TRANSCRIPT:

Spotlight on Migraine

Season 3, Episode 13

Nerivio: A Drug-Free, Wearable Migraine Treatment

Alon Ironi

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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.

Theranica CEO Alon Ironi talks to us about their wearable therapeutic pain treatment device, the Nerivio, explaining how it differs from a TENS unit and how it works to relieve migraine symptoms. He also reports on efficacy and safety findings and explains how patients can get the device.

This presentation was originally published at the Migraine Symposium on October 3rd, 2020.

Alon Ironi: Hi, everybody. I’m going to introduce the Nerivio to you today. So the Nerivio is a new wearable for the acute treatment of migraine. It was authorized by the FDA in 2019. It requires a physician prescription, and the mechanism of action deploys a technology that is called remote electrical neuromodulation, REN. I’m going to use this term throughout the presentation, R-E-N, REN, remote electrical neuromodulation. The mechanism of action is based on an electrical waveform that triggers an endogenous descending pain-inhibition mechanism in the brain stem that’s called conditioned pain modulation, CPM.

The Nerivio is a disposable device in the sense that every device is good for treating 12 migraines. Every treatment is 45 minutes, and then you recycle the device. It is placed on the upper arm, as you can see in the picture, upon the onset of headache or aura migraine symptoms, and it is fully operated by a smartphone application that is available free of charge over the App Store or the Google Play store. The application comes with an interactive migraine diary that is sharable with your healthcare provider.

What I’m going to talk about today is how the device works. I’ll share with you a lot of the clinical evidence that we have accumulated over the last few years and talk about patient types and how to effectively use the device.

So let’s start with the mechanism of action. So CPM is the name of the mechanism in the brain stem which is triggered by the Nerivio. It’s an endogenous mechanism, so in this sense, the Nerivio really helps the patient help himself. 

The principle is that there is an existing pain, what we call target pain. In this case, obviously, it’s the headache caused by the migraine, and also other symptoms, not only pain. And this target pain is inhibited by a second stimulus, which is remote. That’s a very fundamental principle, that the second stimulus would be provided remotely from the location of the first stimulus or the first pain. So the remote stimulus has to be strong, but it can be — and it is — below the perceived pain threshold, which is individual, and we will talk about that later.

The area in the brain where this all happens is the brain stem. So the signal from the device travels up the arm, arrives at the brain stem, where it triggers the CPM. The result of triggering the CPM is a global release of serotonin and norepinephrine throughout the entire neural system.

One question that comes up frequently is in what sense this device is different from a TENS unit. So as you can see in the table, there are a lot of differences. Actually, other than both types of devices having electrodes and based on electrical signal, they are quite different. So this table explains the differences, and it compares the TENS and the REN, R-E-N, the technology. 

So, first of all, the mechanism of action — as I said before, TENS unit deploys what’s called gate theory of pain. It’s an ascending pain inhibition. Basically, it blocks the pain locally from traveling through the central neural system, while REN is a descending inhibition. It actually receives the pain and then triggers a mechanism which spreads down and blocks the pain from coming up.

They are also different by the types of nerve fibers that are utilized by each one of them. TENS unit typically recruits Aβ fibers, which are touch fibers, while REN — the Nerivio, in this case — deploys C fibers and Aδ fibers. These are nociceptive fibers. Their role in the body in the neural system is to transfer painful sensation. In this case, the sensation of the Nerivio is sub nociceptive — it’s below the pain threshold — while in the case of TENS, it’s just, [inaudible], touch sensation.

The location of the body — we talked about that. TENS has to be located exactly at the location of the painful area in the body, while with REN, it’s very important to locate the device remotely from the painful location. From the electrical standpoint, the waveform is very different. TENS unit would deliver a signal that has between 40 to 80 Hz cycles per second, with pulses that typically would have a duration of between 50 up to 300 microseconds. In the case of Nerivio, the frequency is higher, between 100 and 120 Hz, and the pulses are actually longer, 400 microseconds. The impact of the TENS unit is local, very limited to the location where you place the TENS, while with REN, it’s a global impact over the entire neurosystem.

Let’s talk about safety. So the results that you see here are taken from the pivotal study that was the basis for receiving the FDA authorization for the Nerivio. It was a double-blind placebo-controlled study with 252 patients participating. And, as you can see, first of all, more than 96 percent of the patients did not have any device-related adverse events. All of the adverse events that were reported were mild. They did not require any medical treatment, and actually they were resolved shortly after the treatment.

Look at the graph. You can see that the percentage of each one of the different types of adverse events is very small. There’s no difference or almost no difference between the active and the sham device. By the way, there were no discontinuations of patients in the study because of any of these adverse events. You can see that all of them are local. You can see redness, numbness, and things like that. None of these adverse events is systemic. And so with Nerivio, there’s no risk of abuse, no risk of drug–drug interaction, and no risk of medication overuse headache.

