NeurAxon Focusing On Migraine With Aura For nNOS Inhibitor

Based on a post-hoc analysis of a failed Phase II trial, NeurAxon will focus further development of the neuronal nitric oxide synthase inhibitor on the subset of migraine patients who experience aura

NeurAxon will focus development of its migraine candidate NXN-188 on patients with aura based on a post hoc analysis of data from a failed Phase II trial, the company said Sept. 5, after presenting data at the European Headache and Migraine Trust International Congress in London.

NXN-188 is a potential first-in-class small molecule drug with a dual mechanism of action, neuronal nitric oxide synthase (nNOS) inhibition - NeurAxon's area of expertise - and 5-HT agonism, the mechanism of action already used in triptans for the treatment of migraine.

By selectively inhibiting nNOS, the enzyme that produces nitric oxide in the central nervous system, NeurAxon hopes NXN-188 will offer a longer duration of action and better cardiovascular safety profile compared to triptans, CEO Lawrence Bloch said.

The randomized, double-blind, placebo-controlled Phase II study, with 60 patients ages 18 to 65 who met the International Headache Society criteria for migraine, failed to meet the its primary endpoint, reduction in pain at two hours.

Patients treated with NXN-188 experienced a 15 percent greater effect in migraine pain relief at two hours compared to placebo. As a secondary endpoint, patients experienced a 32 percent and 35 percent greater effect versus placebo, respectively, at four and six hours.

A post hoc analysis, however, showed a stronger benefit on pain in patients with a history of aura, a group that included 47 percent of the study patients. Of patients with aura, 22 percent, 48 percent and 68 percent, respectively, experienced relief compared to placebo at two, four and six hours.

"We clearly did not get a triptan-like response," Bloch said of the post hoc analysis. "If you took a 100 mg dose of sumatriptan [GlaxoSmithKline's Imitrex ] and 100 mg dose of our drug, you would have had a 30 percent higher sustained relief than with sumatriptan, so our goal is to validate that prospectively."

One reason migraine sufferers with aura could have a better response to the medication is that those patients have been shown to have higher markers of nitric oxide activity, as measured by platelet nitrates, compared to patients without aura, the company noted.

This quarter, NeurAxon intends to initiate a study exploring the maximum tolerated dose for NXN-188. The company will then begin a Phase IIa validating study in migraine patients with aura in the first quarter of 2009, the exec said. While that trial design is still being finalized, NeurAxon said it would consider including a triptan comparison arm.

Following completion of proof-of-concept and Phase II, NeurAxon will seek a partner to run the Phase III trial and commercialize the drug, Bloch said.

There are no FDA-approved drugs specifically to address migraines with aura, the warning symptom that includes visual phenomena and numbness prior to the onset of a migraine.

GSK's next-generation triptan Treximet (sumatriptan/naproxen), a combination drug developed with Pozen, was approved in April for acute treatment of migraine attacks with or without aura, after a lengthy FDA review process that assessed cardiotoxicity concerns (¹ (Also see "GSK/Pozen Win Long-awaited Approval For Combo Migraine Drug" - Pink Sheet, 16 Apr, 2008.)).

Aura is experienced by 20 percent to 30 percent of migraine sufferers, and is associated with comorbidities, including an eight-fold increase in risk of stroke versus those with migraines without aura. Data linking migraines with aura to cardiovascular events such as stroke, angina and heart attack, were separately presented at the congress by Harvard Medical School neuroepidemiologist Tobias Kurth.

NX-188 is the lead drug for privately held NeurAxon, which develops next-generation pain drugs targeting nNOS. The firm, with five candidates in development, intends to file an IND for a second drug by the end of the year, an nNOS inhibitor for neuropathic pain.

- Jessica Merrill ([email protected])