In an interview with SmartTRAK, Robert Levy, MD, president of the International Neuromodulation Society (INS), provides a preview of the research, emerging technologies, and trends in neuromodulation that will be at the INS 2019 14th World Congress to be held May 23-30, 2019 in Sydney, Australia.
The meeting will highlight several important topics, including the use of neurostimulation to reduce opioid use, closed-loop neurostimulation, and advances in non-invasive brain stimulation, including for the treatment of post-traumatic stress disorder, depression, and for enhancing memory and learning.
In terms of research, Dr. Levy said Sam Eldabe, MD of the United Kingdom will provide a critical evaluation of clinical trials in neuromodulation. Researchers will also present the latest insight into mechanism of action, new data on neurostimulation for cardiac ischemia, as well as research on use of deep brain stimulation (DBS) for obesity, eating disorders and addiction. Researchers will also present important pivotal trial results, including: the Evoke Study (Saluda Medical), evaluating closed-loop spinal cord stimulation (SCS); the SURF study (Stimwave Technologies), comparing different wireless SCS frequencies and waveforms; and the ReActiv8 trial (Mainstay Medical), evaluating the use of a restorative neurostimulation system for nocioceptive chronic low back pain.
On the technology front, the INS’s Innovation Day will highlight disruptive innovations in neuromodulation, and will feature panel discussions and presentations by researchers and major shareholders from early stage start-ups, middle-stage start-ups and well-established companies.
To find out more about the INS World Congress, click on the following video to listen to SmartTRAK’s interview with Dr. Levy recorded via phone from his office in Florida. A transcript of the interview is also provided below.
SmartTRAK: Hi, Anne Staylor here with BioMedGPS. Today I'm talking on the phone to Dr. Robert Levy, the president of the International Neuromodulation Society. Dr. Levy, thanks for talking with me today.
Robert Levy, MD: Oh, it's my pleasure.
Well, the INS meeting in Sydney is just around the corner, so I wanted to talk to you in order to get a glimpse of what we can expect at the meeting, and to find out what's next in neuromodulation. So what are some of the exciting things we'll see at this year's INS meeting?
Robert Levy, MD: As you know the International Neuromodulation Society has its major meeting once every two years, and a tremendous amount has developed over the course of the past two years since our last meeting in Edinburgh. We are now meeting in Sydney and there are a number of topics that I think will be very important for patients and medical personnel as well. One of the biggest issues that has come to a great head over the past two years of course, has been the overwhelming opioid crisis, both in the United States and abroad, with a significantly increasing number of deaths due to the use of opioids. Whether they'd be medically prescribed opioids or unfortunately as patients find those to become inaccessible or too expensive, they move on to use heroin or even more dangerous drugs like fentanyl or carfentanil.
We now know that over 60,000 people a year are dying from opioid overdoses. And one of the few available technologies to provide pain relief and decrease the need for opioids is neuromodulation. There are techniques involving mostly spinal cord stimulation but also peripheral nerve and brain stimulation that can significantly decrease pain. And one of the things that we're going to be seeing at this meeting is the first data that demonstrates that these therapies can and do decrease the need for opioids, the opioid doses and the number of chronic pain patients taking opioids when these therapies are used. So that will be a major feature that will have profound both personal and public health implications.
Another area that will be highlighted during the special day of the conference are the tremendous advancements in non-invasive brain stimulation. This is an area that was originally felt to be sort of a small interesting but satellite field of neuromodulation that is providing stimulation usually of the brain but without implanted devices. Well, this area has just taken off and has become one of the major areas of both research and clinical development in neuromodulation. And so for example, we will have Nir Grossman who was this year's Science Magazine slash PINS award winner presenting his research on being able to perform deep brain stimulation non-invasively, which will, as it develops, have a major impact on our field of neuromodulation.