With that, let’s talk about some of the efficacy results and efficacy aspects. So these data are taken from the same study, the pivotal study. And so let’s talk about headache. On the left-hand side, you see the two-hour results, so that’s two hours after the start of the treatment, after applying the device. You have a pair of graphs. One is showing the pain-relief results, pain relief meaning transitioning two hours from moderate or severe down to mild or no pain, and on the right-hand side, pain free, complete disappearance of pain, within two hours from starting the treatment. In both cases, you can see high numbers on the green, low numbers on the black, which is the placebo device, very large statistical significance between the two, which shows high efficacy. So that’s two hours.

On the right-hand side, you can see the sustained response in terms of pain. Forty-eight hours after the treatment, without taking medication, without re-treating with the device, you can still see a very significant difference between the device and the placebo. So the efficacy comes up rapidly within two hours and is sustained over 48 hours after the treatment.

That was pain. Migraine, obviously, as you know, has other symptoms. Sometimes they’re called associated symptoms. So in this graph, you can see the results of the MBS relief. MBS stands for “most bothersome symptoms.” It’s any one of the three — nausea or vomiting; sensitivity to light, which is photophobia; and sensitivity to sound, phonophobia — which is defined by the patient as the most bothersome at the beginning of the treatment. And so two hours later, you can see the percentage of patients that report relief, significant relief, of that particular MBS, or most bothersome symptom. And, again, you can see a statistical significance between the device and the placebo device, which shows high efficacy.

So that was the pivotal study. Over the couple of years since the pivotal study, there were other studies that pretty much repeat the results. Some of them are explained here. One study that was published in Frontiers in Neurology this year demonstrates the reduction in usage of acute medications for migraine by patients. So 117 patients — it’s an open-label extension of the previous study — which were using medications in 84.6 percent of their attacks when they did not have Nerivio. When they got the Nerivio, when the Nerivio was in their disposal, only 10 percent of them, or a little bit more than 10 percent, used other medications. 

And with respect to efficacy, pain relief ratio was the same between the two periods with medication and with Nerivio, and pain relief actually increased from 23 percent to 31 percent. So you can actually decrease or reduce the usage of medication not only without compromising on efficacy, but actually maybe even getting better results.

There were two studies in chronic migraine patients. This is one of them that has been published by now. It’s a relatively small study. It was published in Pain and Therapy this year. Basically, it showed that 73.7 percent out of the patients, 39 chronic migraine patients, achieved pain relief in at least 50 percent of all of their treatments, and they had a lot of treatments in this study. 

Another evidence that was published in Pain Medicine this year is a real-world analysis done on 1,400 patients, a lot of patients, focused on consistent response across multiple attacks. A consistent response means the percentage of patients that report a certain response, whether it’s pain or associated symptom, in at least 50 percent of their treatments. And so this study shows high efficacy in a serial of different symptoms: pain; sensitivity to light, sound; nausea; return to normal functionality; and so on. And in terms of safety, only 0.5 percent of the patients reported any adverse event.

This is a more recent — this has not been published yet, but this is data on file that was collected from the Nerivio application from almost 1,900 patients in the United States. It provides, again, the consistent response of patients with respect to pain relief, pain free, improvement in functionality, return to normal functionality, and the disappearance of associated symptoms.

So what are the aspects that should be considered when you think about whether or not using the Nerivio? One is the potential advantage of the Nerivio in avoiding the risk of medication overuse headache. Medication overuse headache is caused by frequent use of acute medications. For migraine, it could be just over-the-counter painkillers or prescribed medications. 

All of them, basically, once they’re used in high frequency, they potentially can cause medication overuse headache. So the thumb rule is that for over-the-counter medication, using more than 15 days a month is considered a risk for MOH, for medication overuse headache, and for prescribed medication such as triptans, using more than 10 days per month would place the patient in a risk of MOH.

Evidence shows that 15 percent of migraine patients have medication overuse, and this is a vicious cycle. A patient can start with low-frequency, episodic migraines, start taking medications that would increase the frequency — again, not always, but potentially increase the frequency to high episodic. More medications are consumed, and then eventually resulting in chronic migraine. So these are some of the risks of consuming too much medication. And, obviously, one way to avoid it is to use a nonpharmacological acute therapy.

This is an insight of the AMCP [inaudible]. This is the results or the publication of a conference that was held earlier this year and was published around March or April, and it compares a few acute treatments of migraine: three different medications — the lasmiditan, the rimegepant, and the ubrogepant — and then the Nerivio. You can take a look; the results are taken from papers that are publicly available. Of course, this is not a head-to-head comparison — we have to be careful about comparing these results — but take a look at the numbers, the nominal numbers of pain-free results in the bottom line and also the difference between the active and the placebo device or drug, which is called the net medical benefit or the net clinical benefit of each one of the therapies.

So which patients are actually more adequate or better for using Nerivio? And so, several types. The first type are simply patients who do not get consistent efficacy from their acute medications. Nerivio deploys a different mechanism of action, so in many cases, we saw that patients that could not or did not respond to drugs — prescribed drugs or over-the-counter drugs — actually responded to Nerivio. So that’s one type of patient.

