Vagus nerve stimulation has proven effective in refractory RA

WASHINGTON – According to the results of a study conducted in a phase 3 trial.

Of the 242 patients in the RESET-RA study, all had a VNS device implanted but did not know whether the device was turned on. At 12 weeks, 35.2% of patients receiving daily stimulation achieved a 20% improvement in American College of Rheumatology Response Criteria (ACR20) compared with 24.2% of patients with an inactive device. The response was more pronounced among patients who had previously received only one b/tsDMARD. A higher proportion of patients in the overall treatment group also achieved low disease activity or remission compared with those who did not receive stimulation.

The study was presented as a recent poster at ACR 2024 Annual Meeting.

“This is a particularly difficult patient group to treat because the patients included were considered refractory to biologic therapy,” said Elena Sciopu, MD, professor of medicine in the division of rheumatology and director of clinical research at the Medical College of Georgia. at Augusta University. More than a third of patients in the study had tried three or more b/tsDMARDs before starting the study. “I’m very encouraged by these results,” she added. Sciopu was the principal investigator of RESET-RA and enrolled two patients in the study.

These positive results are the first in the treatment of VNS in rheumatic diseases. Previous studies demonstrating the potential therapeutic effect of this implantation approach have primarily been open-label, proof-of-concept, or pilot studies. Non-invasive wearable stimulation devices have also shown promising results in open-label studies; however, a sham-controlled study published in 2023 found that transcutaneous ear vagus nerve stimulation was effective. no more effective than placebo.

But how does it work?

The device, developed by SetPoint Medical in Valencia, Calif., is about the size of a multivitamin and is implanted in an outpatient setting. During the 45-minute procedure, surgeons isolate the vagus nerve on the left side of the neck and place a nerve stimulator using a silicone positioning device to hold it in place.

The device is programmed to stimulate for 1 minute every day and requires charging for just 10 minutes once a week, which is done remotely using the necklace.

The device uses the anti-inflammatory properties of the vagus nerve by stimulating the nerve to help regulate the overactive immune system of a person with RA, explained David Chernoff, MD, chief medical officer of Setpoint Medical.

“We are replicating what nature has developed over millions of years, which is a connection between the brain and the immune system that turns out to be mediated by the vagus nerve,” he said. Medscape Medical News.

This new approach to VNS also does not pose the same immunosuppressive safety concerns as drugs commonly used to treat RA, he said.

“We can regulate the amount of inflammation without causing the problems with the body’s defenses,” which are present in some of these drugs, he continued.

SetPoint Medical pilot study Use of the device in 14 patients showed promising results. Five of 10 patients randomized to active VNS experienced clinical improvement over 12 weeks, as measured by the 28-joint disease activity score based on C-reactive protein (DAS28-CRP) and the Clinical Disease Activity Index. The remaining four patients who received sham stimulation (where the device was implanted but not activated) did not experience clinical improvement.

RESET-RA Details

The most recent, much larger phase 3 study included patients from 41 sites in the United States. Patients were on average 56 years old and had a body mass index of 30; 86% were women. A total of 39% had previously tried one b/tsDMARD, 22% had tried two, and 39% had tried three or more. Patients had an average of 15 tender joints and 10 swollen joints. Patients stopped taking b/cDMARDs before the procedure and continued taking conventional DMARDs during the study, including methotrexate, hydroxychloroquine, and sulfasalazine.

The researchers randomly assigned patients 1:1 to active (treatment) or inactive (control) stimulation.

“The perception of stimulation varies from patient to patient, which in itself is useful for blinding because there is no expected perception of whether stimulation will be felt and how it will be felt,” Chernoff explained. According to him, the 1-minute stimulation was scheduled for early morning, when the patient usually sleeps.

Patients were excluded from analysis if they were treated with steroids or b/tsDMARDs at week 12. After week 12, the control group was switched to stimulation, and effectiveness was assessed again at week 24.

Higher ACR20 response, lower disease activity

In addition to meeting the primary endpoint of ACR20 response, patients in the active stimulation group showed lower disease activity at week 12. Compared with 15.8% of patients in the control group, 27% of patients in the treatment group achieved DAS28-CRP ≤ 3.2.

Active stimulation was particularly effective in patients who had previously received only one b/tsDMARD. In this subgroup of patients, 44.2% in the treatment group achieved ACR20 compared with 19.0% in the control group.

During this sham-controlled study period, 13.1% of patients in the treatment group and 18.3% of patients in the control group reported procedure- or device-related adverse events (AEs), most commonly vocal cord paresis or dysphonia. In the treatment group, 8.2% reported stimulation-related AEs, most commonly mild/moderate pain, which could be controlled by adjusting the stimulation level.

Serious adverse events (SAEs) were relatively rare, with four treatment-related SAEs in both study arms. No AEs led to study discontinuation before week 24.

The 12-week results mirror initial studies of Humira and Enbrel in the late 1990s and early 2000s, Sciopu said, although in those studies patients were not taking biologics and some were naive to methotrexate. A more appropriate comparison would be a biologically experienced population, she said.

At week 24, the percentage of patients achieving ACR20 increased to 51.5% in the treatment group and 53.1% in the previous control group, who were now switched to active stimulation. In this secondary phase, patients can add any additional treatments such as steroids or b/tsDMARDs. After 24 weeks, 81% of patients continued to receive stimulation without requiring additional medications beyond continued DMARD use.

The results also show “continuous improvement over time,” Sciopu said, with response rates increasing at 24 weeks.

Schiopa is particularly excited about the possibility of using this device for stimulation in older patients who may have been on immunosuppressive medications for decades.

“In addition to chronic immunosuppression, their immune system is more fatigued (due to age),” she said. With a VNS therapy like SetPoint, “we could offer (these patients) a less immunosuppressive alternative that is still immunomodular enough to treat RA.”

Sciopu is a consultant for Johnson & Johnson and has reported receiving research funding as a principal investigator from SetPoint, Galapagos, Johnson & Johnson, Boehringer Ingelheim, Lilly, argenx, EMD Serono, Priovant, Novartis, Bristol Myers Squibb, Zena Pharmaceuticals, and Horizon /Amgen.