Trigeminal Nerve Stimulation: an interview with Dr Leon Ekchian, President and CEO of NeuroSigma

Interview conducted by April Cashin-Garbutt, MA (Editor)Sep 14 2012

Please could you give a brief introduction to Trigeminal Nerve Stimulation (TNS)? What is TNS used to treat?

Trigeminal Nerve Stimulation (TNS) is a novel medical treatment in which mild electrical signals stimulate branches of the trigeminal nerve in order to change the activity of targeted brain regions. The trigeminal nerve is the largest cranial nerve, and provides sensation to the face and head. Because it is a large sensory nerve, the trigeminal offers a high-bandwidth pathway for electrical signals to enter the brain. The brain areas targeted by TNS are known to play key roles in seizures, mood, and attention.

A series of clinical studies performed at UCLA and USC demonstrated the effectiveness of TNS for treating both epilepsy and major depressive disorder (MDD). Based on the results of these studies, NeuroSigma recently received CE Mark for its Monarch™ external Trigeminal Nerve Stimulation (eTNS™) system, and will make this treatment available to patients in the European Union starting in the fourth quarter of 2012. It should be noted that the Monarch has not yet received FDA approval and is limited to investigational uses only in the United States.

How common are epilepsy and clinical depression?

Epilepsy and depression are both very common disorders. Approximately 1% of the population has epilepsy and approximately 16% of the population will be diagnosed with an episode of major depression at some point in their life.

What is currently used to treat epilepsy and clinical depression?

Medications are the primary treatment for both epilepsy and depression. Unfortunately, large numbers of patients continue to experience seizures or depressed mood despite trying multiple drugs. In the case of epilepsy ~1/3 of all patients will continue to have seizures. These patients are categorized as having drug resistant epilepsy (DRE). Options for patients with DRE include resective surgery of the brain regions involved in their seizures, and invasive neuromodulation techniques such as vagal nerve stimulation (VNS) or deep brain stimulation (DBS).

For depression, there are similar limitations to what the currently-available drugs can do. The United States’ National Institute of Health (NIH) STAR*D trial examined rates of remission in over 4000 patients with MDD. What they found was that only 28% of patients remitted with a single medication, and that even after trying four medications over 25% were still depressed. Therefore there is significant need for new therapies to treat these common and disabling conditions.

What is the difference between external TNS (eTNS) and subcutaneous TNS (sTNS)?

The Monarch external trigeminal nerve stimulation (eTNS) system is a non-invasive neuromodulation device for adjunctive treatment of epilepsy and depression. This system has two components: a hand-held pulse generator that creates the electrical signal, and a disposable custom electrical patch that delivers the signal to its target, the trigeminal nerve. The electric patches can be worn in the evenings and while asleep, and should be replaced daily for proper adhesion. To initiate treatment, patients apply the electric patch to their forehead and connect it to the pulse generator. Most patients describe eTNS as a mild “tingling” sensation that does not interfere with other activities of daily life or sleep.

In contrast, the subcutaneous Trigeminal Nerve Stimulation (sTNS™) system is an implantable device that is still under development. sTNS will require surgical implantation of a pulse generator in the patient’s pectoral region, similar to a pacemaker. The pulse generator powers electrodes which are implanted under the surface of the patient’s forehead. An advantage of sTNS is the ability to deliver therapy on a continuous basis throughout the day, without requiring any patient interaction with the device.

Because the therapeutic target of both eTNS and sTNS is the same (i.e. both devices stimulate the same nerves), NeuroSigma considers eTNS and sTNS to be complementary platforms. Interested patients can try eTNS as a non-invasive, low-risk neuromodulation treatment. For most people, the eTNS system will be sufficient. Some patients, however, may eventually desire implantation with the sTNS system, particularly if they have a more severe form of the disease. A unique advantage of this treatment paradigm is that eTNS can be used to screen for the effectiveness of sTNS, so that patients can be confident that the sTNS device will be effective before committing to an expensive and invasive surgical procedure. Thus there is the potential to eliminate risky, costly, and unnecessary surgical procedures. NeuroSigma believes that this is a compelling treatment model for patients, physicians, and payors alike.

How does the eTNS reduce seizures in patients with epilepsy and improve mood in patients with depression?

While more research is needed to confirm the mechanism of action, evidence indicates that eTNS changes the activity of key brain regions. For example researchers used a rat seizure model to demonstrate that stimulation of the trigeminal nerve results in decreased firing of nerve cells in the sensorimotor cortex, a brain region known to be involved in the initiation and propagation of seizures. Additionally, a clinical study of people with depression receiving eTNS for the first time, revealed significant inhibition of brain regions associated with seizures, and activation of brain regions associated with mood and attention.

