Anticipated vagus nerve stimulation approval may fill ‘demand’ in rheumatoid arthritis
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When researchers at ACR Convergence 2024 presented positive data from the RESET RA study regarding vagus nerve stimulation in rheumatoid arthritis, it represented the latest milestone on a long and unpredictable journey for the treatment.
It’s a journey that, according to those researchers and other experts, will likely end in FDA approval for RA, possibly as early as this year.
“The idea of using vagus nerve stimulation to treat RA really came about after an accidental result in my lab,” Kevin J. Tracey, MD, president and CEO of Northwell Health’s Feinstein Institutes for Medical Research, in New York, and pioneer of vagus nerve research, told Healio.
Tracey and colleagues had been investigating a molecule for the treatment of RA when they observed that it controlled TNF and neuroimmune inflammation in mice.
“We could not understand how this molecule blocked TNF and other cytokines,” Tracey said. “The answer turned out to be that the molecules in the brain were controlling the vagus nerve to control TNF.”
In 2007, Tracey co-founded SetPoint Medical, with the “singular purpose” of developing a vagus nerve stimulator for the treatment of autoimmune diseases.
The science behind this quest is sound, according to Vibeke Strand, MD, adjunct clinical professor in the division of immunology/rheumatology at Stanford University.
“We know that the cholinergic anti-inflammatory pathway is a regulatory mechanism that uses the vagus nerve to reduce inflammation,” she said.
Aside from inhibiting production of TNF, interleukin (IL)-1-beta and IL-6, the vagus nerve is also involved in the phosphorylation of Janus kinase (JAK)-2 and signal transducer and activator of transcription (STAT)-3, according to Strand.
“It is everywhere, essentially,” she said.
All of this ultimately led to the RESET RA trial.
A big RESET
In RESET RA, patients underwent implantation of a Setpoint System, where a device approximately the size of a vitamin tablet is placed on the left cervical vagus nerve in an outpatient procedure, and programmed to deliver automatic stimulation for 60 seconds daily.
Results showed a statistically significant benefit of vagus nerve stimulation compared with controls in terms of ACR20 response at week 12 (P = .0209). For patients with one prior exposure to a biologic or traditional synthetic disease-modifying antirheumatic drug, ACR20 response rates were 44.2% for the treatment group and 19% for controls (P = .0054), according to the researchers.
John R.P. Tesser, MD, FACP, of Arizona Arthritis & Rheumatology Associates and Midwestern University, presented the findings at the ACR Convergence.
“The study results are statistically positive,” he said.
However, perhaps the study’s most important conclusion pertains to a sub-analysis of patients who had failed multiple prior therapies vs. those who had only experienced one prior therapy, according to Tesser.
“When you tease out the subgroup analysis, you see that two-thirds of the cohort were very difficult to treat patients, having had two or more advanced therapies,” he said. “One-third had only experienced one TNF inhibitor. The effect size was much higher in this group that had only experienced one therapy. This puts things into context.”
Further findings from 12 weeks suggested that active vagus nerve stimulation statistically significantly improved DAS28-CRP LDA/remission rates over controls, while the rate of erosion progressors, as assessed via MRI, were significantly lower in the treatment group. In addition, MRI results demonstrated that synovitis and osteitis scores had tracked lower in the treatment group.
After the initial 12-week endpoint, controls then crossed over for an extended open-label phase of the study. By week 24, ACR20 response rates increased to 51.5% for the active treatment group and 53.1% for the control patients who had crossed over. Meanwhile, DAS28-CRP LDA/remission rates continued to improve for the treatment group through week 24.
“After the week 12 crossover, only 20% of patients had conventional advanced RA therapies added,” Tesser said. “This speaks to the effectiveness of vagus nerve stimulation.”
‘Not a newfangled procedure’
Safety data from RESET RA suggested that serious adverse events occurred in just 1.7% of patients treated with the nerve stimulator. According to Tracey, this figure is indicative of just how common the treatment is in other specialties.
“This is what is often overlooked and warrants commenting on,” he said. “Somewhere between a quarter and a half a million people already have some kind of vagus nerve stimulator in the body.”
Tracey noted that such devices have been used to treat epilepsy, depression and stroke.
“This is not a newfangled procedure,” he said. “We know this surgery is safe.”
According to Strand, the procedure, and the SetPoint device, have only improved on the devices used since 1997, when the first FDA approval came down for a vagus nerve stimulator in epilepsy.
“It is not hard for any neurosurgeon to do the implantation, and they will have to pass a proficiency test,” she said. “This is a really simple procedure.”
However, perhaps the most important impact is what nerve stimulation does not do.
