Vagus Nerve Stimulation for the Masses: Interview with electroCore CEO J.P. Errico

Medgadget Exclusive / Neurology

Vagus Nerve Stimulation for the Masses: Interview with electroCore CEO J.P. Errico

by Tom Fowler on May 22, 2014 • 6:05 pm

 

electroCore, a Basking Ridge, New Jersey company co-founded in 2005, is developing non-invasive Vagus Nerve Stimulation (nVNS) therapies which can be delivered using their proprietary gammaCore technology to treat various neurologic, psychiatric, gastric motility, and respiratory conditions. Founded on the pioneering concept of using vagal neuromodulation to acutely treat patients with severe bronchoconstriction during an asthma attack, electroCore has used this concept to expand beyond the acute emergency indications and produce a prophylactic vagus nerve stimulation therapy option. Their initial focus on asthma expanded quickly into migraine and cluster headaches, based on patient feedback from their early studies, and new trials are continuing to investigate new uses for nVNS for gastric motility, pain, and sleep disorders, as well as depression and anxiety. I asked co-founder and CEO J.P. Errico about their gammaCore product, the technology behind it, and his role at electroCore.

Tom Fowler, Medgadget: Tell us how you progressed from being an MIT aeronautical engineering student to a patent attorney to leading a medical device company.

J.P. Errico: I was strongly influenced by my parents, one who was a practicing physician, and the other who had a law degree, to go, professionally, beyond my initial training as an engineer,. So, after graduating from MIT, I went to Duke Law School, where I branched out and simultaneously received a graduate degree in engineering. Because of my focus on patent law, after graduation I was approached by a family member who was a prominent spine surgeon, and within a very short time, our inventive and entrepreneurial bent had us building the first of several healthcare companies. The ventures were largely centered on inventions that could be licensed to market leading companies. The next stage was to begin the clinical development of more innovative technologies, but again these were purchased away from us by the same sort of market leaders. These ventures were successful in generating more than $500 million for our close network of investors. With electroCore, and nVNS, we are committed to building a ground breaking, paradigm-shifting product line. And with recent developments in our clinical and product design programs, I am increasingly confident of our ability to do just that.

Medgadget: How do you foresee gammaCore transforming the standard of care for headache treatment?

J.P. Errico: I foresee physicians, who have as their first obligation to do no harm, offering gammaCore as a first line treatment for their patients. As one of the world leading headache specialist said; “Why would you not use gammaCore first?” I think he is spot on. Through everything we have done, nVNS with gammaCore has been consistently safe, and it is easy for patients to use. Patients can continue with their existing treatments and if it does not work for some of them (nothing works for everyone), they can stop using it. Medications flood the entire body with exogenous chemicals, and thus, invariably have side effects. GammaCore uses the body’s own neural pathways to carry our nVNS therapy, which some refer to as an “electroceutical”, directly to the areas in the brain that release the endogenous chemicals many drug therapies try to modulate. SSRIs, SNRIs, and GABA analogues are some of the largest classes of drugs on the market, and they are designed to alter brain chemistry, and specifically serotonin, GABA, and norepinephrine (also known as noradrenalin). nVNS modulates these same neurotransmitters, but does so without requiring the patient’s liver, kidneys, and other organs to be exposed to foreign chemicals. The other huge benefit, from a patient’s perspective, is that he or she can likely continue with existing medication(s) if they choose, as there have been no observed interactions of nVNS with other treatments, For these reasons and others, electroceuticals is, and will continue to be a rapidly expanding area of healthcare, with GSK starting a new division and investing in multiple bioelectronics companies, and Merck investing in electroCore. I expect many other pharma and medical device companies will follow suit and become involved in this exciting space, and their traditional drugs will, we believe, will slide to the second or third choice… I also believe that patients will demand a non-invasive option that has fewer and more benign side effects than medications as a first option. We expect payors, as well, will appreciate the fact that nVNS can be used both prophylactically and acutely to manage headaches, and with innovative payment options, we hope to make patients and those who hold the purse strings champions of gammaCore.

Medgadget: What is the technology behind gammaCore therapy and are there any risks involved in having patients self administer the nVNS therapy?

