Voice-over: Welcome to Spotlight on Migraine, hosted by the Association of Migraine Disorders. Join us for fresh perspectives by medical experts and advocates as we explore the spectrum of migraine and dig deeper into this complex disease. This episode is brought to you by our generous sponsor, Lundbeck.
Dr. David George discusses Nocira’s investigation of a new device that is designed to treat migraine by making subtle pressure changes in the ear. He explains the neuroanatomy of the area stimulated, as well as positive efficacy data and the current status of this treatment that is still in development.
Lundbeck is a global pharmaceutical company that is committed to improving the lives of people living with brain diseases. Lundbeck is pleased to offer a treatment option for migraine prevention. To learn more, visit LundbeckUS.com.
David George: Hello, everybody. My name is David George. I am chief science officer and co-founder of a company called Nocira. My focus as a clinician is primarily in neurodiagnostics and neurorehabilitation, and I was also an early investigator for some of Nocira’s clinical data being presented today. I appreciate the opportunity to present Nocira’s investigational new device platform and clinical results, which I hope you’ll find very interesting, promising, and perhaps even groundbreaking.
Before we begin, here are my disclosures.
Nocira calls its new device approach for treating migraines “automated variable pulse insufflation” therapy, or AVPI. The AVPI device noninvasively creates subtle pressure changes in the outer ear as an entirely new approach for neuromodulation. In this talk, I’ll briefly explain the unique pressure-responsive neuroanatomy of the ear that is harnessed by AVPI to create a rapid and profoundly relieving therapeutic response in acute migraine.
I’ll then describe the evolution of this new approach through refinements and increasingly encouraging stages of clinical evaluation. Finally, I’ll explain the current device system as it has been further evolved and designed to be even more effective, safe, and user-friendly — and even more than that, to actually be an enjoyable and pleasurable product to use.
The science behind Nocira’s novel therapy is based on a unique combination of multiple cranial nerves and related pressure receptors that serve as therapeutic conduits into the brain. The convergence of these multiple pathways in a small, concentrated area at the ear is really unique and unlike any other place in the body. These include branches of nerves you may have heard of called vagus, trigeminal, facial, and glossopharyngeal nerves.
Each of these nerves is involved with different areas of the brain associated with migraine pathophysiology. For example, the vagus nerve is associated with the brain’s autonomic system, which recent scientific literature suggests may actually be the primary instigating system in the migraine process. The trigeminal nerve, on the other hand, is associated with the trigeminal nucleus, which is the brain stem’s primary pain processing center.
Other branches of these nerves are already targeting for migraine treatment by other neuromodulation approaches, typically using electricity. Examples include another branch of the trigeminal nerve at the forehead and another branch of the vagus nerve in the neck. But those approaches are generally limited to only a single nerve pathway and its associated brain regions.
However, by simply creating subtle air pressure changes in the outer ear, Nocira’s approach is highly advantaged by accessing each of these therapeutic nerve pathways simultaneously and in a location where these nerves are particularly responsive. Put simply, the very reason that these multiple nerves innervate the ear with pressure sensors is to allow the autonomic and trigeminal systems to be responsive to environmental pressure changes in nature. Nocira merely harnesses those same functions, but to create therapeutic relief by interfering with multiple migraine-associated processes in the brain.
The first-ever case series using ear insufflation to treat migraine attacks was published in 2013 by Dr. David Sullivan, one of Nocira’s cofounders. Using a manual otoscope and while visualizing the ear drum, he delivered a series of pressure pulses to the external ear canals of 13 patients while they were experiencing a migraine attack. As you can see, headache pain scores were significantly reduced from pretreatment baseline, and then at short and longer time periods after treatment, as shown at the top right of the slide.
The bottom right graph also shows the high rate of patients who achieved complete pain freedom, indicated by the solid blue bars, and at least 50 percent headache relief, shown by the lighter bars. No significant side effects or adverse events were reported.
However, while we were obviously impressed by these results, a number of concerns arose about patients manually pressurizing their own ears in the personal-home-use setting. This concern was confirmed by internal lab tests which showed that commercially available manual-insufflation bulbs can reach pressures far above the published maximum limits for ear pressure safety.
Nonetheless, the success of this pioneering first study provided a launch pad from which to develop an automated, controlled device that provides a safer, more therapeutic, and adoptable approach for widespread personal use.
