Going right to the head

NEW YORK—It's rare, perhaps, but sometimes an old standby can be repurposed with good effect—which is true of Tonix Pharmaceuticals Holding Corp.’s Phase 2 drug for tension headaches. Tonix, a clinical-stage company developing next-generation medicines for fibromyalgia, post-traumatic stress disorder and episodic tension-type headache, presented nonclinical data from its TNX-201 (dexisometheptene mucate) program in two posters at the 57th Annual scientific meeting of the American Headache Society in Washington, D.C. Tonix is currently evaluating TNX-201 in a Phase 2 proof-of-concept (POC) study in episodic tension-type headache.

The active ingredient in TNX-201, dexisometheptene mucate, contains (R)-isometheptene, or (R)-IMH, a single optical isomer of isometheptene. Racemic IMH, a mixture of both the (R) and (S) isomers, had been widely used as a single-agent prescription medicine and as a component of combination drug products (e.g., Midrin) for many decades in the U.S. for various indications including tension-type headache. IMH was introduced as a pharmaceutical prior to 1962, and no products containing IMH are currently approved by the U.S. Food and Drug Administration (FDA) for any indication. TNX-201 is being developed as a new chemical entity for the treatment of episodic tension-type headache, based on current FDA drug registration requirements.

Dr. Seth Lederman, chairman and CEO at Tonix, points out that the R-isomer is more than seven times as potent as the old racemic mixture. Along with TNK-201, Tonix has two other drugs in the clinic focused on war-related PTSD and fibromyalgia, Lederman points out.

The points made in the poster presentations at the Headache Society meeting, including data from receptor binding studies, taken together with the recent description of a decreased pain threshold in imidazoline-1 receptor (I1R) knockout mice, suggest that I1R may be the primary site of action for racemic IMH’s analgesic effects. Since (R)-IMH, the active ingredient in TNX-201, binds I1R with approximately 60-fold greater affinity than (S)-IMH, TNX-201 may be responsible for the therapeutic effect of racemic IMH.

In anesthetized rats, treatment with (S)-IMH resulted in dose-dependent and statistically significant blood pressure increases that were higher relative to those produced by the (R)-isomer.

In the second abstract (PS58), the effects of (R)-IMH and (S)-IMH were evaluated in two rat models of trigeminal pain which feature aspects of chronic migraine: the inflammatory soup (IS) model and the spontaneous trigeminal allodynia (STA) model. These models had been developed to allow for the testing of therapeutic compounds for migraine. Both of these models experience similar symptoms to human migraine patients such as episodic or chronic trigeminal hypersensitivity, phonophobia, responsiveness to abortive and prophylactic headache treatments and sensitivity to migraine triggers. In the IS model, treatment with 30 mg/kg of (R)-IMH mucate significantly increased trigeminal thresholds at each of the 0.5 hour (hr) (2.3-fold, p<0.01), 1.5 hr (3.0-fold, p<0.01), 2.5 hr (2.9-fold, p<0.001) and 3.5 hr (1.7-fold, p<0.05) time points.

In the STA model, treatment with 30 mg/kg of (R)-IMH mucate significantly increased trigeminal thresholds at the 0.5 hr (7.8-fold, p<0.01), 1.5 hr (4.3-fold, p<0.05), 2.5 hr (4.5-fold, p<0.01), 3.5 hr (8.5-fold, p<0.01) and 24 hr (8.2-fold, p<0.01) time points.

Treatment with 30 mg/kg of (S)-IMH mucate had no effect on trigeminal sensitivity in either the IS or STA models.

“Our findings that TNX-201 selectively modulates a receptor in the central nervous system that appears to regulate pain perception and responses, together with positive data in two rodent models representative of migraine, support the development of TNX-201 as a therapeutic for headache and potentially other pain indications—and one that may be differentiated from currently approved products,” said Dr. Bruce Daugherty, Tonix’s chief scientific officer. “We look forward to reporting the results of our Phase 2 POC study in episodic tension-type headache in the fourth quarter of this year.”

Episodic tension-type headache is the most common type of headache. It is estimated that approximately 30 percent of U.S. adults experience frequent episodic tension-type headaches (one to 15 headaches per month over a three-month period). Tension-type headache pain is often described as a constant pressure on both sides of the head, and typically lasts for several hours. All of the FDA-approved prescription options for tension-type headache contain barbiturates.

Tonix Pharmaceuticals is focused on the development of next-generation medicines for common yet challenging disorders of the central nervous system, characterized by chronic disability, inadequate treatment options, high utilization of healthcare services and significant economic burden. Tonix’s Tonmya is currently being evaluated in the Phase 3 AFFIRM study in fibromyalgia. TNX-102 SL, the same proprietary product candidate as Tonmya, is currently being evaluated in the Phase 2 AtEase study in post-traumatic stress disorder. A Phase 2 proof-of-concept study of TNX-201 in episodic tension-type headache is ongoing.

TNX-102 SL and TNX-201 are Investigational New Drugs and have not been approved for any indications.