Splenic nerve stimulation continues development as potential RA treatment option
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The ongoing development of splenic nerve stimulation has continued to provide a window into the potential future of bioelectronics in medicine, according to Kristoffer Famm, PhD, president of Galvani Bioelectronics, based in the U.K.
The technique, which involves the insertion of a small implant into the patient’s abdomen, allows for the electrical stimulation of the patient’s splenic nerve. Famm said it has shown early positive impacts in animal models of rheumatoid arthritis.
In an interview with Healio, Famm discussed the development of the technique, its status, and how it could impact the treatment of RA in the future.
Healio: How was the splenic nerve stimulation therapy developed?
Famm: Splenic nerve stimulation is an early example of a bioelectronics medicine , a field of therapy that seeks to yield new treatments for a wide range of diseases. Therapy is delivered by electronic devices implanted inside the body that use tiny electrical currents to dial up or down the activity of nerves which control the functions of specific organs. By doing this, one may be able to help the body restore a healthy organ function or correct itself in diseases where a different level of those functions is needed.
A major promise of bioelectronics is the specificity of the treatment that may be achieved by interacting with a nerve right next to the organ (“near organ”); you are trying to affect the one that matters for the disease. While neuromodulation has existed for some time (spinal cord, deep brain stimulation, vagus nerve stimulation, etc.), splenic nerve stimulation required the development of a new neuromodulation system to address near-organ, abdominal nerve targets. ... Galvani Bioelectronics, in partnership with Verily engineers and surgeons from U.S. and U.K., has developed the world’s first active neuromodulation system that can be fully implanted using a minimally invasive keyhole surgery.
The implant is delivered through a small incision in the belly button, minimizing the visual signs of surgery as well as maximizing the probability of speedy recovery from surgery. The implanted electronics utilizes a custom designed stimulator built using integrated circuit technology, which delivers a precise dose of electric current to the splenic nerve in predefined time without a need for any intervention from the user. This integrated circuit also continuously checks the electrodes’ status on the target nerve and ensures reliable therapy delivery.
The implant incorporates a novel flexible interface which can be attached around a splenic artery and nerve fascicles that travel with it. Such flexible neural interface architecture is designed for long-term safety and eliminates the need for advanced microsurgical techniques, while exciting the nerve fascicles traveling around the artery.
The implanted components use materials that have established medical device history to maximize safety.
Bluetooth technology is built into the implanted electronics so the implant can communicate wirelessly with external electronics such as a patient remote, such as a smartphone, and physician tablet. Through this communication, the user can check the status of their implant and physicians have access to therapeutic parameters that can be adjusted according to patient need. The implant utilizes a rechargeable battery and wireless charging technology so patients can re-charge their battery in the convenience of their homes using an external charger. The physician tablet controls therapeutic settings of the implant.
Famm: The spleen’s function is regulated by the splenic nerve. Preclinical and human ex vivo, in vitro, and in silico evidence has demonstrated that electrical stimulation of the splenic nerve generates signals to the spleen leading to the release of neurotransmitters that affect passing immune cells and shift them from an inflammation-driving to an inflammation-resolving state. As the blood filters through the spleen during its circulation, the reprogrammed cells then flow to the sites of injury in disease, for example the joints, leading to potential reduction or resolution of the inflammation there.
The spleen is also the ultimate target organ for other, more indirect neuromodulation approaches in clinical development such as cervical vagus nerve stimulation. The near-organ approach pioneered by Galvani, by stimulating the nerve directly controlling and immediately adjacent to the spleen, is anticipated to have larger benefits and fewer limitations and side effects that have been observed for vagus nerve stimulation and other indirect approaches. This anticipated large, so-called “therapeutic window” makes near-organ stimulation attractive as a new treatment class.
Healio: What kind of potential healing effects does splenic nerve situation show on RA?
Famm: Clinical studies are ongoing and we will need to wait to see the results in RA patients.
Galvani and its collaborators have published the results of preclinical research demonstrating improvements in animal models of RA as well as of acute inflammation, suggesting that being able to effectively evoke this immunomodulatory mechanism could offer treatment benefits in patients. Benefits have been shown both as a stand-alone treatment and when combined with current targeted molecular therapies, getting more animals into remission of their disease. The ongoing trials are designed to provide initial potential demonstration of these benefits to patients.
Healio: How could the development of this therapy impact RA treatment in the future?
Famm: This previously unutilized approach to modulate excessive immune response could provide a new overall means and lever for RA treatment. The ongoing trials are designed to provide initial potential demonstration of benefits to patients as a standalone treatment and when combined with targeted molecular therapies.
As a standalone treatment, splenic nerve stimulation could potentially offer a treatment alternative to targeted molecular therapies, including for patients with inadequate response to targeted molecular therapies and where cycling to the next molecular treatment option comes with diminishing prospects of improved treatment outcomes.
In combination with targeted molecular therapies, splenic nerve stimulation could potentially help bring more patients to lasting remission without elevated immunosuppressive risks and side effects.
As a connected electronic therapy, splenic nerve stimulation is also likely to impact the treatment delivery and optimization through offering remote monitoring and high patient engagement with their therapy.
Healio: What stage are we at in terms of trials and tests?
Famm: There are two ongoing feasibility studies with Galvani’s splenic nerve stimulation therapy, one is in Glasgow in the U.K., and a second study in the U.S. and Netherlands is being scaled to a dozen rheumatologists. The studies are for patients who have failed two or more biologic or targeted synthetic disease modifying drugs like JAK inhibitors. In the U.S. study, splenic stimulation is tested alone as well as in combination with a currently available targeted therapy. Initial results from these studies are expected in late 2023 and 2024.
Successful feasibility studies will be followed by potential optimization studies and then confirmatory/pivotal studies for potential marketing approval applications.
Healio: What are the next areas that you feel you need to continue to study to make this treatment as effective as possible?
Famm: Galvani will work to unlock the full potential of splenic nerve stimulation across lines of treatment in RA, in a pipeline of immune-mediated inflammatory disorders beyond RA, as well as exploring other nerve targets for diseases such as type 1 diabetes.
To conclude, think of bioelectronics as, in many cases, an emerging major therapeutic option with the potential to affect biological function, orthogonal and complementary to small and large molecules. It will take time, at least 5 years, before these new treatments come to market and perhaps 10 years and more before they become commonplace, but the role bioelectronics may have in treating disease and bringing benefits to patients could be far-reaching.
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