Hence evolved Nocira’s AVPI platform. Improving over the initial manual approach, the Gen 1 AVPI device now used automation to deliver and precisely control very gentle air pressure patterns through comfortable ear pieces in the patient’s outer ear. These automated controls optimize the stimulus for a therapeutic response while also limiting those same pressures to remain well within published ear pressure safety limits.
The AVPI approach is also hands-free and allows the patient to passively relax whilst receiving the therapy. As you might imagine, for someone in the midst of a disabling migraine attack, this is also a clear advantage versus having to manually pump an insufflator bulb for a prolonged period of time into their own ears.
So a feasibility trial was conducted using the first-gen prototype of this improved AVPI system to treat 17 patients during a moderate to severe migraine attack. This now shows those feasibility trial results from those 17 patient treatments using that first-gen AVPI device. Headache pain scores using an 11-point numeric pain scale are shown on the left. As shown, the average headache pain score was significantly reduced from a mean of over 7 points at pretreatment baseline to below 1 by the end of just a 20-minute treatment. This significant pain reduction was also sustained through 24 hours.
As shown on the right, and also by the end of just a 20-minute treatment, 71 percent of the patients achieved complete pain freedom, while 94 percent reached a 50 percent or greater headache pain reduction. This relief, again, was also sustained through 24 hours. These results confirmed the merits of taking the leap to the automated-control pressure modulation technique of AVPI.
The next-gen AVPI device reflected further refinements in the preprogrammed controlled pressure patterns and related therapeutic technique. This was then evaluated in a next pilot study, which was also a more rigorous randomized patient-blinded sham-controlled clinical-trial design. This trial was also conducted over a larger patient population and with expanded data collection to include more standardized migraine outcome metrics and endpoints.
This study also limited migraine severity to only moderate to severe migraines. In addition, as was also the case with the preceding studies, there were no limits placed on time from migraine onset to treatment or on migraine frequency. This allowed for the inclusion of certain patients and migraine attacks that are typically considered more resistant to treatment and which are thus often excluded from other acute migraine trials. Most notably, this trial included a significant cohort of chronic migraineurs.
Now on to our pilot RCT results. This graph shows the mean headache pain scores over time between active and sham treatments per a numeric pain scale from zero for no pain to 10 for most severe pain. Both active and sham groups had equivalent pain of about 7 out of 10 at pretreatment baseline. However, as shown, the active group rapidly enjoyed significantly more pain relief, dropping to a mean score of only about 1 by the end of the 20-minute treatment, which was then sustained and actually even trended lower at 2 and 24 hours.
The graph here on the left shows the percentage of patients who reached complete pain freedom at different time points after treatment. A 60 percent majority of the active-AVPI-treated patients reached complete pain freedom just by the end of a 20-minute treatment, which even increased to a two-thirds majority of patients by 2 hours.
The other graph on the right instead shows the percentage of patients who achieved at least 50 percent reduction in their headache pain post-treatment. Ninety percent of the active-AVPI-treated patients had at least 50 percent headache pain relief by 20 minutes. This score grew to 93 percent at 2 hours, with very high sustained relief in over 80 percent of patients through 24 hours.
As I’ve mentioned, this trial included a cohort of subjects with chronic migraine. I also suggested that these patients are generally considered more difficult to treat than non-chronic or episodic migraine patients, one of the primary reasons these patients are generally excluded from most other clinical trials.
And so, with that in mind, this slide shows once again the pilot RCT patient outcomes for headache pain, but as those results are now broken out between chronic and episodic cohorts. As shown here, the complete-pain-freedom rates were very high for both episodic and chronic patient groups. In fact, half of the chronic migraineurs were pain-free by the end of the 20-minute treatment, with a near two-thirds majority of those chronic patients being pain-free by 2 hours.
This now shows the percent of patients who achieved at least 50 percent or greater headache pain relief between those same chronic and episodic cohorts. You may find it especially remarkable to note that all — that is, 100 percent — of the episodic patients had at least 50 percent headache pain relief by 2 hours, with over 90 percent sustaining this relief through 24 hours. Perhaps even more remarkable, nearly 90 percent of the chronic patients reached at least 50 percent headache pain relief by only 20 minutes, 75 percent at 2 hours, and a 63 percent majority sustained this relief from 2 to 24 hours.