The application of non-invasive stimulation to post-traumatic stress disorder, to learning networks and enhancing learning and memory with transcranial magnetic stimulation, advancing techniques using non-invasive stimulation for the treatment of depression. And a randomized control trial of what is called theta burst stimulation for patients with mild to moderate Alzheimer's disease. These are profound advances in the field of non-invasive stimulation and so a whole day of the program immediately preceding the major program has been put over to examining non-invasive brain stimulation.
In the main program, there are several important talks that are going to be given, some having to do with less clinical but more critical and scientific evaluations of this field. So for example, Dirk DeRidder, who was the developer of the burst spinal cord stimulation pulse train will be talking about a novel model of brain function, which gives us a different way of potentially approaching brain stimulation. In addition, Dr. Sam Eldabe from the United Kingdom will provide a critical evaluation of clinical trials in neuromodulation and will help to identify not only the strengths but more importantly some of the weaknesses that we see most recently in our clinical trials.
Perhaps of greatest clinical importance will be the presentation and discussion of what are now called closed loop systems for both spinal cord stimulation and deep brain stimulation. These are systems that can sense in real time from the human brain and from the human spinal cord and measure the response of the brain and the spinal cord to stimulation, and adjust the stimulation in real time with every single pulse, millions of times a day, adjusting the output of spinal cord and deep brain stimulation systems to maintain the desired optimal stimulation of the brain or spinal cord. These are novel techniques now, but I can't imagine that in the near future these will be part of all neuromodulation devices.
Another exciting area is for the first time there is stimulation data to demonstrate that one can treat what we call nociceptive back pain, as opposed to what we have treated in the past which is neuropathic back pain. That is when there is peripheral nerve injury or spinal cord injury that leads to chronic back pain, we have for decades stimulated the spinal cord to deal with that pain more or less successfully. But we have had nothing to offer patients who have musculoskeletal chronic low back pain, which is a much more common malady. And we will hear of a prospective randomized clinical trial that was performed and demonstrates significant efficacy in treating patients with chronic low back pain due to injuries that involve the muscles and the joints of the back as opposed to the nervous supply to the back.
Can you provide examples of some of the need to know research that will be presented at the meeting?
Robert Levy, MD: I think that there are a lot of areas of research that fill in so much of what we need to know in order to really advance the field of nervous system stimulation. And we are seeing some of that now presented at the International Neuromodulation Society meeting. And a lot of it has to do with mechanisms of action but also some having to do with new clinical applications based on solid science. And so for example, there will be three talks mixing both science and new clinical studies having to do with deep brain stimulation for obesity, for eating disorders and for addiction.
And these studies are based upon very potent models of addiction and obesity and where stimulation should be initiated in order to treat these problems. And as you recognize as much as I do, these are some of the critical large scale disorders that affect our society. We have an epidemic in the United States of type 2 diabetes, and it's leading to early death and disability. And to be able to take the patients who are most badly afflicted in terms of eating disorders and obesity, if they have failed everything else, deep brain stimulation is minimally risky with a significant potential impact.
I think further there is renewed interest in stimulation for the treatment of cardiac ischemia. We used to think that cardiac bypasses and now the use of stents, were all the people with cardiac ischemia needed. But we are revisiting the field that was developed in the 1980s and there was a section on stimulation for cardiovascular disorders that discusses the current need for stimulation for cardiac ischemia.
Another area that I think we all know is part of the coming wave has to do with brain machine interfaces and using information from the brain, decoding it and using it to provide function for either the loss of motor activity or the loss of some sense. And we have several talks within the meeting on these subjects including a keynote talk by Leigh Hochberg on the progress that has been made in the last few years on brain machine interfaces.
Are there any pivotal trial results that we should be looking for?