How did the development of the eTNS originate?

eTNS was invented by Dr. Christopher DeGiorgio, Professor of Neurology at UCLA. Dr. DeGiorgio was a pioneer of vagus nerve stimulation (VNS) for the treatment of epilepsy, and began to develop eTNS as a non-invasive alternative to VNS. eTNS has now been used for a decade in clinical studies at UCLA, and NeuroSigma is proud to make this innovative treatment available to patients throughout the European Union.

Were any side effects found with the eTNS treatment?

To date, there has not been a single severe side effect associated with the use of eTNS. Minor side effects have been reported by some patients in the clinical trials. These include skin irritation at the site of the electric patch and headaches. The new generation of electric patches, which will be introduced in the EU, have been designed to mitigate skin irritation, while headaches can be reduced by decreasing stimulation duration and intensity.

How does the eTNS fit with Neurosigma’s aims?

The Monarch eTNS System is NeuroSigma’s flagship product. NeuroSigma believes that eTNS represents a paradigm shift in the field of neuromodulation and the treatment of neuropsychiatric illnesses. Most neuromodulation systems available today are expensive, implantable devices that require the patient to undergo a surgical procedure. Oftentimes it is unknown whether the patient will ultimately respond to the device prior to implantation. This exposes patients to substantial risks, and the healthcare system to potentially unnecessary costs

In contrast, eTNS is a non-invasive neuromodulation treatment that can be delivered in a cost-effective, low-risk manner without the serious side effects of many pharmaceuticals. Because eTNS is low-risk and non-invasive, NeuroSigma believes that there will be significant demand among patients with epilepsy and depression for this novel treatment.

Neurosigma’s eTNS has recently been awarded CE certification. What impact will this have?

CE certification is required for any medical device sold within the EU. NeuroSigma is extremely pleased to have received the CE mark and will make the Monarch eTNS system available to patients throughout the EU starting in the fourth quarter of 2012.

Where will the eTNS be available?

NeuroSigma has adopted an innovative business model designed to bring this important treatment to patients throughout the EU. Interested patients with a prescription may obtain the Monarch via direct purchase from NeuroSigma or through major epilepsy and depression centers. We will release more information about how patients can acquire a device in the coming months. Please check our website for regular updates on the Monarch.

What are NeuroSigma’s plans for the future?

Over the next several years, NeuroSigma will be focused on bringing eTNS to patients throughout the EU. NeuroSigma anticipates that direct purchases from the company and through major treatment centers will create a significant user base for the product. Simultaneously, we will seek to obtain approvals in other parts of the world.

In the United States, we will be submitting a request to the FDA for an Investigational Device Exemption (IDE) to commence a multi-center pivotal trial of eTNS for epilepsy. Over thirty major centers in the US and Europe have expressed interest in being part of this pivotal trial. We will also be developing the implantable sTNS system to establish a fully integrated neuromodulation platform for patients suffering from epilepsy and depression throughout the world.

How do you think the future of eTNS will develop?

NeuroSigma strongly believes that the Monarch eTNS system has a bright future. Pharmaceutical treatments for epilepsy and depression have reached a point of diminishing returns, where even the newest drugs yield incremental gains in the numbers of patients that can be helped. In contrast, neuromodulation represents a fundamentally new approach to treating these diseases. However, the majority of the available systems are invasive and expensive, which has limited their market penetration and the possibility for them to help the many patients who need new treatments. The NeuroSigma Monarch is at the forefront of a new trend where non-invasive and minimally-invasive neuromodulation systems will make these treatments available to much larger patient populations. Therefore, NeuroSigma is excited about the future of eTNS and looks forward to helping patients and their families worldwide.

Where can readers find more information?

www.neurosigma.com

About Dr Leon Ekchian

Leon Ekchian is NeuroSigma’s President and CEO. Prior to co-founding NeuroSigma in 2008, Leon served as President of Arrowhead Research Corporation, a publicly-traded company that commercializes innovative nanotechnologies in the electronic and biotech industries. Prior to Arrowhead, Leon served as President and CEO of Litex, a venture capital backed company which was spun out of Lockheed Martin, focused on commercializing an advanced automotive emission-control technology. Earlier, Leon worked as a business development executive at Lockheed Martin focusing on formation of new ventures, evaluating new business plans and licensing opportunities, and as a program manager at Litton Industries developing ground-based and airborne tracking systems.

Leon received a BS, MS and PhD in electrical engineering from MIT and an MBA from UCLA’s Anderson School of Management.