December 2021 issue, BioElectRx Business Report
December 31, 2021 | One of the first indications to be targeted by vendors of bioelectronic medicine was heart failure. Although there are dozens of FDA-approved drugs for heart failure, they don’t help everybody—particularly patients with the most severe cases, NYHA Class III and IV—and there are side effects. Unfortunately, the history of bioelectronic medicine approaches to treating heart failure is replete with commercial and clinical trial failures. But new understanding of the mechanisms of action of neuromodulation approaches promises to transform that trend and create new market opportunities in the years ahead.
The market for treating heart failure represents a significant opportunity for manufacturers of bioelectronic medicine systems. Heart failure affects more than 5 million people in the U.S., according to the American Heart Association, and it costs the U.S. about $32 billion per year. Heart failure is generally broken down into two categories: heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Left-ventricle ejection fraction below 40 percent is indicative of HFrEF. HFpEF can result from stiffness in the left ventricle, which causes impaired filling.
Drugs approved for heart failure generally work via one of three broad mechanisms: vasodilation of blood vessels to allow more blood flow with less pressure, diuresis to reduce blood volume and salt concentration, or heart rate reduction. Manufacturers of implantable cardiac devices such as defibrillators, left-ventricular assist devices, and pacemakers also target the market for heart failure. Cardiac resynchronization therapy involves direct stimulation of the heart in order to coordinate the action of the heart chambers. These devices are often used in the most severe cases of heart failure, NYHA Class IV. By contrast, bioelectronic medicine approaches are largely targeted at less deadly Class II and Class III cases. More specifically, these approaches target HFrEF, although there is at least one firm targeting HFpEF.
Of the many early failures of bioelectronic medicine approaches to HF, two that stand out involve two of the largest neuromodulation firms. Boston Scientific’s NECTAR-HF trial evaluated vagus nerve stimulation in 96 HFrEF patients. That trial missed its primary endpoint in 2014.
In 2010, Medtronic invested $70 million in an Israeli firm called BioControl Medical, which sponsored a trial of VNS for heart failure called INNOVATE-HF. Medtronic also obtained an option to buy BioControl outright for $550 million upon FDA approval. That trial of 707 patients also failed and BioControl ceased operations without Medtronic exercising its option to buy them out at a reduced price.
Other notable failures in this space include Enopace Biomedical, another Israeli firm, which pursued stimulation of the arteries as an approach to treating heart failure. The company’s Harmony system consisted of a stent-like stimulator implanted in the inner wall of a vessel using a catheterization procedure, plus an external wearable unit that powers the stimulator via RF energy. Sorin (now LivaNova) invested $7 million in this startup in 2011, and in 2017, Enopace gained recognition as the top medical innovation company at the Transcatheter Interventional Congress. But few other details about this company have emerged since then.
Likewise, an Irish startup called NeuroTronik raised $23 million in 2017 for a cardiac autonomic nerve stimulation therapy for acute heart failure delivered via the company’s NeuroCatheter, placed temporarily in a vein just above the heart. It worked in combination with an external NeuroModulator, positioned bedside. The result of stimulation was intended to be enhanced cardiac output free of elevated heart rate. A feasibility study was completed in 2016, but we were unable to find any published results and the company appears to have ceased operations.
Another now-dormant bioelectronic medicine approach to heart failure was offered by a company called Sunshine Heart, which changed its name to CHF Solutions and more recently Nuwellis. The company’s C-Pulse system, which included a cuff wrapped around the outside of the aorta, was designed to strengthen the failing heart by adding a secondary pulse to every heartbeat. The idea was to increase coronary blood flow, decrease load on the left ventricle, and improve cardiac function. The company received a CE Mark in Europe for C-Pulse before abandoning the heart failure market.
But despite these failures, several investigators and commercial firms believe there is a solid foundation for bioelectronic medicine therapies for heart failure. At the Neurotech Leaders Forum in San Francisco last month, Warren Grill, a professor of biomedical engineering at Duke University, offered insight into the reasons that the NECTAR and INNOVATE trials failed. In animal trials, investigators achieved considerable success by increasing the amplitude of stimulation until it produced a 10 percent reduction in heart rate—an effect similar to what’s achieved with beta blockers. But in the two pivotal trials, investigators limited the level of stimulation in order to reduce side effects such as voice changes or coughing. As a result, trial participants were improperly dosed, said Grill.
He pointed out that a better understanding of the anatomy of the vagus nerve, with its heterogeneous population of nerve fibers, would have led to a better outcome in both trials. The vagus nerve contains several very large-diameter myelinated axons that are 10 to 15 microns in diameter. It also includes smaller-diameter myelinated axons and a lot of very small one- to two-micron diameter non-myelinated axons. How those complementary nerve fibers are activated influences the therapeutic effects of VNS, he said.
“This is an example where the pivotal, multicenter clinical trials were not done in such a way as to adequately engage the therapeutic mechanism,” Grill said. “They did not stimulate those small diameter B fibers that are required to produce a 10% reduction in heart rate.”
