The clinical utilization of neuromodulators is extending the way chronic health conditions are being treated. Findings by Frost & Sullivan show expansion of clinical trials for the treatment of heart failure, hypertension and Crohn’s disease in recent years.
Neuromodulation therapy remains at the forefront of medicine. Neuromodulation describes technology that modulates, or alters, neural activity through either electrical stimulation or chemical delivery. The first application of modern neuromodulation therapy, called deep brain stimulation, was used to treat pain. Since then, the clinical utilization of neuromodulators is extending the way chronic health conditions, including cardiac and inflammatory diseases, are being treated. Findings by Frost & Sullivan show expansion of clinical trials for the treatment of heart failure, hypertension and Crohn’s disease in recent years. Contraindications and multiple medication interactions have pushed complex patients to opt for neuromodulation as a treatment alternative and opened doors for companies with innovative technologies.
Cardiac Contraction Modulation for Heart Failure
Congestive heart failure (CHF) is the heart’s inability to adequately circulate blood to the body’s organs and tissues. Inadequate cardiac output can lead to capillary fluid leakage resulting in edema, fatigue and shortness of breath. Many things can weaken the myocardium over time and reduce its pumping efficiency. Underlying heart disease is a leading contributor to developing or worsening CHF, especially in people taking over-the-counter anti-inflammatories or any medicine that affects sodium retention.
Impulse Dynamics, headquartered in Stuttgart, Germany, has developed the Optimizer IVs, a minimally invasive, implantable pulse generator (IPG) for treating moderate to severe CHF. Weighing only 46 grams and with an area of 30 cubic centimeters, this more compact, and thus more patient friendly update to its predecessor, the Optimizer III delivers atrial ventricular intervals of up to 400 milliseconds.
The Optimizer IVs is placed into the right pectoral region and connects to three standard pacemaker leads in the right ventricle. Unlike many conventional pacemakers that require battery replacement, the Optimizer IVs’s rechargeable system includes an easy-to-use charging device with an LED display of charge status that allows patients to charge their device at home. The charger contains a separate battery, eliminating the need for an external power source during the 30- to 40-minute charging time. Paired with the company’s OMNI II programmer, which is powered by OMNI Smart application software, specialist support is available 24/7 via the Internet. Optimizer IVs can sense and measure atrial and ventricular electrical output. Rather than attempting to regulate cardiac rhythm as a standard pacemaker, it uses two high-precision electrodes attached two centimeters apart at the ventricular septum to send an electrical impulse during the absolute refractory period. This cardiac contraction modulation (CCM) therapy strengthens the myocardium.
Impulse Dynamics is conducting a multicenter, prospective, single-arm continued access study of the Optimizer Smart system with CCM therapy—a new version of the Optimizer IVs—in the United States through April as it waits for the U.S. Food and Drug Administration (FDA) to issue a premarket device application order. The device has already been approved for CHF treatment by the China FDA.
Helping Hypertension through Baroreceptor Stimulation
Minneapolis-based CVRx combines technology with homeopathic medicine to combat illness. The Barostim Neo is an implantable neuromodulator that acts on baroreceptors to manage resistant hypertension (RHTN) and CHF.
Baroreceptors are specialized stretch neurons that detect distension of the carotid sinus and aortic arch in response to elevation of blood pressure during systole. When these changes occur, baroreceptors reflexively send afferent nerve impulses to the medulla, triggering a reduction of efferent sympathetic nervous system discharge to the heart and peripheral vasculature resulting in negative inotropy, or weakening of muscle tone, in these areas. Parasympathetic outflow is simultaneously increased, resulting in a reduction of both heart rate and oxygen demand. In RHTN patients for whom medication no longer provides therapeutic benefits, baroreceptors lose their ability to initiate a baroreflex autonomically.
The Barostim Neo uses baroreflex activation therapy, in which an IPG connected to standard pacemaker leads with a single electrode are sutured to the carotid artery; electric impulses stimulate the baroreceptors. The IPG weighs 60 grams and fills about 40 cubic centimeters of subcutaneous chest volume. Information captured by the device is wirelessly exported to a separate programmer, allowing clinicians to adjust device settings based on the interpreted data.
The company is recruiting patients for a Phase III clinical trial in North America, which the U.S. FDA has designated as an expedited access pathway. The device is already available in more than 20 countries in Europe and Asia.
Coin-Sized Bioelectronic Device for Managing Resistant Hypertension
Valencia Technologies of Valencia, Calif., has developed the electroceutical coin, or eCoin—a nickel-size technology that stimulates nerves in the periphery to improve conditions such as RHTN. Subcutaneous placement of the eCoin in both forearms delivers periodic stimulation to the median and deep-peroneal nerves for management of RHTN. When activated, eCoin reduces the sympathetic nervous system’s response to changes in blood pressure. The input sends afferent messaging to the hypothalamus, midbrain and medulla, which creates a response similar to a baroreflex. Although the response and results are similar to the Barostim Neo, the exact mechanism of action using nerves in the forearm to reduce RHTN is unknown. While no peer-reviewed studies are available, Valencia’s unpublished clinical trials show a “high probability of success” in reducing RHTN in patients receiving treatment when compared with a sham group.
In 2016, eCoin received a U.S. FDA investigational device exemption for the treatment of drug-resistant hypertension. The company has active clinical trials in New Zealand, Taiwan and Canada, and hopes the results of those studies will hold up against similar studies in the United States approved by the FDA.
Implantable Neuromodulation for Inflammatory Disease
Valencia-based SetPoint Medical has developed proprietary implantable neuromodulation therapeutic devices targeting inflammatory diseases, such as Crohn's disease and rheumatoid arthritis, by modulating the inflammatory reflex through stimulating the vagus nerve. The device consists of an implantable microregulator, a wireless charger and a mobile app that physicians can use to customize treatment.
Bioelectric therapy predicates on the use of T cells to inhibit the production of specific proteins responsible for inflammation. Clinical trials show that electric stimulation of the vagus nerve can elicit this inflammatory reflex. The microregulator responsible for creating the charge is implanted in the right subclavian region. SetPoint uses a bipolar electrode sutured onto the vagus nerve in the cervical region to deliver the charge. Proprietary wireless software allows treatment customization and wireless charging. According to SetPoint, the wireless charger extends the life of each implanted device for up to 10 years.
In December 2017, SetPoint received an investigational device exemption for a clinical study on bioelectronic therapy for rheumatoid arthritis. An open-label pilot study of the device is being administered across Europe.
The Road Ahead
Chronic pain relief continues to be the most common indication for neuromodulation therapy; however, the therapeutic benefits of neuromodulation applications are not limited to a single condition. Deep brain stimulation, for example, can also be used in the treatment of movement disorders, depression and obsessive-compulsive disorder. The eCoin has shown promising results in treating overactive bladder when applied to the tibial nerve. Devices can also stimulate a response to repair sensory issues, as in the case of restoring hearing using cochlear implants. As researchers gain a better understanding of neural circuitry and its effect on health, Frost & Sullivan expects implantable neuromodulators to become a primary treatment option for the management of complex diseases.
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