. Pace-Schott EF, Germain A, Milad MR. Sleep and REM sleep disturbance in the pathophysiology of PTSD: the role of extinction memory. Biol Mood Anxiety Disord. 2015;5:3.
  9. Moldofsky H, Gendreau RM, Clauw DJ, Gendreau J, Vaughn B, Daugherty B, Forst A, Sullivan G, Lederman S. Relationship of sleep quality and fibromyalgia outcomes in a phase 2b randomized, double-blind, placebo-controlled study of bedtime, rapidly absorbed, sublingual cyclobenzaprine (TNX-102 SL) [abstract 2307]. Arthritis Rheumatol. 2015;67(suppl 10):2785-2786.