“We know it does not cause immunosuppression, which is the major side effects of the current drugs,” Tracey said.
That said, every surgery comes with some risks, according to Ronald van Vollenhoven, MD, PhD, chair of the department of rheumatology and clinical immunology at the Amsterdam Medical Center, and director of the Amsterdam Rheumatology Center Academic Medical Center.
“The device must be on and delivering a current for a short time every day, and during this time the voice is affected,” he said. “A very small postoperative risk of longer-lasting damage to the voice box seems also present.”
Although the device is compatible with MRI scanning, van Vollenhoven stressed that further investigation of its utility in other settings is necessary.
“Potential interaction with other biophysical devices must be sorted out in future clinical trials,” he said.
Meanwhile, Strand said she is optimistic that future studies will lead to FDA approval of the device, possibly as early as 2025.
“I was part of a meeting with the FDA’s device division,” she said.
“The fast-track designation from this division puts the SetPoint device on a good pathway to approval,” Strand added.
Although Tesser is similarly optimistic for approval, he cautioned that the process for approving devices will require from more stakeholders than is the case with pharmacologic agents in rheumatology.
“The device division is very different from our usual experience of approval for pharmacotherapeutic medications,” he said. “This division will require input from a lot of other specialists to help them understand the context, the disease of RA, the mechanisms of immunity and autoimmunity.”
Rheumatologists, neurologists, neurosurgeons and immunologists, among others, will be involved, according to Tesser.
“It is a totally different process,” he said.
Once FDA approval is obtained, rheumatologists will then be tasked with the challenges inherent to uptake in the clinic.
‘A broader range of patients’
Although the cost of the procedure has not yet been announced, Strand noted the major obstacle faced by patients treated with current therapies.
“Biologic drugs can cost between $50,000 and $100,000 per year,” she said.
It is unlikely that the SetPoint device and procedure will come with such a price tag, according to Strand.
“Also, the cost will not recur annually, as the price of biologics does,” she added.
RESET RA might offer some insight on the pricing equation, at least in terms of impacting pharmacologic therapy use. At 24 weeks, 81% of patients were being treated with neuroimmune modulation therapy alone and did not require additional biologic or traditional synthetic DMARDs.
However, whether all trials — to say nothing of real-world use — result in such a reduction in pharmacotherapy use remains to be seen.
The next consideration is determining which patients might be good candidates for vagus nerve stimulation. According to van Vollenhoven, the first patients in line will likely be those with inadequate responses to previous treatments.
“At first, this treatment will find a place for patients who have tried various kinds of drugs — such as conventional disease modifying drugs, biologicals, JAK inhibitors — without obtaining sufficient relief and/or having limiting side effects,” van Vollenhoven said. “Although this happens less often today than in the past, this is still a substantial group of individuals. At a later stage, if the treatment continues to prove beneficial, it could even be offered to a broader range of patients.”
In these cases, shared decision-making between the rheumatologist and patient is likely to come into play, depending on the parameters of an FDA approval, according to Tesser.
“If the only approval is for people with past TNF experience, then other populations, including those at risk for infections, malignancies or cardiovascular outcomes, could use it off-label,” he said. “But this will be a decision involving the clinician, the patient and their insurance carrier, because someone will have to pay for it.”
According to Tracey, the fact that the RESET RA study had featured refractory patients was mostly due to practical concerns involved in analyzing a new therapy in rheumatology. He urged patience when discussing potential uptake of the device.
“When you are developing a completely new therapy, you have to go one step at a time,” Tracey said. “For obvious reasons, we started with refractory patients who could not tolerate biologics. When a new device comes along, the first way to test it are in the sickest patients. When you consider the RESET RA participants were out of options, the VNS results are wonderful.”
It is possible that in future trials, patients who are biologic-naïve may also derive benefit from this device, according to Tracey.
“But we have to do those trials,” he said.
However, Tracey added that he believes there is an appetite for this research.
“Patients are going to demand this,” he said. “They are looking for an alternative to medications with black box warnings that cost $100,000 annually.”
Additionally, that demand may not be limited to patients with RA.
“As vagus nerve stimulation could potentially downregulate a great variety of autoimmune responses, I will be very interested to see these indications being explored,” van Vollenhoven said.
Studies in Crohn’s disease and multiple sclerosis are currently underway, and Tracey suggested that inflammatory bowel disease, metabolic syndrome, diabetes and other forms of autoimmune and autoinflammatory conditions could all be fair game for vagus nerve stimulation.
“We have 25-plus years of experience with this mechanism, which points to the root causes of these conditions,” he said.
References:
Tesser J. Abstract L10. Presented at: ACR Convergence 2024; November 14-19; Washington, DC. Abstract L10.
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