J.P. Errico:Vagus Nerve Stimulation was pioneered, twenty-five years ago, by our friends at Cyberonics (Houston, Tx). They were the first to introduce gentle electrical stimulation of the vagus nerve and show that it can selectively stimulate the subset of the nerves in the vagus that have the ability to quiet the surge of activity associated with epileptic seizures. They have recently announced that more than 100,000 patients, world-wide have received their implants, and the profile of safety of their device has been very positive In fact, I believe that the only reason that this therapy option hasn’t climbed the continuum of care from a last resort to front line therapy is the cost and requirement for surgery. GammaCore offers the best of both worlds, the same underlying mechanism of action, without the requirement for surgery and the astronomical cost. In terms of putting it in the hands of patients, I can only say that it takes less time to train a patient to use gammaCore than it takes to train a person to use inhaled medications, and with over 500,000 doses administered to date, we haven’t found any device related adverse events. If the patient doesn’t like it, the therapy can be discontinued in a fraction of a second. In the modern world, we put oxycontin in the hands of patients for headaches, and we feed amphetamines to children with ADHD. Once those pills are ingested, it takes near-heroic efforts to clear those chemicals from the body.

Medgadget: Surgically implanted VNS has been used for some time in the treatment of refractory epilepsy and depression. What is the cost and effect comparison of implants vs. electroCore’s nVNS?

J.P. Errico: Last I heard, Cyberonics was selling their implantable device for over $24,000 in the US. I am not aware of the price point in the EU, or other markets around the world, but of course, that doesn’t include cost of the neurosurgeons’ time, the operating room staff, the anesthesiologist, the long-term maintenance, adjustments, battery replacement, and explanation of the device, if necessary. All of these costs add up to well over $30,000 in the US. Most importantly, VNS doesn’t work for everyone, so the cost for gaining benefits in those for whom it works have to include all the patients in whom it doesn’t (Cyberonics doesn’t give a rebate if the therapy doesn’t work). Reports indicate that 5 years out from the implantation of the device, close to 60% of patients have experienced significant benefit. That means, the real cost for gaining a patient with significant benefit is over $50,000. With gammaCore, while the final pricing of the therapy hasn’t been established, I am very confident to say that we don’t expect payors to commit anywhere near the same amount just to determine in whom the therapy will work. Our goal is to limit the cost of therapy for the payors as closely as can be to just the patients who are gaining the benefit. We are much more like a pharmaceutical in this way, i.e., think of the gammaCore as a bottle of pills containing 300 treatments. When it is used up, it is disposed of and you get another one. Of course, that isn’t quite as socially responsible to the environment – to be tossing things into the garbage all the time – so we intend to introduce reload-able devices that can be refilled with a new prescription, and the fee structure for this would be just like a chronic medication.

Medgadget: You are a named inventor on more than 125 issued US patents, and more than 100 pending patents. What are three tips for those of us that are applying for patents, particularly in the medical device field?

J.P. Errico: This is going to sound corny, but I would say the first thing you want to do is to make sure that whatever it is that you are trying to patent is actually innovative and has potential value to the world. It is an honor to receive a patent, and it is certainly something to be proud of, but they are expensive to obtain, and cost many thousands of dollars to maintain once you’ve gotten them. Make sure it is going to be worth the effort. Second, I would advise people to get an attorney to help. They really do an important service for inventors, and I would NOT suggest to anyone to do it alone. The scope of the patent, and its enforceability are critical to the value they have, so having a professional working with you is critical. Third, and this is specific to the medical field, which is invariably very crowded and intimidating, I would advise anyone with a good idea to commit yourself to your belief. So long as you are not violating the laws of physics, the only thing that stands between you and success is the energy you are willing to expend to make it happen.

Link: electroCore…

 

Tom Fowler

Tom Fowler worked as a programmer in the healthcare IT industry before settling back in school to learn how to become a doctor. He likes to dabble with biotech startups, write postcards to his relatives, and play his ukulele. He was a TEDMED '13 scholar, has published research in biomedical informatics, and continues to advocate for international maternal and child health. Currently in the SELECT MD leadership program at USF Health Morsani College of Medicine.

http://www.medgadget.com/2014/05/vagus-nerve-stimulation-for-the-masses-interview-with-electrocore-ceo-j-p-errico.html

Int J Emerg Med. 2013 Mar 19;6(1):7. [Epub ahead of print]

Non-invasive vagus nerve stimulation for the treatment of acute asthma exacerbations--results from an initial case series.