Robert Levy, MD: Several clinical trials that are the end stage randomized control trials will be presented at this meeting. For example, the Evoke Study results, which presents the results of the Saluda closed-loop feedback system, will be reported. Robert Bolash from the Cleveland Clinic will be presenting a blinded randomized control trial on different spinal cord stimulation waveforms called the SURF study. Dr Chris Gilligan, who is at the Brigham and Women's Hospital in the Harvard system, will be presenting the data from Mainstay Medical on the multifidus peripheral nerve stimulation randomized controlled trial, which is called Reactivate. And there is a randomized controlled single blinded multicenter trial that will be reported by Jason Pope demonstrating that anatomical lead placement, that is placing spinal cord stimulation leads at a specific level of the spinal cord, is equally or more effective than placing the leads as we have historically by stimulating and ensuring that stimulation induced paresthesias overlap the area of pain and that may have significant implications for how we do spinal cord stimulation.
There is also the long-term results from the Avalon study, which is a Saluda feedback control trial that was performed in Australia. And for the first time we will have long-term outcome data using feedback regulation. Some of the science that I think is particularly important highlights the importance of the glial cells, not only in the modification and modulation of pain in the spinal cord, but also as a target for spinal cord stimulation. We've always had this very pure model that suggests that everything is from nerve to nerve to nerve. But there are actually two highlighted presentations by the group that is headed by Ricardo Vallejo, who is in Illinois, looking at genetic studies, gene expression and glial nerve activity in response both to chronic pain and spinal cord stimulation.
As I mentioned before, the decreasing need or use of opioids after neuromodulation procedures is a key topic around the world but particularly in the United States and Australia. And Nandan Lad's group out of Duke will present the results of a large scale study looking at opioid dose reduction after spinal cord stimulation.
I know you have a separate Innovations Day. Can you tell us about that? What can we expect on the technology front?
Robert Levy, MD: The Innovations Day gives us an opportunity to sit with the major shareholders of both early stage start-ups, middle stage start-ups and well- established neuromodulation companies to be exposed to the issues that face companies along the trail from early ideas all the way through commercialization of novel neuromodulation products. We will have a keynote presentation given by Josh Makower on looking for physiologic signals and using physiologic signals as the source of innovation for neuromodulation. It's something that is often forgotten but critically important in the development of new products.
We will hear from several early stage companies including Synergia out of Belgium. We'll hear from GTX Medical, Aldan’s Health, Thermaquil, Cala Health. All of these are early start-up companies taking novel approaches to neurostimulation. For example, the Synergia development is along optical fibers as opposed to electrical fibers to create a non-metallic and non-electrical method of neurostimulation. Cala Health specializes for example in novel methods of peripheral nerve stimulation to treat neural disorders. That then progresses to a discussion with intermediate stage companies and here we're talking about Mainstay, Nalu Medical which just got its product FDA approved. Saluda Medical, which has just completed the Evoke Trial. And StimRelieve which is a spinoff company of Stimwave, and they'll be talking about the use of externally powered systems as well as feedback-related systems, and systems trying to treat pain that was not effectively treated in the past such as muscular low back pain.
Then toward the afternoon we have keynote presentations from David Putrino at Mount Sinai and George Madis at the University of Cologne. Followed by a discussion of the really main players within the neuromodulation market. And here we have been honored to have the chief officers of Abbott Neuromodulation, Medtronic Neuromodulation, Boston Scientific Neuromodulation, as well as the presidents of Nuvectra and Stimwave, really talking about how to identify disruptive technology, how to make smaller companies, start-up companies more appealing to these larger companies in terms of acquisition.
And then really how to determine whether there really is a role for these new products in the marketplace or whether the marketplace is saturated. And then to recapitulate a discussion about disruptive technology and how important it is for the field. So in this one day we hope to cover the whole scope from idea to full market implementation for concepts in neuromodulation, with advice from business leaders in every phase of that spectrum.
Well, that sounds awesome. Now, in my job I cover technology in the market for neuromodulation. I'm interested in finding out what you think are some of the top technology trends you're seeing in neuromodulation right now.
