TNX-102 SL (cyclobenzaprine HCl sublingual)

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.

Formulations

TNX-102 SL (cyclobenzaprine HCl sublingual) for Fibromyalgia

ApprovedApprovedFibromyalgia indication →

Lead, FDA-approved indication for TNX-102 SL (sublingual cyclobenzaprine HCl), marketed as TONMYA. On 15 August 2025 the FDA approved Tonmya for the treatment of fibromyalgia in adults — the first new FDA-approved fibromyalgia therapy in more than 15 years and a first-in-class non-opioid, once-nightly bedtime analgesic. Recommended dosage is 5.6 mg (two 2.8 mg sublingual tablets) once daily at bedtime, titrated from one 2.8 mg tablet for the first 2 weeks. The therapeutic rationale is bedtime treatment of non-restorative sleep to reduce the chronic widespread (nociplastic) pain of fibromyalgia, via cyclobenzaprine's multifunctional antagonism at 5-HT2A, H1, alpha-1 and M1 receptors. Approval was supported by two double-blind, randomized, placebo-controlled pivotal Phase 3 trials enrolling ~960 patients combined: RELIEF (NCT04172831; topline 7 Dec 2020; primary endpoint of Week-14 reduction in daily diary average pain NRS met, p=0.010) and RESILIENT (NCT05273749; topline 20 Dec 2023; p=0.00005, with significance across all six key secondary endpoints; published in Pain Medicine, 9 Jul 2025). FDA granted Fast Track designation for fibromyalgia (announced 25 Jul 2024); the NDA was accepted on 17 Dec 2024 with a PDUFA action date of 15 Aug 2025. Tonix's broader fibromyalgia program also included an earlier Phase 2b study (AFFIRM) and a Phase 3 RALLY study (NCT04172843) that was stopped at a pre-planned interim analysis for futility; only the two approval-enabling pivotal trials are tracked here.

TNX-102 SL (cyclobenzaprine HCl sublingual) for Post-traumatic stress disorder

DiscontinuedDiscontinuedPost-traumatic stress disorder indication →

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.)

TNX-102 SL (cyclobenzaprine HCl sublingual) for Acute Stress Disorder

Phase 2RecruitingAcute Stress Disorder indication →

Investigator-initiated Phase 2 study (OASIS, NCT06636786) of bedtime TNX-102 SL for the early reduction of acute stress reaction (ASR) and acute stress disorder (ASD), and prevention of adverse post-traumatic neuropsychiatric sequelae (including PTSD), in recent trauma survivors. The trial is led by the University of North Carolina (UNC) Institute for Trauma Recovery under a Physician-Initiated IND, funded by a ~$3 million U.S. Department of Defense grant, with Tonix Pharmaceuticals supplying study drug (CT.gov-listed collaborator alongside McLean Hospital and Cooper University Health Care). Approximately 180 motor-vehicle-collision survivors are randomized in the emergency department to a two-week course of TNX-102 SL (an initial 2.8 mg half-dose in the ED followed by 5.6 mg nightly for 14 days) versus placebo. Primary endpoint is change in the 14-item Acute Stress Disorder Scale at weeks 1 and 3. The study is recruiting; topline data are expected in the second half of 2026. No FDA expedited designation has been reported for this indication. This program is distinct from, and developmentally separate from, the discontinued TNX-102 SL PTSD-treatment program.

TNX-102 SL (cyclobenzaprine HCl sublingual) for Major depressive disorder

Phase 2RecruitingMajor depressive disorder indication →

New Phase 2 monotherapy program in major depressive disorder (MDD). After a positive Type B Pre-IND meeting with the FDA (announced 18 Sep 2025), Tonix received FDA clearance of its IND and announced the potentially-pivotal Phase 2 HORIZON study on 24 Nov 2025. HORIZON (NCT07621237) is a 6-week, randomized, double-blind, placebo-controlled, parallel-group study of TNX-102 SL 5.6 mg (2 x 2.8 mg) taken sublingually at bedtime versus placebo as first-line monotherapy in adults (>=18 y) with a moderate-to-severe major depressive episode; ~360 participants at ~30 US sites; primary endpoint is change from baseline in MADRS total score at Week 6, with secondary endpoints covering global impression, anxiety, and sleep-disturbance measures. The therapeutic hypothesis is that bedtime H1/5-HT2A/alpha-1 antagonism targets the disturbed sleep of depression (described by the company as a novel mechanism of action); the MDD rationale cites exploratory depressive-symptom signals on the MADRS from the PTSD program and on the Beck Depression Inventory-II from the fibromyalgia program. TNX-102 SL is already FDA-approved as TONMYA for fibromyalgia (15 Aug 2025); MDD is a separate development indication and is not the lead/approved indication. As of this research the trial is registered as recruiting with an estimated study start of June 2026.

Clinical trials