Results of an investigational US pilot study have shown that a proprietary bioelectronic microregulator device, manufactured by SetPoint Medical, can benefit patients with rheumatoid arthritis (RA), resulting in a positive clinical response and reduced Disease Activity Score (DAS). Study data were presented during a press conference at the 2019 European Congress of Rheumatology (EULAR), held June 12 to 15 in Madrid, Spain.1

The multicenter, double-blind, randomized trial evaluated the safety and tolerability of the device, a vagus nerve stimulator, for the treatment of refractory RA in patients with insufficient response to 2 or more biologic or targeted synthetic disease-modifying antirheumatic drugs, with at least 2 modes of action. In addition, 9 of the 14 participants failed to respond to treatment with a Janus kinase (JAK) inhibitor.

“The first 3 patients that entered this study were done as an open label. This is the first time this device was implanted in a human, so the first 3 patients all knew they were getting the device and that the device was turned on,” said Mark C. Genovese, MD, Director of Rheumatology Clinic in the Division of Immunology and Rheumatology at Stanford University School of Medicine, in an interview with Rheumatology Advisor. After these first 3 patients had undergone implantation and stimulation with the device and it was found safe, Dr Genovese and his colleagues randomly assigned 11 additional patients to receive either a minute of stimulation once daily, a minute of stimulation 4 times daily or sham stimulation.

Rheumatology Advisor: Could you provide a brief overview of the most remarkable results of the US pilot study presented at EULAR?

Dr Genovese: The study was designed to assess a new implantable microregulator that would be able to provide stimulation to the vagus nerve. The goal would be to impact the inflammatory reflex, which is recognized as a neuroimmunologic synapse, where, through a neurologic signal to the vagus nerve, there is release of various inflammatory mediators. By providing signaling to that nerve, we can impact the amount of those immune mediators that are being released from certain cell types.

We were fortunate enough to be able to do this as a first in humans. There are previous data available in the public domain from a very good study that has been published in the Proceedings of the National Academy of Sciences where a different type of device was also used to stimulate the vagus nerve, yielding clinical improvement.2

Patients were followed for a period of 12 weeks once therapy titration began. We were fortunate that we didn’t see a lot of adverse events. The device seemed to work fine, without any issues associated with it, and we didn’t have any serious treatment-related adverse events.

I will draw your attention to the fact that there were some patients who suffered from surgical-related adverse events. We had a variety of patients who had different issues, such as inflammation of the surgical site post-surgery, but there were also 2 more severe events: one was Horner syndrome and the other was transient left vocal cord paralysis. Both these surgical events, which have been previously reported with vagus nerve stimulation (VNS) procedures, have now appropriately been resolved.

The second aspect of this study was to see whether or not the stimulation these patients received actually resulted in the improvement of their disease.

Those who received sham treatment did not improve at all. For those first 3 patients, there was a notable improvement in their disease, meaning an improvement that was greater than the clinically important difference in the DAS. In the second group (those who underwent randomization), we saw that patients who received stimulation once a day were also able to achieve an important difference in the DAS. Then, interestingly, those who received stimulation 4 times a day did not appear to improve.

Over time, of those patients who had been receiving once-a-day stimulation, 2 patients were able to achieve the definition of remission. We also saw that there was a correlation between stimulation and a reduction in cytokine analysis based on stimulated cytokine bioassays, suggesting that there was some biologic activity that was taking place as well.

Lastly, as part of the study, we also performed magnetic resonance imaging (MRI)s, looking to see whether or not changes that were reported clinically also had a radiographic — or in this case, an imaging — component. During the course of the study, we didn’t see any notable changes across the population in either synovitis or osteitis, but we did see a reduction in erosions in patients who were receiving once-a-day stimulation.

Overall, I would say that the most important aspect of this study was that the device could be successfully implanted in patients with biologic refractory RA and well tolerated. I think the bonus was that we saw clinical improvement in some of these patients achieving minimally clinically important differences in their DAS scores. We also saw a reduction in some inflammatory cytokines.

I think it’s still too early to understand what the trends we saw on the MRIs represent over time, but certainly enough to be enthusiastic about saying that this device may, in fact, be useful. Additional studies need to be conducted on more patients with RA and, potentially, other chronic inflammatory diseases.

Rheumatology Advisor: Could you briefly describe the mechanism of action behind the implant? Why, specifically, was the vagus nerve a target of interest?

Dr Genovese: There has been research going back more than a decade, originally starting with Kevin J Tracy’s work [on the inflammatory reflex].3 Other researchers have continued to build from there.

There was a clinical trial, done with a traditional VNS device, which was repurposed and implanted in the chest wall, with the leads wrapped around the vagus nerve.2 That previous trial demonstrated a significant benefit to patients whose disease failed to respond to methotrexate (MTX) therapy or in patients whose RA did not respond to biologic therapy. The initial trial included 17 patients with that device; it also demonstrated that when the device was turned off, the disease returned.

There was certainly precedence from animal models and work that had been done in vitro. But now there’s also that human trial published in 2016.3 It was proof-of-concept work like these that led to the development of this new, potentially commercial device that would be implantable and directed specifically for use as a vagus nerve stimulator.

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Rheumatology Advisor: What are the benefits of bioelectronic implants vs disease-modifying antirheumatic drugs (DMARDs), specifically in patients with RA?

Dr Genovese: I think it might be too early for us to know. The idea of us implanting something, obviously, takes on some degree of permanence, although it certainly can be removed. The idea that we may be able to stimulate, without resulting in the same type of side effects as, say, with either a pill or a biologic, is a potential.

However, I also want to recognize that if we’re substantially modulating the immune system through this mechanism, there may potentially be adverse events as well.

Rheumatology Advisor: Is there a specific profile of a patient with RA who would most benefit from this therapy?

Dr Genovese: I don’t think we know that yet. Based on the preliminary 17 patients that were studied in Europe with the traditional VNS device,3 it was just as it worked in less refractory and more refractory [RA]. In the study that we completed, it was only studied in patients who [did not respond to] multiple biologics or JAK inhibitors; in fact, 9 of the 14 participants had tried a JAK inhibitor in the past. We were looking at [people with] significant refractory [disease]. Our data suggest that there was some improvement in that patient population.

The question is, could [this implant] have utility in other populations, either by itself or in combination with other approaches? It very well might, but those still need to be studied.

Rheumatology Advisor: On that note, are there any future studies or research avenues planned specifically for this product?

I know that there is another study ongoing by SetPoint using the traditional VNS device in patients who have inflammatory bowel disease. I believe that this device has only been studied in RA at this point. I would hope that there is an additional opportunity to see other studies in RA in the future, much larger studies demonstrating the safety and efficacy for potential utilization in this device. There’s also the opportunity that [this technology] could have value in a variety of other autoimmune diseases over time, although it’s too early to speculate.

References

1. SetPoint Medical. SetPoint Medical reports positive results from its US pilot study in rheumatoid arthritis [news release]. https://setpointmedical.com/setpoint-medical-reports-positive-results-from-its-u-s-pilot-study-in-rheumatoid-arthritis/. Published June 17, 2019. Accessed June 27, 2019

2. Koopman FA, Chavan SS, Miljko S, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci U S A. 2016;113:8284-8289

3. Tracey KJ. The inflammatory reflex. Nature. 2002;420(6917):853-859