Dr. Tracey: Inflammation is redness, swelling, pain, loss of function and heat. It is what happens when you sprain your ankle or have an infected pimple on the back of your arm. The right amount of inflammation is absolutely critical to recovering from injury and to fighting off infection.

Host: That’s Dr. Kevin Tracey, the president and CEO of the Feinstein Institutes for Medical Research.

Dr. Tracey: However, if inflammation spills into the body or becomes excessive, now you have a problem that can progress to damaging tissues. So, rather than heal the ankle or heal the affected joints in your hand or your fingers, it can actually destroy them. It can destroy the cartilage. It can destroy the tissues.

Host: Dr. Tracey is describing chronic inflammation, which is when inflammation lasts longer than it’s needed to heal an injury or infection.

For context, diseases associated with or made worse by chronic inflammation account for 40 million of the 60 million deaths worldwide each year. Finding a solution has taken Dr. Tracey on a decades-long odyssey: And what he discovered is that it all comes down to solving one problem…

Dr. Tracey: The problem being, how does the brain turn off inflammation?

Host: Through extensive research — and a partnership with Murthy Simhambhatla, now the CEO of SetPoint Medical — Dr. Tracey and colleagues have found a way to flip the switch on chronic inflammation. Most remarkable of all? They don’t need drugs to do it.

We used an antibody to block TNF, and those antibodies ultimately moved their way into clinical use for diseases such as rheumatoid arthritis and inflammatory bowel disease. They have names like Humira, Remicade, and Enbrel. They are very important drugs in treating inflammation, but they are not the final answer. They have side effects. They are very expensive. They are invasive. They have to be injected. They only work in about 40% or 50% of the patients. My colleagues and I were looking for an alternative new drug to treat inflammation and stop cytokines.

Host: In 2007, Dr. Tracey founded SetPoint Medical, a company focused on creating medical devices to treat diseases caused or made worse by chronic inflammation. Just two years prior, in 2005, he assumed the role of president and CEO of the Feinstein Institutes for Medical Research, Northwell Health’s research arm. The key to his work in both arenas would be the vagus nerve: It’s the pathway the brain employs to control inflammation — just one of many important body functions mediated by this huge cranial nerve.

Dr. Tracey:  The vagus nerve is a bundle of nerves. We call it the vagus nerve, but actually, you have two. You have one on each side like two kidneys, two thumbs, and two vagus nerves. On each side of your neck, you have a bundle of nerves. These vagus nerves contain 100,000 fibers, so you really have 200,000 vagus nerves. Some of them control your heart rate. Some of them control your pancreas and your insulin production. Some of them control other organs.

Host: And because the vagus nerve touches so many systems in the body, it’s proving to be the key to treating the myriad conditions that are driven by inflammation. Conditions like rheumatoid arthritis, Crohn’s disease, multiple sclerosis and dozens more.

Dr. Tracey: Our discovery that launched SetPoint was the discovery that some of the fibers in the vagus nerve control how many cytokines are being produced. If you can decrease the amount of cytokines being produced by activating the vagus nerve, it is like stepping on the brakes in your car. You can slow down the amount of inflammation.

Host: After years of refining the technique, Dr. Tracey knew he would need someone to lead SetPoint who had experience bringing medical devices to market.  And this is where Dr. Simhambhatla enters the story.

Dr. Simhabhatla: I had just taken my prior company public. I thought I would take some time off, and then I got a call out of the blue from SetPoint Medical… This was 2018. The first time we spoke was on a phone call… They were talking about this idea of treating autoimmune disease by stimulating nerves, which I thought was absolutely crazy.

Host: It was a common reaction to this idea, Dr. Tracey told us.

Dr. Tracey: People had not heard of it. People did not know about it. But when they scratched the surface and saw the simple elegance of the idea, then when they looked into the clinical problem that would be solved by this relatively simple idea, it became sort of a eureka or holy crap moment. If this is true, it is really important. I think it did not take you long to decide to join us after that if I recall correctly.

Dr. Simhambhatla:  I felt that the science was pretty solid, and that there were some signs that it worked in humans in both rheumatoid arthritis and Crohn’s disease. Now going from a feasibility study to getting a therapy all the way across the finish line in a commercial setting is a pretty complex process. Knowing that the science was pretty solid, and the therapy had a very strong foundation gave me a lot of confidence to invest my time and energy in working with the team at SetPoint to develop this therapy all the way forward to when patients to when patients can have access to this therapy. We can talk about all of the steps along the way.

All of this was very appealing to me. Just knowing we had a very solid foundation and that the unmet need was massive gave me a lot of confidence to take on this project.

Host: Dr. Simhambhatla found the science fascinating. The further he dug, the more interested he became.

Dr. Simhambhatla:  Yeah. First off, the way the inflammatory reflex works as Kevin and his colleagues discovered and described it is the vagus nerve senses excessive levels of inflammation and rings an alarm bell in the brain stem. The signal from the brain stem then goes to various parts of the body to turn down inflammation. 

