TNX-102 SL · program
TNX-102 SL (cyclobenzaprine HCl sublingual) for Post-traumatic stress disorder
- Breakthrough Therapy
Indications for TNX-102 SL: Fibromyalgia · Approved Acute Stress Disorder · Phase 2 Major depressive disorder · Phase 2 Post-traumatic stress disorder · Discontinued
Phase 3 bedtime monotherapy program in PTSD (TNX-102 SL 5.6 mg sublingual). FDA granted Breakthrough Therapy designation for PTSD on 19 Dec 2016. The Phase 2 AtEase study (NCT02277704) missed its primary CAPS-5 endpoint at Week 12 for the 5.6 mg dose. Two pivotal Phase 3 studies followed: HONOR (NCT03062540) was stopped at a pre-planned interim analysis (Jul 2018) for inadequate separation on the primary CAPS-5 endpoint, and RECOVERY (NCT03841773) missed its primary CAPS-5 endpoint (20.7 vs 18.5 unit reduction, p=0.343; reported 21 Dec 2020) and was terminated. A planned follow-on Phase 2 (NCT05372887) was withdrawn without enrollment in 2022 for business reasons. Tonix deprioritized the PTSD indication in its 2023 pipeline update (delaying a planned Kenya study) and redirected resources to fibromyalgia, for which TNX-102 SL (TONMYA) was FDA-approved on 15 Aug 2025. The PTSD program is treated here as discontinued/dormant. (An investigator-initiated, DoD-funded Phase 2 study, OASIS, for acute stress reaction/prevention of post-traumatic sequelae is a distinct effort and is not part of this PTSD treatment program.)
Development timeline
- Tonix 2023 pipeline prioritization deprioritized PTSD (delaying a planned Kenya study) to focus on fibromyalgia and other CNS programs; the PTSD treatment program has remained dormant. Earlier follow-on Phase 2 NCT05372887 was withdrawn (n=0) in 2022.↗
- missedPhase 3 RECOVERY missed its primary CAPS-5 endpoint (p=0.343); PTSD program later deprioritized.↗
- missedPhase 3 HONOR stopped at interim for inadequate separation on the primary CAPS-5 endpoint in military-related PTSD.↗
- FDA granted Breakthrough Therapy designation to TNX-102 SL for PTSD; company described it as Phase 3-ready.↗
- Phase 2 AtEase study (NCT02277704, n=245) completed; primary CAPS-5 change at Week 12 for TNX-102 SL 5.6 mg vs placebo was not statistically significant, with sleep-related signals.
Readouts
- 2020-12-21ReportedTopline datamissedNCT03841773
Phase 3 RECOVERY missed its primary CAPS-5 endpoint (p=0.343); PTSD program later deprioritized. ↗
- 2018-07-27ReportedTopline datamissedNCT03062540
Phase 3 HONOR stopped at interim for inadequate separation on the primary CAPS-5 endpoint in military-related PTSD. ↗
Clinical trials in Post-traumatic stress disorder
NCT05372887TNX-CY-P308Phase 2Discontinued
A Phase 2, Double-Blind, Randomized, Multicenter, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Daily Bedtime TNX-102 SL in Participants With PTSD
terminatedprimaryMean change from baseline in total CAPS-5 score at Week 12
Withdrawn before any participants were enrolled (actual enrollment 0); registry reason 'stopped due to business reasons.' No results generated.
NCT03841773TNX-CY-P302Phase 3Discontinuedn=192
A Phase 3, Double-Blind, Randomized, Multicenter, Placebo-Controlled Study to Evaluate the Efficacy and Safety of TNX-102 SL in Participants With PTSD Taken Daily at Bedtime (RECOVERY)
missedprimaryMean change from baseline in total CAPS-5 score at Week 12 — 20.7-unit reduction (TNX-102 SL) vs 18.5-unit (placebo) (0.343)
Primary endpoint not met: TNX-102 SL 5.6 mg did not separate from placebo on CAPS-5 at Week 12 (p=0.343) in the modified ITT population (n=163 of 192 randomized). Nominal separation on CGI-Severity (p=0.024) and PGIC (p=0.007) and a trend on PROMIS Sleep Disturbance (p=0.055). Study terminated; PTSD program subsequently deprioritized.