The Nocira AVPI treatment also showed high success rates in the majority of patients for treating other primary associated migraine symptoms of nausea; photophobia, or light sensitivity; and phonophobia, or sound sensitivity. Shown first here for nausea are complete pain freedom [for — at least?] freedom rates on the left and at least 50 percent relief rates on the right. High success rates were enjoyed by a significant majority of patients for each of these nausea-relief measures, including at the early and then later post-treatment time points.
As shown here, for photophobia, success rates were also very high at each early and later post-treatment time points for reaching complete freedom, shown on the left graph, and also for reaching at least 50 percent relief, shown on the right graph.
As you can see here, the success rates were also very high for phonophobia, or sound sensitivity. Of particular note, all of the 23 patients who had phonophobia, when they treated with the active AVPI device, had at least 50 percent reduction for that symptom by 2 hours, while a majority of them again also achieved complete — that is, 100 percent — relief from that symptom.
One of the indicators of perceived relief for migraine is medication use. The study protocol allowed patients to use their chosen migraine medications if they felt they needed it following treatment. However, those medication uses were considered rescue medications and thus treatment failures when calculating the success rates for headache pain and other bothersome symptoms that we showed in the prior slides.
Those actual percentages of rescue medication use for active and sham treatments are shown here. As you can see, drug use was much higher in the patients who received the sham. In fact, within just 2 hours from treatment, 41 percent of the sham group used a rescue medication, whereas none of the patients who received the active AVPI treatment used any rescue medication. Even by 24 hours, only 10 percent of the patients receiving active treatment felt the need to use medication, versus nearly two-thirds of the sham group, who ultimately used rescue medications for relief.
As with most migraine trials, most of these pilot study patients have been plagued with disabling migraines for years — for some, most of their life — and for most, nothing they have ever tried has ever given them meaningful, complete, and consistent relief. So as you can imagine, when their migraine is completely resolved in less than 20 minutes by using the Nocira device, what they have to say is quite remarkable.
But beyond that, the patient experience in terms of what this therapy feels like is very unique. Actual subjects frequently reported that it feels soothing, it feels relaxing, and even some reported that it felt really cool. And regarding the relief itself, multiple patients have commented similarly that it feels like their headache was just sucked out of their head through their ear or shut down in their head like a light switch. I must say that as a clinician that has treated and observed these subjects responding to AVPI, it’s an impressive response that I have yet to get used to.
So this is an illustration of the current state of Nocira’s AVPI device system. The device is operated by a mobile-phone-based application, which interacts with the user during a migraine to deliver a custom treatment that responds and adapts during a treatment session in response to the user’s evolving relief. The AVPI device itself is a small palm-size device that generates our varying preprogrammed and refined pressure profiles in a near-silent and comfortable manner. This is done through comfortable earplugs seated in each ear.
As you can see, as a person uses the device, it looks like they are listening to music. The user is free to lie down, sit down, or move around as they feel necessary. The typical usage session is between 20 to 30 minutes, but with that said, the average time to headache pain freedom in our trials to date is around 15 minutes. This more advanced AVPI system is the subject of additional ongoing clinical evaluation, while Nocira will continue to work to identify and make further refinements and improvements into the foreseeable future.
So in summary, Nocira’s novel AVPI approach harnesses the unique neuroanatomy of the ear to deliver a novel migraine therapy. Since the first publication in 2013, Nocira has continued to refine the AVPI device and technique, with progressive evidence of clinical effectiveness, safety, and high user satisfaction.
The most recently published pilot RCT showed the AVPI device was well tolerated, safe, and rapidly effective, with high relief and complete freedom rates for treating moderate to severe migraine in a population that included chronic migraineurs. Ninety percent of the pilot RCT patients also reported that the AVPI therapy was comfortable and even pleasant.
More robust trials to evaluate further product enhancements are ongoing and planned in the relative near term, including in order to support regulatory submissions for market clearance.
So, with that said, I’d like to thank you very much for your time and attention today, and I would especially like to thank the wonderful staff at the Association of Migraine Disorders for the invitation and the opportunity to present today. Thank you very much.
Voice-over: Thank you for tuning in to Spotlight on Migraine. For more information on migraine disease, please visit MigraineDisorders.org.
This podcast is sponsored in part by Lundbeck.
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