Steyn E, Mohamed Z, Husselman C.

Abstract

A prospective multicentre clinical study was initiated to evaluate the safety and potential clinical benefit of non-invasive vagus nerve stimulation (nVNS) for the treatment of bronchoconstriction exacerbations in asthmatics. Due to slow enrolment and design changes of the device, the study was prematurely terminated after enrolment of four eligible patients. Three of the four patients were considered treatment successes based on improvement in FEV1, improvement in VAS dyspnoea scoring, and the absence of device-related adverse events. ClinicalTrials.gov Identifier NCT01385306.

PMID:

23510361

[PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/pubmed/23510361

The Internet Journal of Asthma, Allergy and Immunology 2009 :     Volume 7 Number 2

Treatment of asthmatic bronchoconstriction by percutaneous low voltage vagal nerve stimulation: case report.

  Pedro Sepulveda MD Director, Alamo Clinical Research Center, San Antionio, TX                                                              

  Gorav Bohill MD Emergency Department Director, Christua Santa Rosa Hospital, San Antonio, TX                                                            

 Thomas J. Hoffmann BS ElectroCore LLC, Morris Plains, NJ                                                            

Citation:          P. Sepulveda,        G. Bohill &       T. Hoffmann : Treatment of asthmatic bronchoconstriction by percutaneous low voltage vagal nerve stimulation: case report.. The Internet Journal of Asthma, Allergy and Immunology. 2009 Volume 7 Number 2

---

Keywords: Asthma | vagus nerve stimulation | bronchoconstriction | bronchodilation | dyspnea | FEV1 | spirometry

Abstract

Background: A 34 year old Hispanic male patient presented himself in the emergency room with recurring severe asthma that was unresponsive to b-adrenergic and steroid therapy. Spirometry demonstrated significant airflow obstruction. Objective: We sought to test the ability of low voltage vagus nerve stimulation to induce bronchodilation and improve airflow.Method: A percutaneous electrode was inserted into the patient’s neck and positioned to lie in the vicinity of  the carotid sheath. Following placement,  stimulation was administered and the signal amplitude slowly increased until muscle twitching or discomfort was reported by the patient then reduced to a comfortable level.  Results: Within minutes of stimulation, the patient reported reduced dyspnea that was confirmed by spirometry fifteen minutes later (FEV₁ increased from 2.70 L to 3.18 L).   The FEV₁ remained elevated during the 180min treatment (3.29 ± 0.04 L) and at 30min post stimulation (3.36 L).  The FEV₁ then decreased to 2.84 L 60min after stimulation ended. Conclusion: This finding indicates that low voltage vagus nerve stimulation could be a useful critical care treatment to alleviate smooth muscle bronchoconstriction and offer a new therapeutic approach to the treatment of acute asthma. 

---

Financial Support

This study was conducted as part of an FDA IDE and sponsored by ElectroCore LLC, Morris Plains, NJ.

Abbreviations

VNS: Vagal nerve stimulation
FEV₁ - forced expiratory volume in 1 second

Introduction

Asthma is a common chronic lung disease characterized by pulmonary inflammation and bronchoconstriction resulting in dyspnea. When severe, asthma can be life threatening and require emergency medical treatment and hospitalization. In a recent American Lung Association report, there were 1.8 million emergency department visits and 3,816 deaths per year attributable to asthma  ¹ . Medical treatment may include supplemental oxygen to treat the hypoxemia, and pharmacologic agents such as -agonists to relieve the bronchoconstriction, anticholinergics to treat the vagal reflex component of bronchoconstriction, and corticosteroids to treat inflammation. Here we report on the first patient to be treated with a new pulsed electrical vagal nerve stimulation device that may open a new therapeutic approach for the temporary treatment of acute asthma. This study was conducted as part of an FDA IDE, and was completed under IRB supervision.