Robert Levy, MD: I think that this is a very exciting time for the field of neuromodulation and in fact I often wish I was born 20 years later to be at the height of my career now as opposed to the dark ages where we had very little advancement in the field. And so there are two or three most important concepts that I think are new and exciting and will drive the future of neuromodulation that will be highlighted at the meeting. One is the use of and demand for feedback technology in all areas of neuromodulation. Once we can identify the key signal that reflects the output that we want, something that correlates with pain relief as Saluda has done identifying that the degree of ECAP, evoked compound action potential activation, correlates with dorsal column activation, which correlates with pain relief.
Once you have that established, then to have a feedback system that can control and regulate the system has not only tremendous benefits for the patients but even for industry when we can see that that automatic feedback system significantly decreases reliance on representatives and clinical specialists to keep reprogramming devices. The device becomes automatic for the most part. And whether it's deep brain stimulation or spinal cord stimulation or any other types of stimulation, feedback mechanisms are at the forefront.
The second major area is an area that we have called casually novel waveforms, but what we're really talking about now are novel pulse trains. And what we should be talking about soon are true novel waveforms to determine whether these things, which are under our control can increase the efficacy of our devices. And the area that I believe is most important is not whether device A or B can give 5% or more better populations statistics for some definition of success, but something that when applied can result in the lack of tolerance to stimulation. One of the biggest problems that we have with all modes of neurostimulation is that one way or another, the body finds a way to adapt to stimulation and whether it is as a result of synaptic plasticity and the regrowth of pathways or some other mechanism, what we see is that for many if not most of our devices, after a period of a year or two years, they become less effective. And they lose their impact on patients' quality of life. And then we're left with having an expensive therapy that fails in the long-term. And using these novel waveforms, using novel pulse trains, what we should be able to do is to alter the signal that we use to stimulate the spinal cord and alter the areas of the spinal cord or brain that we're stimulating in such a way as to make the signal novel over time. And as a result of continuing novel stimulation paradigms result in a significantly decreased or lengthen time that it takes for tolerance to develop.
Are you talking about multi waveforms or some feedback mechanism that if it detects some sort of tolerance it will automatically change to a different waveform?
Robert Levy, MD: I think that on one hand a device such for example is the Saluda device, which can detect changes in evoke compound action potential, both shape and amplitude over time, have the potential to predict when tolerance is beginning to occur and therefore could initiate a change in the waveform or pulse train that's being used. In addition, one of the issues that I will be talking about is trying to increase the randomness of the stimulation signal by using pink noise or white noise. These are random or pseudo random signals that hopefully would have the same effect on the pain pathways as blocking or decreasing pain transmission, but at the same time have enough built in randomness that they would be less likely to invoke tolerance. And that's an important issue that is facing us. As I mentioned, I'll be speaking on that topic at the meeting in Sydney and there is a lot of research that is currently being around those areas.
So you mentioned closed-loop technology, you mentioned waveforms. What other kinds of trends are you seeing right now in neuromodulation?
Robert Levy, MD: I believe that the other important trends have to do first with better understanding and better education around neuromodulation to help improve penetration of these important therapies into the population. In the United States for example, which is where the system is best developed, our penetration in the pain market is only about 8% and then the spasticity market is only about 3%. And we talk about penetration, although it sounds like sales and marketing terms, what I'm really talking about is patient access. If only 3% of patients with profound spasticity get exposed to the neuromodulation therapies for spasticity or 8% of those patients with chronic pain, then the massive group of patients who suffer from these disorders are not getting access to our therapies.
And one of the things that we have done poorly is education of other doctors, education of patients, and in fact education of third-party payers and government, such as these are therapies that they really should be supporting and promoting as opposed to avoiding. And so a lot of the meeting, as I mentioned, we're going to be critically assessing the data to support our therapies. We are going to be adding significant high Level 1 evidence to support our therapies and identifying the need for better education and delivery of that type of therapy.
So one of the lectures that I will be giving is on developing Centers of Excellence for Neuromodulation around the world, so that we can better focus the best and most qualified implanters, the expert implanters of these devices. So there will be better systems, more efficient systems, more patient-centered systems, and better outcomes from these therapies using the Center of Excellence model, which I think will develop the future of how these devices are administered if you will, throughout the world.
