Therapeutic Potential of Neuroimmune Modulation in Treatment Paradigm of Relapsing Multiple Sclerosis

David Chernoff, MD, chief medical officer at SetPoint

Relapsing multiple sclerosis (MS), a form of MS characterized by episodes of new or worsening neurological symptoms followed by periods of partial or complete recovery, has traditionally been treated with disease-modifying therapies (DMTs). These therapies aim to reduce the frequency and severity of relapses by modulating the immune system. While effective at slowing disease progression and modulating the immune system, most DMTs primarily work by suppressing immune activity to prevent new damage rather than promoting repair of existing damage. As a result, these treatments often fail to address one of the critical aspects of MS pathology: the progressive loss of myelin sheaths around nerve fibers.

In early October, the FDA granted investigational device exemption (IDE) approval to SetPoint Medical to study its proprietary neuroimmune modulation platform in patients with relapsing-remitting MS. The multicenter, randomized, double-blind, sham-controlled pilot study will be initiated in 2025 and will enroll up to 60 patients across the United States. If successful, this neuroimmune modulation approach could offer a novel treatment avenue for MS that complements or even surpasses traditional DMTs by providing neuroprotection and supporting nerve repair.

Following the announcement, David Chernoff, MD, chief medical officer at SetPoint, sat down to provide some clinical insight on the mechanism behind the neuroimmune modulation platform and how it may help patients with relapsing MS. In the conversation, Chernoff stressed that this approach contrasts with conventional treatments that often suppress the immune system, increasing infection risk. Instead, SetPoint’s platform activates pathways that reduce inflammation and promote neuroprotection, potentially supporting remyelination. In addition, he gave some commentary on what the upcoming trial looks like, and how SetPoint’s prior study in patients with rheumatoid arthritis, supported the platform’s safety and efficacy for further development.

NeurologyLive: How does the neuroimmune modulation platform operate? Talk about its mechanism, and some of the advantages it holds?

David Chernoff, MD: Neuroimmune modulation involves tapping into neural reflex arcs that allow the brain to communicate with the immune system to maintain immune homeostasis. The vagus nerve is the longest of the 12 cranial nerves, and directly or indirectly interacts with almost all organ systems. It is therefore ideally suited to act as an immune sentry by being able to detect danger signals and immune perturbations and relay that information back to the specific regions of the brainstem. Those specialized brain stem centers act as immune rheostats and send back information via the vagus to organs, including the brain itself, resetting how robust the immune reaction should be. SetPoint Medical’s therapeutic platform, which is comprised of a miniaturized, integrated neurostimulation device, is designed to deliver targeted electrical stimulation to the vagus nerve to activate these innate pathways.

One of the advantages of amplifying an established neural reflex arc is that the responses are immune modulating but not immunosuppressive, in that these alterations in immune responses do not interfere with or compromise host defense against infections. As opposed to drugs used to treat MS, which by design, knock out specific pathways and mediators and increase infection risk, neuroimmune modulation does not cause that degree of immunosuppression because it only partially reduces the ability of white blood cells to secrete pro-inflammatory cytokines.

Another advantage is that activating these pathways, by stimulating the vagus nerve, also releases specialized pro-resolving mediators that aid in neuroprotection by increasing clearance of cellular debris and upregulating genes that promote remyelination. Since MS is characterized by neuroinflammation and extensive demyelination, an approach that has the potential to reduce demyelination and promote remyelination could provide a differentiated option to treat MS.

What would a clinical trial assessing the platform in relapsing-remitting MS look like? Are there any considerations when designing a trial evaluating a neuromodulation approach?

With respect to the MS trial design, the preclinical rodent models used to assess neuroimmune modulation showed not only reduction in disease activity but also a very strong signal for remyelination. This observation does not occur with the use of approved MS drugs, which by virtue of their MOAs prevent new damage from occurring but do not promote repair of damaged axons. Although neuroimmune modulation has anti-inflammatory activity in rodent models, it is the remyelinating properties that will be the focus of evaluation in SetPoint's MS study.

The pilot study in relapsing-remitting MS (RRMS) will be a multicenter, randomized, double-blind, sham-controlled study that will be initiated in 2025, and enroll up to 60 patients across the United States. RRMS patients with stable disease who have deficits in their visual and other functional pathways while on their disease-modifying therapy (DMTs) will be implanted with the SetPoint system and randomized to active stimulation versus sham stimulation for six months. After six months, all participants will have the opportunity to receive active stimulation and be followed up long-term.

Since this is the pilot study, we will be evaluating numerous endpoints to best understand the potential of remyelination with SetPoint’s neuroimmune modulation device. This includes safety assessments and serial assessments of visual pathways using OCT, VEP, visual acuity, and brain MRI quantification of myelin using MTR (magnetization transfer ratio).

What were the greatest takeaways from the previously completed RESET-RA study? Were there any insights from that study that helped you shape this upcoming trial?

The key takeaway from the RESET-RA study was that the implant procedure that places the SetPoint System is safe and the rates were very low with procedure, device, or stimulation related adverse events. The study also demonstrated the anti-inflammatory and joint-protective potential of neuroimmune modulation as it met the primary endpoint of improved effectiveness in rheumatoid arthritis (RA) patients.

What does the safety look like of the platform? To date.

As mentioned above, in the RESET-RA study no safety concerns have been observed during the first 12 weeks and long-term follow-up, as available. Adverse event rates were low for both the implant procedure and stimulation therapy, and overall treatment was effective and well-tolerated.