Case Presentation

A 34 year-old Hispanic male patient with a four year history of severe asthma and a former smoker was admitted to the emergency department with an acute asthma attack. He reported self treatment with albuterol without success. Upon admission, the patient was alert and calm but demonstrated bilateral wheezing, elevated blood pressure (BP) (163/92 mmHg) related to chronic hypertension, acute bronchitis, and mild throat hyperemia. All other vital signs were normal. The patient was administered conventional pharmacologic therapy over a 9 hour period without benefit. Treatment included albuterol (2.5mg), prednisone (60mg PO), and zithromax (500mg PO). At five hours, spirometry assessment of the lung function revealed a Forced Expiratory Volume in 1 second (FEV₁) of 2.68 L or 69% of predicted  ² . After eight hours, the patient was provided information on this study, was consented, and entered a 90 minute observation period. During this time, the patient continued to receive pharmacologic therapy (2.5mg albuterol) and began supplemental oxygen (2 L/min). The patient then underwent placement of a percutaneous, bipolar electrode to stimulate the right vagus nerve (figure 1).
The patient was prepped and draped and, using anatomical landmarks and ultrasound guidance, the electrode lead was inserted to a position parallel to the right vagus nerve in the vicinity of the carotid sheath. The patient remained fully conscious and responsive during the procedure and received only local anesthesia at the insertion site. The electrode insertion was uneventful and a sub-threshold test confirmed the device was functioning. Spirometry was repeated and FEV₁ remained impaired at 2.70 L. Stimulation strength was gradually increased until the patient felt a mild muscle twitch at 7.5 volts (25Hz, 200s pulse width signal) then reduced to 7 volts. This setting achieved therapeutic levels without discomfort and the patient was able to repeat the FEV₁ test without difficulty. At the 15min test point, FEV₁ had improved to 3.18 L and stabilized during 180 minutes of testing (3.29 ± 0.04 L, 85% predicted). Benefit remained during the first thirty minutes after terminating treatment (3.38 L) then decreased. At 60 minutes post stimulation, FEV₁ was only modestly elevated above pre-stimulation levels (2.84 L, 73% predicted) (figure 2). The patient remained under observation overnight to monitor the concomitant hypertension and then discharged. At the 1-week follow-up visit, the exam showed complete healing of the insertion site, and the patient reported no after effects from the treatment.

Figure 1. Patient with a percutaneous VNS electrode

Figure 2. The effect of VNS on FEV₁

Discussion

Here, we report on the first use of vagus nerve stimulation (VNS) in a human asthma patient to treat bronchoconstriction. Although a form of VNS has been in clinical use for over ten years  ³  for the non-pharmacologic treatment of seizure disorders and depression, until now, VNS has not been applicable for the treatment for asthma. Indeed in one report on a patient with intractable seizures, VNS Therapy™ was associated with dyspnea although this was easily remedied after reprogramming the stimulation signal ⁴ . A further limitation of VNS Therapy™ is that the procedure requires direct visualization and manipulation of the vagus nerve in order to attach an electrode array. In the treatment report here, invasive surgery was not required. Instead a minimally invasive, percutaneous approach was used to position an electrode in close proximity to the nerve. This was a relatively simple and rapid procedure that was performed in the emergency department and completed in approximately 10 minutes without evidence of bleeding or scarring.

The neural pathways of the parasympathetic nervous system are the primary regulators of pulmonary smooth muscle tone. Postganglionic parasympathetic nerves mediate both cholinergic contractions and inhibitory nonadrenergic noncholinergic (iNANC) relaxations. It is the close balance between these two that ultimately determines airway caliber. Electrophysiological studies suggest that these relaxation and contraction responses are through anatomical and physiological distinct vagus nerve pathways  ⁵ .

In animal studies, relatively high levels of direct vagal nerve stimulation have been used to induce bronchoconstriction  ^6,7 . Recently, our group has found that similarly applied low voltage stimulation could be used to reduce histamine induced bronchoconstriction in two animal models  ⁸ . This has led to the development of a new percutaneous proximity neurostimulator for stimulating the cervical vagus nerve that was used in this study.

In animal models, VNS is frequently used to investigate the neural pathways and receptors involved in controlling the airways and their association with asthma. Electrical stimulation of the vagus nerve can result in the release of acetylcholine from its pulmonary endings to activate muscarinic acetylcholine receptors on airway smooth muscle cells and induce bronchoconstriction. In contrast, we have demonstrated previously in animal models  ⁸  and now in a human patient that VNS can be used to reduce bronchoconstriction associated with asthma. Although the mechanism has not been fully established, iNANC nerves constitute a likely neural pathway since they can be activated by electrical stimulation and are known to mediate relaxation in human airways  ⁹ .