Quick facts about the vagus nerve: 

The vagus nerve is:

• close to the brain stem on the left side
• about three to five centimeters deep
• directly or indirectly involved in every part of the body

We felt it important to be as close to the brain stem as possible. There are so-called neuromodulation approaches with superficial nerves for essential tremor. There is tibial nerve stimulation. These nerves are very superficial. They are not as deep as the vagus nerve. We studied a number of different approaches like non-invasive, transcutaneous, and proximity electrodes. Ultimately, we determined that for the most reliable activation of this reflex, we had to directly stimulate the vagus nerve, hence our design.

Host: There are two main types of vagus nerve stimulation: 

• Direct: a stimulation device is implanted directly on the vagus nerve
• Indirect: stimulation is delivered non-invasively, over the skin

Dr. Simhambhatla:  First, let us start with traditional vagus nerve stimulators. Traditional vagus nerve stimulators have a pulse generator, which is typically a metal can with the electronics and a batter in the can. In the context of vagus nerve stimulation, those cans are implanted in a cavity in your chest. A wire called a lead wire is coiled around the vagus nerve and tunneled to connect it to the battery and pulse generator. It is pretty involved.

Our device (called the SetPoint System or MicroRegulator Implant) is the size of a large multivitamin. It has no wires. The electrodes are integrated on the device. The implanting surgeon, typically a neurosurgeon or an ENT surgeon, makes an incision in the crease of the patient’s neck. The incision can be about three centimeters long. The act and the process of accessing the vagus nerve is exactly the same as for epilepsy. It is a technique that has been around for 20-plus years. 

They access the vagus nerve, and they place our device directly in contact with the vagus nerve with no lead wire to tunnel and no battery to place in the chest. The battery is integrated into a device. It is a rechargeable battery. 

Once implanted, the device can autonomously deliver its stimulation for just one minute a day. The patient is sent home with a wireless charger that they wear around the neck for just five to ten minutes once a week to top up the charge in the device.

Host: This approach also offered another benefit.

Dr. Simhambhatla: It is a bit much to expect patients to spend half an hour stimulating themselves every day. We know how compliance is with therapies involving chronic conditions. We felt that a set-it-and-forget-it approach where you implant the device and it autonomously delivers the dose, is probably best from the patient compliance perspective.

Host: Once the device was refined, the next step was setting up a trial of the device: The RESET-RA trial — RA stands for rheumatoid arthritis. Their device, called the SetPoint System, received Breakthrough Device Designation from the FDA in 2020 for patients with moderate-to-severe RA who didn’t respond to one or more biologic medications, like those Dr. Tracey mentioned earlier. 

The FDA grants this status to medical devices that, among other qualifications, offer significant advantages over existing alternatives.

Host: Many pivotal moments have followed with research exploring vagus nerve stimulation in many conditions. Perhaps the most significant came on November 18 of this year, when SetPoint announced that its RESET-RA trial, a randomized, sham-controlled, double-blind study, met its primary effectiveness endpoint. There was objective evidence of reduced progression of bone erosion with MRI in treatment versus sham.

Dr. Simhambhatla: One of the most important things to demonstrate in the context of RA is that you can protect the patient’s joints. We interrogated the joints with MRI to determine how treatment impacted the progression of joint erosion, and we were very pleased with what we saw. The FDA uses a template of a benefit-risk analysis. The benefits of any new therapy need to outweigh the risks. We have already established the unmet clinical need. You can talk about efficacy only if your therapy is relatively safe.

Host: Another significant result from the RESET-RA Trial has to do with safety: Side effects were generally mild, the most common being temporary hoarseness of the voice.

Dr. Simhambhatla: I am really excited about RA and about what we can potentially do for patients. We talked about patients, but there is also a huge societal impact when we get this across the finish line. These drugs are very expensive. They list for $60,000 to $70,000 a year per patient.

Host: Dr. Simhambhatla is referring to the biologic therapies for RA, like Rinvoq and Humira, which Dr. Tracey mentioned earlier.

Dr. Simhambhatla: For the healthcare system and for payers, we spend about $80 billion a year on autoimmune drugs. RA is about $30 billion. They have gotten expensive enough that, as you know, some of these drugs are under consideration for price controls by Medicare. There is a patient aspect. There is a societal aspect. 

Ultimately, all of us, through our premiums and our employers’ premiums, pay for these drugs. Then there is the physician perspective. If drugs have a lot of side effects, physicians sometimes spend as much time managing the side effects as they deal with the RA itself. 
From all of these perspectives, I am really, really excited about getting RA across the finish line.

Host: Both Dr. Simhambhatla and Dr. Tracey see RA as just the beginning for this kind of treatment.

Dr. Simhambhatla: At SetPoint, we are laser-focused on autoimmune conditions. Clearly, there is a lot of benefits to vagus nerve stimulation outside of autoimmune disease, as we have spoken about whether it is epilepsy or stroke rehabilitation. We are sure there will be other applications over time. At least at SetPoint, there are so many millions of patients suffering from autoimmune diseases that we want to keep our focus there. Systematically assess each of these disease states in clinical trials.

Host: As we wrapped up our conversation, Dr. Tracey had this to say about the ongoing story of vagus nerve stimulation.

Dr. Tracey:  The trajectory of this journey has never wavered from the idea of using great science to reveal mechanisms that can be controlled using devices to the benefit of patients in the future. That is the trajectory of this story. It is a 30-year story, perhaps, but the trajectory has never changed. Murthy and his team at SetPoint have now pushed it into a hopefully soon-to-be clinical reality.