Will cheap nerve stimulators replace blockbuster biologics? Welcome to the exciting world of bioelectronics medicine

The use of electricity in medicine is hardly new; two millennia ago, the Roman Emperor Claudius received shocks from an electric fish to treat the imperial headache, and over the past century electrotherapy has been used to help patients with conditions as varied as pain, neuromuscular dysfunction and incontinence, as well as psychiatric disorders. More recently, deep brain stimulation has shown remarkable efficacy in the treatment of Parkinson’s disease, chronic pain and major depression.

However, one area that has been attracting a lot of attention in the past few years is the use of nerve stimulation to modulate disease pathways, or bioelectronics medicine. “We are an overnight success after working on this puzzle for 20 years,” says bioelectronics medicine pioneer and president of the Feinstein Institute at Northwell Health, Dr Kevin Tracey. “Bioelectronic medicine is a new way of thinking about disease. Drug companies start with a disease and the molecular mechanism but they move directly to making a drug. In bioelectronics, we also begin with the molecular mechanism but then identify the nerves that control it. We use electrons rather than drugs.”

From early beginnings in treating central nervous system conditions such as headache, the potential impact of bioelectronics medicine has blossomed, says Dr Tracey. “There are a lot of mechanisms under active study. Researchers are looking at how nerve signals and neurotransmitters regulate cancer growth and progression and there is tremendous interest in diabetes with some very interesting data looking at the role of neural signals in the pathogenesis of diabetes and insulin resistance. And that’s just mentioning the two biggest diseases left in the world,” he says.

As with all innovations, questions abound. What do these potential new treatments mean for the pharma industry? Will a zap from a neurostimulator consign pill-popping to history as some of the media hype suggests? Is it possible that a £250 handheld device can have the same effect as a highly targeted, exquisitely designed pharmaceutical?

The wandering vagus nerve

The approach that is attracting the most attention is modulation of the vagus nerve, the largest of the cranial nerves into the brain and the only one that enters the body. Originating in the brain stem, it travels down the neck into the body and connects with most of the body’s organs. This unique nature has led researchers to send signals up into the brain – to treat central nervous system conditions as varied as cluster headache, migraine, epilepsy and depression – and down into the body to treat diseases such as rheumatoid arthritis, irritable bowel disease and even obesity.

ElectroCore is one company focused on using bioelectronic medicine to treat CNS conditions. “Some people are using the phrenic nerve to help people with lung failure to breathe properly while others are focused on the trigeminal or occipital nerves, but we’re interested in vagal nerve stimulation,” says chairman and CEO, JP Errico. “The conditions we are looking at – headache, epilepsy, stroke, concussion, Alzheimer’s disease etc – are considered to be problems with neurotransmitters, the chemicals in the brain that control brain function.”

The company’s most advanced programmes are in headache. “We are looking in two areas: cluster headache, a relatively rare but exceedingly painful and underserved condition; and migraine, a common condition that affects over 10 percent of the population. We have run four studies in cluster headache and we have 10 pilot studies in migraine that we are expanding into large clinical studies, so we’re confident we have the data to show effectiveness in headache,” says Errico.

However, the company is keen to test its handheld device, gammaCore, outside of headache. “We have done some really interesting data work in patients who suffer from widespread symptoms that are common to pain disorders, headaches, depression, anxiety, irritable bowel syndrome, sleep disorders, even asthma,” he says. “By and large, these patients don’t just suffer one symptom alone – 90 percent of patients diagnosed with headache have one or more of these other problems, and the same is true of depression. In fact, if you pick any one of these conditions you find the patients are experiencing the symptoms across the spectrum.”

To explore this, the company is conducting a large-scale patient registry. “We have found that, while the therapy doesn’t work for everybody, when it does work it has a broad spectrum effect. It doesn’t just impact the headache but also affects pain or IBS symptoms. The magnitude of effect on quality of life is akin to that experienced after a surgical procedure like a knee replacement,” says Errico.

Taking part in this study is Dr James Ward, a GP with a special interest in headache. “Around 40 patients in our practice are taking part as just one of 13 or 14 practices across the north of England using the external vagal nerve stimulator. The patients have multiple symptoms around headache or IBS or depression and they are offered the opportunity to try this as an alternative to the usual pharmaceutical or psychological treatment route. They receive some instruction from a pharmacist and use the device for two minutes on each side of the neck three times a day, with a boost if they develop a headache.”