And the last area that I think is most exciting are the tremendous number of novel applications of both brain, spinal cord and peripheral nerves stimulation devices. There will be discussions by true experts about the value of these modalities in treating not only visceral pain but visceral function, improving disorders of gastric emptying, disorders of colonic transport time, disorders of bowel function, disorders of bladder function, dealing with issues as we've mentioned, depression, Alzheimer's disease, as well as obesity, addiction. These are things that we never considered when I was earlier in my career and now we're starting to get exciting new carefully collected data to support these novel applications.
Let's talk about all this in terms of the market. Can you discuss how these new technologies will drive growth in the market for neuromodulation?
Robert Levy, MD: As you have mentioned before, this year for example, has not been a great year for neuromodulation across the board. And what I mean by that is that while there has been growth, there has not been growth of the degree that we would have hoped for and expected. And part of that reason has to do with the decreasing resources that many of us practitioners have available to us. That is around the world there are decreasing public and private expenditures for medical care in general and for neuro technology in specific. Health care systems are being squeezed and people are looking for the appropriate kind of safety and efficacy data to support the use of some therapies and not others under this constrained economic environment.
And one of the problems that we have is that we have for decades emphasized that most of our neuromodulations therapies, unlike a cardiac pacemaker, are not lifesaving. Well, that's wrong and it is wrong because we know for example that people with untreated or poorly treated Parkinson's disease, patients with poorly treated obesity and diabetes, patients with chronic opioid use disorders die, and they die early and they die at significant numbers as a result of their progressive disorders and we have therapies to help it. And things like depression, we know that the rates of suicide are increasing in certain populations significantly. And that the incidence of treatment resistant depression is high.
We know that the growing burden of Alzheimer's disease is potentially bankrupting of our US healthcare system because it is so rapidly progressing as the population ages. So we need to make more clear the fact that these therapies lengthen life, prevent death, as well as improved quality of life and show that the cost effectiveness is strongly in favor of stimulation as opposed to non-stimulation therapies. And there will be several discussions in our meeting having to do not only with the ethics of spinal cord stimulation or brain stimulation, but also on how best to get these messages across and what kind of studies need to be done in order to convince societies, healthcare systems and other payers for healthcare as well as patients of the importance and potential lifesaving value of these therapies.
That's awesome. Is there anything else you'd like to tell us about Dr. Levy?
Robert Levy, MD: I am a consultant to many of the companies in the field of neuromodulation, and so I believe that by consulting with anyone who asks for my services, I then favor no one. But I am profoundly biased toward neuromodulation therapies as a whole, because I believe that they have the potential to train a number of neurological and non-neurological disorders at low risk with very high potential outcomes.
And what excites me most is the fact that we're getting better and better pain relief with our therapies, better and better control of movement disorders with our therapies. But also are now moving on to tackle disorders that have a significant impact on human suffering. Again, things like Alzheimer's disease, things like depression. That, combined with the fact that there is increasing acceptance of the use of neuromodulation to treat these disorder, I believe that the future for the treatment of many disorders, including disorders we don't even think of as neurologic disorders, will be done with neurostimulation.
The devil of course is in the details, and it's providing the high-quality data, the education, and the techniques for doing it safely, effectively, and proving that it's cost effective because in the United States and around the world, we're facing a situation of decreasing resources. And it would be heartbreaking to see patients not have access to these important therapies because either they are not affordable or are not cost effective.
I appreciate your time and I look forward to seeing you in Sydney.
Robert Levy, MD: I look forward to it as well.
Click the button below to read Anne's fascinating article on "Spinal Cord Stimulation: Top Trends to Watch in 2019 and Beyond" in which she takes a look back at 2018 and identifies continuing and emerging trends in the market for spinal cord stimulation (SCS) that are likely to shape the landscape in 2019 and beyond.