In this patient, normal pharmacological therapy with β₂-agonist inhalation was ineffective. It is possible that the airway limitations and reduced inhalation volume created inefficiencies in airflow dynamics. Therapeutic aerosol delivery involves impaction, sedimentation, and diffusion  ¹⁰ . During an acute asthma episode, the air flow changes from what is largely laminar under normal circumstances to a pattern with increasing velocities and turbulence. This makes delivery of the pharmacological inhalation agents to the distal lungs difficult, both by reducing transport and by depleting the concentration through impact and absorption in the upper respiratory tract. The application of this new VNS treatment bypasses airflow limitations to bring immediate bronchodilation. The resulting improvement in airflow dynamics provided by VNS can then facilitate the delivery of standard inhalation therapies to achieve prolonged remission of asthma symptoms.

Conclusion

The specific VNS signal applied in this study suggests that stimulation can safely reduce bronchoconstriction. This offers an exciting new opportunity to provide a non-pharmacological and non-airflow dependent treatment modality to emergency department practice for acute asthma as well as a potential new rescue treatment in critical care settings.

Correspondence to

Dr. Pedro Sepulveda
Phone:             210-223-3010
Fax:                 210-222-2942
Email:             psepulveda@acra-sa.com

References

1. American Lung Association, Epidemiology & Statistics Unit.  Trends in asthma morbidity and mortality.  November 2007.  Available at http://breathehealthy.org/uploads/2007_Asthma_Trend_Report.pdf.  Accessed February 12, 2009.(s)

2. Crapo RO, Jensen RL, Lockey JE, Aldrich V, Elliott CG. Normal spirometric values in healthy Hispanic Americans.  Chest. 1990; 98:1435-9.(s)

3. Cyberonics, Inc. Corporate profile. Houston, Texas U.S.A. 77058, Available at:  http://www.cyberonics.com/corporateprofile.  Accessed January 19, 2008.(s)

4. Bijwadia, JS, Hoch RC, Dexter DD.  Identification and treatment of bronchoconstriction induced by a vagus nerve stimulator employed for management of seizure disorder. Chest 2005; 127:401-402(s)

5. Mazzone SB, Canning BJ. Evidence for differential reflex regulation of cholinergic and noncholinergic parasympathetic nerves innervating the airways. Am J Respir Crit Care Med 2002; 165:1076-1083(s)

6. Jooste E, Zhang Y, Emala CW. Neuromuscular blocking agents' differential bronchoconstrictive potential in Guinea pig airways. Anesthesiology. 2007; 106:763-72.(s)

7. Blaber LC, Fryer AD, Maclagan J. Neuronal muscarinic receptors attenuate vagally-induced contraction of feline bronchial smooth muscle. Br J Pharmacol. 1985; 86:723-8.(s)

8. Hoffmann TJ, Mendez S, Staats P, Emala CW, Guo P. Inhibition of Histamine-Induced Bronchoconstriction in Guinea Pig and Swine by Pulsed Electrical Vagus Nerve Stimulation.  Neuromodulation. in press(s)

9. Maarsingh H, Leusink J, Bos TS, Zaagsma J, Meurs H. Arginase strongly impairs neuronal nitric oxide-mediated airway smooth muscle relaxation in allergic asthma. Respir Res. 2006; 7:6 .  http://respiratory-research.com/content/7/1/6.  Accessed February 2, 2009.(s)

10. Newhouse MT, Dolovich M. Aerosol therapy of reversible airflow obstruction. Concepts and clinical applications. Chest. 1987; 91: 58S-64S.(s)

---

This article was last modified on Fri, 23 Oct 09 21:23:45 -0500

This page was generated on Mon, 07 Feb 11 20:23:34 -0600, and may be cached.

http://www.ispub.com/journal/the_internet_journal_of_asthma_allergy_and_immunology/volume_7_number_2_22/article/treatment-of-asthmatic-bronchoconstriction-by-percutaneous-low-voltage-vagal-nerve-stimulation-case-report.html