Feedback from patients has been largely positive, he says. “Patients seem to tolerate it well and there haven’t been any major side effects issues. A number of patients have found it useful in reducing their symptoms or the amount of medications they require, although it hasn’t worked for everyone. Some people get an odd tingling sensation around the lip that took some getting used it and one patient reported a worsening of his cluster headache but apart from that there were no major issues.”

For doctors, the stimulator is welcome as an alternative to pharmaceuticals, says Dr Ward. “When you see patients with chronic long-term problems, you can see their hearts sink a little when you just offer them another pill. An alternative to oral medications is attractive for many patients who do not want to take a drug due to potential side effects, plus many patients take multiple medications and so non-pharmaceutical treatments are less likely to cause interactions with other medications.”

Amazing results

With a growing body of evidence in CNS conditions, Dr Kevin Tracey from the Feinstein Institute has spent several years now looking below the neck. His work has focused on tumour necrosis factor or TNF, the target for biological drugs such as Remicade and Enbrel.

“We looked at TNF as the molecular mechanism and put under the control of the electron,” says Dr Tracey. “It is an incredibly exciting area of science and there have been six to eight major advances in the last few years. There is very interesting work taking place in Japan looking at multiple sclerosis and other groups looking at the GI tract and how nerves interact with the microbiome, and that’s just a snapshot. We are at a start of a new field of research.”

SetPoint Medical, a company Dr Tracey co-founded, has been testing navel nerve stimulation in patients with rheumatoid arthritis. “Many of these patients have been put into remission by blocking TNF with electrons not drugs. There have been two cohorts; the first were methotrexate failures who had no access to biological treatments so they had no other hope, the second was in patients who had failed on biological. One case study featured in the media was a woman in Amsterdam who had been unable to even pick up a pencil prior to treatment and had tried a lot of drugs. After the trial, she was in remission after years of suffering, and what’s more, the beneficial effects have persisted over time.”

The patient, Monique Robroek, told Sky News: “I have my normal life back,” having had the implant fitted a year ago. “Within six weeks I felt no pain. The swelling has gone. I go biking, walk the dog and drive my car. It is like magic.”

Although such results may seem like magic, Dr Tracey is quick to emphasise the quality of the science behind them. “Yes, these results are amazing but this treatment is not snake oil. It’s also not surprising to me because the clinical results were predicted by 15 years of lab work and the science translated beautifully.”

One of the researchers behind these trials is Dr Peter Paul Tak, a leading rheumatologist and senior vice-president and head of Immuno-Inflammation R&D at GlaxoSmithKline. “This patient is in a state of remission, in other words total absence of any signs of inflammation. She has been cured, I would say,” said Tak, speaking at the Royal Society of Medicine last year. “As a rheumatologist with a lot of experience, I can tell you I have never seen this before, so there is something quite powerful here. For me, this has been a total paradigm shift.”

Is the future bioelectronic?

With such encouraging clinical outcomes, are nerve stimulators en route to replace pharmaceuticals? “This technology will replace some fraction of the global pharmaceutical market but I’m not going to hazard a guess what percentage of future therapies will be electrons rather than drugs, however, it will be significant,” says Dr Tracey. “I get emails every day from patients who don’t want to take drugs; they don’t like the side effects, the injections, the cost, and they don’t like to put things in their bodies. Drugs have saved many people’s lives and they are here to stay – no one is saying that devices will replace all drugs – but I do believe patients and perhaps payers will be interested in a device that can replace drugs like anti-TNFs, which are expensive, only work in half the patients at best and have serious side effects. To me the big question is, how many mechanisms can we map to nerve circuits and can then control with a device?”

Errico is similarly upbeat about the future of bioelectronics medicine. “As our data show the effects and safety of this therapy, I believe that perhaps 20 years down the line, we may think of it as Vitamin I, something you use every day when you get up. It could be used for a number of different conditions or maybe just to keep the body in balance, to give the autonomic nervous system a boost to keep you feeling well and your body functioning properly.”

We are an overnight success after working on this puzzle for 20 years Dr Kevin Tracey, the Feinstein Institute

The magnitude of effect on quality of life is akin to that experienced after a surgical procedure like a knee replacement JP Errico, ElectroCore