Second type of patients are patients who have all kinds of contraindications to medications, simply are not allowed to use these medications. For example, triptans are contraindicated in patients with coronary spasms, other heart failures, blood pressure problems, and so on. And most of the triptans are also contraindicated during pregnancy and breastfeeding. NSAIDs are contraindicated in patients with renal damage and other gastrointestinal problems. So in those cases, a nonpharmacological therapy would be preferred or could be preferred, and, obviously, the Nerivio is an effective and safe option for them.

Two other types of patients — there are patients that do not have contraindications but do not tolerate the side effects of medications. For example, many patients experience drowsiness after consuming triptans. That obviously reduces their energy and makes it difficult for them to function normally after consuming triptans. Nerivio has a very high safety profile, as you saw before, with no systemic side effects and with a very low percentage of mild, local side effects. So that could be a good alternative for those patients.

Another type of patients are patients that simply prefer not to use drugs. Some patients prefer not to take medications either because they’re pregnant or planning to get pregnant or just want to adopt a more natural, healthy way of living. So, again, Nerivio’s drug-free, noninvasive, extremely safe, and would be a very good option for these types of patients.

Then on the other side of the scale, there are patients who need to watch against MOH, medication overuse headache. So we discussed that. Typically, the maximum dosage of most of the prescribed medications for acute treatment of migraine is 8 to 10 doses per month. However, there are a lot of patients that have more than 10 headache days per month. What would they do? If they continue to consume medications in the rest of the month, they would put themselves at risk for MOH. 

So these patients can actually incorporate Nerivio into their usual care as an adjunct. On some days, they can use triptans or other medications; in other days, they can apply the Nerivio; and by this take care of themselves, treat themselves on every migraine but keep their medication consumption below the threshold.

And the last type of patients are just new patients, patients that are treated for migraine for the first time in their lives, especially young people who start migraine. A lot of physicians think that before starting with medication for a lifetime, a nonpharmacological approach may be offered.

I mentioned earlier the application and the Nerivio migraine diary. So it’s actually more than just a diary. First of all, the American Headache Society and the International Headache Society recommend using a migraine diary for the purpose of better managing migraine. Nerivio has a built-in diary that allows patients to track their migraine patterns, the outcomes of the treatments, and very easily share this information with their physicians of choice, if they want to do so, with a click on the screen. 

The Nerivio application also helps patients and physicians optimize their treatment strategy by providing them real-time data with patient-centered statistical analysis. You can see on the right-hand side the way that the data is presented by the Nerivio application. You can have a statistical analysis of your symptoms, of the outcomes of your symptoms along time. And, again, all this can be easily shared with your physician.

And on top of that, the Nerivio application follows the patients and is able to provide them with tips on how to optimize their treatment, individualized tips. For example, in this case, if the application notices that a patient uses the device too late, not within the first one hour, or uses intensity which is considered less than effective, that creates a message as part of the application that provides this tip to the patient and guides the patients to better adhere to the instructions of use and get better results from the treatment.

How can patients access the Nerivio? First of all, every licensed healthcare provider can prescribe Nerivio. It doesn’t require a neurologist or a headache specialist. Every licensed HCP can provide that. Prescriptions are available on the Internet. You can see the link over there. And signed prescriptions are sent to any one of our specialty pharmacies and are delivered to the patient home within one to three days. 

Nerivio’s also available since April of this year online in certain telemedicine platforms. Cove and UpScript are examples. So patients can go online, can get an appointment — textual or audio or video appointment — with a physician, and can be prescribed the Nerivio very quickly. You have the links here of Cove and UpScript, and we have other partnerships in telemedicine.

With respect to price and reimbursement, the Nerivio is about to be reimbursed by major payers very, very soon.

So, finally, three tips to remember when you treat with Nerivio. Number one, treat early. The best results with Nerivio are obtained if you treat yourself within one hour from the onset of the symptoms, headache or aura. Place the device properly — it’s not very complicated — on the outer part of the upper arm, as you can see here in the picture, about midway between the shoulder and the elbow. And number three, optimize the electrical dosage. Set the intensity to well perceived but not painful. So that’s very easy. When the treatment starts, you have on the screen plus and minus buttons that allow you to click, raise the intensity all the way from the default, which is very low, to intensity which feels strong but not painful, just below the pain threshold. That would be the optimized intensity to treat with Nerivio.

So, with that, I’d like to thank you for listening.

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Voice-over: Thank you for tuning in to Spotlight on Migraine. For more information on migraine disease, please visit MigraineDisorders.org.

*The contents of this podcast are intended for general informational purposes only and do not constitute professional medical advice, diagnosis, or treatment. Always seek the advice of a physician or other qualified health provider with any questions you may have regarding a medical condition. The speaker does not recommend or endorse any specific course of treatment, products, procedures, opinions, or other information that may be mentioned. Reliance on any information provided by this content is solely at your own risk.