Pauline Anderson

April 24, 2015

WASHINGTON, DC — A fast-acting transdermal gel using a proprietary formulation of the nonsteroidal anti-inflammatory drug (NSAID) ketoprofen (Topofen, Achelios Therapeutics) reduced pain severity in patients with severe migraine with and without aura compared with placebo and had few adverse effects.

Results from a phase 2a trial of the gel were presented here at the American Academy of Neurology (AAN) 67th Annual Meeting.

"This research sheds new and highly welcome light on our understanding of how severe headaches are caused by neurogenic inflammation, and how we can rationally interrupt pathologic feed-forward signaling in the trigeminal system," lead researcher, Wolfgang Liedtke, MD, PhD, associate professor of neurology, anesthesiology and neurobiology, Duke University, Durham, North Carolina, and an advisor and consultant to Achelios Therapeutics, told Medscape Medical News.

"Once confirmed in later stages of clinical trials, it can change our neurological practice significantly, possibly heralding a new era of topical, transdermal treatments for migraine and related headaches, and also for other pain disorders."

Oral NSAIDS inhibit the cyclooxygenase (COX) enzyme, which is expressed in trigeminal ganglion nociceptor neurons. They also reduce neurogenic inflammation thought to be a key factor in the development of migraine attacks.

But although these drugs relieve pain and decrease inflammation, they're associated with undesirable gastrointestinal (GI) adverse effects.

It's believed that the main mechanism of action for the new tropical gel is also inhibition of cyclooxygenase 1 and 2, and a reduction of neuroinflammation.

The randomized, crossover, double-blind, placebo-controlled study included 42 adults aged 18 to 65 years with a history of episodic migraine with and without aura at two US centers. Patients were instructed to apply a pea-sized amount of the gel on the skin over the peripheral trigeminal nerve ends, on both sides of the face (six points in total) — even if they had pain only on one side — during five moderate to severe migraines.

Researchers grouped patients according to baseline headache intensity (moderate = grade 2 and severe = grade 3). They asked patients to follow each migraine for 24 hours after applying the gel. Patients recorded their symptoms in an electronic diary.

Researchers assessed efficacy at baseline (ie, immediately before dosing) and at multiple time points up to 24 hours after administration.

Compared to a reference topical ketoprofen gel, the proprietary product was absorbed quickly. At 2 hours, absorption of the competing product is "minimal to nonexistent" compared to the new drug, which "reaches the target because the formulation allowing the drug to go through the skin is so efficient," said Dr Liedtke. "It's so much better than anything we have seen."

The analysis included a total of 130 treated headache attacks. Twenty-two patients experienced 49 severe headaches, with 22 treated with active gel, and 27 with placebo.

Of the patients with severe migraine, 77% treated with the gel had relief of pain and migraine-associated symptoms; 45% had sustained pain relief from 2 to 24 hours compared with 15% of headaches treated with placebo. By 4 hours, 23% of headaches treated with the gel were pain-free compared with 15% with placebo.

At 24 hours, 50% of headaches treated with the active agent had pain relief and were pain-free vs 25% of placebo-treated headaches.

At this time point, "the gel still has the same efficacy as before; it doesn't lose its efficacy at 24 hours," commented Crist J. Frangakis, PhD, president and CEO of Achelios Therapeutics. "There is still drug in the tissue."

The efficacy of the drug is based on the amount accumulated in the tissue rather than the amount circulating in the blood, explained Dr Frangakis. "That's why it's put on in different areas — exactly where the nerves are."

The idea is that in future the gel will be used "as a prophylactic, applied once a day," he added.

Patients whose headaches were treated with the gel were at least three times as likely to experience relief of associated symptoms (nausea, photophobia) as those receiving placebo.

According to Dr Liedtke, the more moderate effect for mild migraine attacks could have been due to confounding by the placebo effect.

"The data are more striking in those who reach the definition of severe," he said. "This is also true for symptomatic relief and for concurrent use of rescue medication."

An unwanted effect of the gel was irritation at the application site, which was predominantly mild or moderate and resolved quickly, said Dr Frangakis.

Phase 2b and 3 studies are now needed, said Dr Liedtke, as well as additional mechanistic studies, including animal and human cell experiments.

A topical gel for migraine offers an alternative to "swallowing pills" and may be one answer to the growing "worldwide" problem of medication-overuse headaches, said Dr Liedtke.

Medication Overuse Headache

Mia Minen, MD, assistant professor, neurology, and director, Headache Services, NYU Langone, New York, agreed that although "a lot remains to be determined with the topical form," this new formulation could protect against medication overuse headache.

She pointed out that taking oral NSAIDs more than 15 days a month can cause such headaches.

A possible advantage of a topical NSAID is that patients might be able to combine it with a triptan drug, said Dr Minen. "For moderate to severe headaches, we may tell patients to take a triptan, but there has been data that shows that the combination of triptan and NSAID can have the best benefit."

She pointed out that triptans are approved by the US Food and Drug Administration for use only 2 days per week.

Another advantage, said Dr Minen, is that a topical agent can be given to patients who because of gastrointestinal adverse effects, such as bleeding, can't take oral NSAIDs.

Dr Minen said she found the presentation on the new topical agent "really interesting" and said its focus on targeting the trigeminal nerve is "exciting."

The study was supported by Achelios Therapeutics. Dr Liedtke reports he is an advisor and consultant to Achelios Therapeutics.

American Academy of Neurology (AAN) 67th Annual Meeting. Emerging Science 013. Presented April 22, 2015.


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