NEW YORK—Tonix Pharmaceuticals, Inc. Holding Corp. has announced the development of a controlled release formulation of tianeptine, TNX-601 CR (tianeptine oxalate controlled release) tablets designed for once-daily dosing. This news comes after the completion of a Phase 1 study evaluating the pharmacokinetics (PK) of different prototypes.
“We are pleased to have the results of this Phase 1 study which enabled us to select a formulation for continued development of TNX-601 CR as a once-daily medicine. We believe the six periods of single-dose testing in each of the 12 volunteers confirmed the favorable safety profile of the proprietary oxalate salt of tianeptine,” said Seth Lederman, M.D., Tonix’s president and chief executive officer.
Tonix plans to develop TNX-601 CR for major depressive disorder, in addition to post-traumatic stress disorder (PTSD). The company plans to start the first efficacy trial ex-U.S. in 2020, and to request a pre-IND meeting with the U.S. Food and Drug Administration (FDA) in the first half of 2020.
“We are also excited to announce the pursuit of the depression indication with TNX-601 CR as we believe this development path can leverage the established efficacy and safety of the tianeptine sodium IR tablets as a treatment for depression outside of the U.S. Depression is a well-established commercial market and despite multiple approved products in the U.S., there remains significant interest in new treatments, particularly for medicines that modulate the glutamatergic system,” Lederman noted. “The tianeptine IR product marketed ex-U.S. is reported to have substantial anti-anxiety effects in depression, and low incidence of sexual side effects. Once-daily dosing is believed to be an advantage over three times a day dosing for adherence.”
Tianeptine sodium (amorphous) immediate release has been available for decades in Europe, Russia, Asia and Latin America for the treatment of depression, and has an established safety profile from decades of use in these jurisdictions. Currently there is no tianeptine-containing product approved in the U.S., and no controlled release (CR) tianeptine product approved in any jurisdiction.
Tonix has discovered a novel oxalate salt of tianeptine that reportedly may provide improved stability, consistency and manufacturability compared to known forms of tianeptine. Tianeptine is believed to work in depression as a modulator of the glutamatergic system. Tianeptine modulates the glutamatergic system indirectly since it doesn’t interact with NMDA, AMPA or kainate receptors. In animals, tianeptine has been shown to reverse the adverse neuroplastic changes that are observed during periods of stress and elevated corticosteroid exposure.
Tianeptine and its MC5 metabolite are weak mu-opioid receptor (MOR) agonists. Neither tianeptine nor MC5 have been shown to bind other neurotransmitter receptors. Tianeptine’s reported pro-cognitive and anxiolytic effects, as well as its ability to attenuate the neuropathological effects of excessive stress responses, suggest that it may be used to treat PTSD by a different mechanism of action than Tonix’s TNX-102 SL.
The completed open-label Phase 1 PK and formulation selection study, conducted outside of the U.S., compared the bioavailability and safety of TNX-601 immediate release (IR) and different CR prototype tablets with the reference product, Stablon (tianeptine sodium) IR tablets, in 12 healthy male and female volunteers over six different dosing periods. The study also evaluated the PK profile of tianeptine and its active metabolite, MC5. Tonix believes that the Phase 1 study demonstrated that TNX-601 CR was well tolerated and that the side effects were consistent with the known safety profile of tianeptine sodium.
Tonix also recently noted that the European Patent Office (EPO) has issued European Patent No. 2968992 to the company on December 11. This patent, “Eutectic Formulations of Cyclobenzaprine Hydrochloride and Mannitol,” includes 14 claims directed to compositions comprising eutectics of cyclobenzaprine hydrochloride and mannitol, and methods of making those compositions. This patent is expected to provide Tonix with market exclusivity until 2034.
“The issuance of this European patent is an important step forward in our efforts to broaden our intellectual property estate on a global basis for TNX-102 SL,” commented Lederman in a press release.
Tonix’s proprietary eutectic formulation of cyclobenzaprine, or TNX-102 SL, is designed for chronic sublingual (under-the-tongue) administration daily at bedtime. The company believes that this facilitates transmucosal absorption of cyclobenzaprine and bypasses first pass liver metabolism.
Currently marketed cyclobenzaprine drug products are limited to short-term use (two to three weeks) and formulated for oral ingestion, which results in significant liver metabolism. Sublingual TNX-102 SL reportedly has a different PK profile than marketed oral cyclobenzaprine drug products. TNX-102 SL is being developed as a treatment for four indications: PTSD, fibromyalgia, agitation in Alzheimer’s disease and alcohol use disorder. The current oral cyclobenzaprine products are only indicated for relief of muscle spasms.