NCT03062540TNX-CY-P301Phase 3Discontinuedn=358
A Phase 3, Double-Blind, Randomized, Multicenter, Placebo-Controlled Study to Evaluate the Efficacy and Safety of TNX-102 SL Taken Daily at Bedtime in Patients With Military-Related PTSD (HONOR)
missedprimaryMean change from baseline in total CAPS-5 score at Week 12
Stopped early at a pre-specified interim analysis of the first 274 (50%) randomized patients for inadequate separation from placebo on the primary CAPS-5 endpoint at Week 12 (study continuation threshold not met). Meaningful improvement in overall PTSD symptoms was observed at Week 4 but not sustained to Week 12 in the overall population.
NCT02277704TNX-CY-P201Phase 2Completedn=245
A Phase 2, Double-Blind, Randomized, Multicenter, Placebo-Controlled Study to Evaluate the Efficacy and Safety of TNX-102 SL Taken at Bedtime in Subjects With Military-Related PTSD and Related Conditions (AtEase)
missedprimaryMean change from baseline in total CAPS-5 score at Week 12 (TNX-102 SL 5.6 mg vs placebo)
Three-arm study (2.8 mg, 5.6 mg, placebo). Primary CAPS-5 change at Week 12 for the 5.6 mg dose vs placebo was not statistically significant; early and sustained improvement in sleep (CAPS-5 sleep-disturbance item) was associated with TNX-102 SL, supporting advancement of the 5.6 mg dose to Phase 3.
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| TNX-102 SL (TONMYA) sublingual tabletsublingual transmucosal disintegrating tablet (bypasses hepatic first-pass metabolism, reducing formation of the long-half-life metabolite norcyclobenzaprine) 2.8 mg starting dose (days 1-14); 5.6 mg target dose (two 2.8 mg tablets, day 15+) once daily at bedtime; maximum 5.6 mg/day | Sublingual | Once nightly | t½ 36 h · Tmax 4.3 h |
Mechanism of action
Cyclobenzaprine is a multifunctional, centrally acting antagonist at several aminergic GPCRs. Reported high-affinity radioligand-binding antagonism at histamine H1 (Ki ~1.3 nM), serotonin 5-HT2A (Ki ~5.2 nM), alpha-1A adrenoceptor (Ki ~5.6 nM) and muscarinic M1 (Ki ~7.9 nM) receptors. In PTSD the therapeutic hypothesis is that bedtime H1/5-HT2A/alpha-1 antagonism improves sleep quality and reduces hyperarousal, with potential disease-modifying effects on sleep-dependent trauma processing. The sublingual formulation is designed to limit the long-lived active metabolite norcyclobenzaprine.
| Target | Action | Affinity |
|---|---|---|
| H1 receptorprimaryHRH1 | Antagonist | Ki 1.3 nMⓘ |
| 5-HT2AHTR2A | Antagonist | Ki 5.2 nMⓘ |
| alpha-1A adrenoceptorADRA1A | Antagonist | Ki 5.6 nMⓘ |
| M1CHRM1 | Antagonist | Ki 7.9 nMⓘ |
← Full TNX-102 SL compound page (identity, identifiers, all indications)
Sources
- AtEase: Phase 2 study of TNX-102 SL in military-related PTSD (NCT02277704) — ClinicalTrials.gov
- Cyclobenzaprine and Its Major Metabolite Norcyclobenzaprine Are Potent Antagonists of Human 5-HT2A, H1 and alpha-Adrenergic Receptors (Daugherty, Gershell, Lederman) — ACR/ARHP Annual Meeting (American College of Rheumatology), 2012
- FDA grants Breakthrough Therapy designation to TNX-102 SL for PTSD — Tonix Pharmaceuticals (GlobeNewswire)
- HONOR: Phase 3 study of TNX-102 SL in military-related PTSD (NCT03062540) — ClinicalTrials.gov
- Phase 2 study of TNX-102 SL in PTSD, withdrawn (NCT05372887) — ClinicalTrials.gov
- RECOVERY: Phase 3 study of TNX-102 SL in PTSD (NCT03841773) — ClinicalTrials.gov
- The Skeletal Muscle Relaxer Cyclobenzaprine Is a Potent Non-Competitive Antagonist of Histamine H1 Receptors — Journal of Pharmacology and Experimental Therapeutics (JPET), 2024
- Tonix announces outcome of interim analysis for Phase 3 HONOR study (stop for inadequate separation) — Tonix Pharmaceuticals / IR
- Tonix announces pipeline prioritization update for 2023 (PTSD/Kenya study delayed) — Tonix Pharmaceuticals / IR
- Tonix reports topline Phase 3 RECOVERY results in PTSD (primary endpoint not met) and outlines future development plans — Tonix Pharmaceuticals / IR
- TONMYA (cyclobenzaprine hydrochloride sublingual tablets) FDA Prescribing Information — DailyMed / U.S. FDA