In an effort to avoid pitfalls like this, LivaNova has expended considerable effort elucidating the anatomical and physiological underpinnings of its autonomic regulation therapy using its Vitaria VNS system to treat HFrEF. In particular, investigators affiliated with LivaNova, including Jeff Ardell and colleagues at UCLA, identified a crucial biomarker they call the “neural fulcrum” that indicates the proper level of dosing. The VITARIA system received CE Mark in 2015 and subsequently received Breakthrough Device designation from the FDA.
At an investor day this month, LivaNova vice president Larry DiCarlo explained how the company achieves the proper dose of stimulation of the vagus nerve by gradually increasing the intensity until activation of afferent nerve fibers that ascend to the CNS and efferent fibers that descend to and control the heart are equal. “During the titration that occurs after implantation, VNS signaling is primarily from afferent at low intensities,” he said. “As intensity increases, efferent signaling increases. As the therapeutic zone is approached, the functional effects of afferent and efferent signaling are balanced.”
LivaNova’s autonomic regulation therapy (ART) uses this neural fulcrum as a key biomarker. It also relies on surface EKG signals to identify changes in heart rate dynamics. As opposed to other device approaches, ART simultaneously engages peripheral and central neural networks, DiCarlo said. By carefully balancing sympathetic and parasympathetic activity, the therapy produces activation of muscarinic and inhibition of adrenergic receptor systems.
Compared to other medtech interventions such as implanted cardiac defibrillators, LivaNova’s implantable pulse generator (IPG) is smaller in volume and does not require vascular access, DiCarlo pointed out. The identification of the neural fulcrum biomarker also enables clinicians to personalize the therapy for individual patients.
Mike Polark, a senior research analyst at RW Baird who tracks LivaNova, points out that the company’s ANTHEM-HFrEF pivotal trial includes open-label and embedded “trial-in-a-trial” design. This could support a two-stage approval process under FDA’s expedited access pathway including initially for symptomatic and functional claims only, he said.
Another bioelectronic medicine firm, CVRx, is using an alternative stimulation therapy. Rather than targeting the vagus nerve, their Barostim therapy targets the baroreceptors located in the wall of the carotid artery. It is designed to restore balance to the autonomic nervous system and thereby improve the symptoms of HFrEF. The company recently announced a new clinical procedure that simplifies the implantation process by using minimally invasive lead placement with ultrasound imaging.
“This new approach to treatment represents a potentially game-changing advancement in the way we manage patients with HF symptoms,” said Wells Brabham of the Moses H. Cone Memorial Hospital in Greensboro, NC, the first vascular surgeon to use the new technique.
In 2019, CVRx announced FDA approval of its Barostim NEO device based on data from the Baroreflex Activation Therapy for Heart Failure Pivotal Trial (BeAT-HF). The therapy is intended for Class II and Class III patients on current guideline-directed medical therapy who are not indicated for CRT.
Still another bioelectronic medicine approach to HF is called cardiac neuromodulation therapy (CNT) from Orchestra BioMed. CNT combines autonomic nervous system regulation with standard pacemaker functions. It mimics the effects of multi-drug hypertension therapy by targeting preload, afterload, and sympathetic tone. The company’s Moderato device received CE Mark approval for treating hypertension in 2019.
As opposed to other efforts targeting HFrEF, CNT for Heart Failure therapy targets HF with preserved ejection fraction. Orchestra recently began a clinical trial targeting Class II and Class III HF patients that are scheduled for ICD implantation or replacement. During the acute, observational study, the ICD leads will be connected to Orchestra’s BackBeat Moderato IPG via an external cable. A range of CNT signal parameters will help assess the effect on sympathetic activity. Ventricular pressure and volume readings from the conductance catheter and arterial pressure readings will be recorded and analyzed to assess the effect of CNT signals on cardiac function, sympathetic activity and blood pressure.
Cardionomic Inc. offers yet another bioelectronic medicine approach to heart failure with its cardiac pulmonary nerve stimulation technology. The therapy seeks to improved hemodynamic function in patients with acute decompensated heart failure (ADHF), a particularly deadly strain of heart failure. The goal of the approach is to improve cardiac contractility. The therapy is founded on the principle that sympathetic nerve stimulation induces cardiac contractility.
The CPNS system is comprised of a stimulation console and a minimally invasive catheter that delivers targeted endovascular stimulation to the pulmonary artery. Early studies have demonstrated that the system increases cardiac contractility in chronic heart failure patients without significantly changing heart rate.
A unique aspect of all of these new approaches to treating heart failure is the potential overlap with another, more mature branch of medtech, namely cardiovascular devices. Bioelectronic medicine vendors targeting heart failure are at once potential competitors and potential collaborators with vendors of cardiac devices. For companies like LivaNova, Boston Scientific, and Medtronic that have explored bioelectronic medicine approaches to HF but also have a traditional cardiovascular product line, the opportunity exists for channel conflict, as neuromodulation reps and cardiovascular reps jostle to see who owns the customer. But it could also create the opportunity for new product and organizational synergies that would yield more than the sum of the parts for these players.
And for startups and emerging bioelectronic medicine firms who lack a traditional cardiovascular product line, the opportunities for partnership or M&A activity with large healthcare firms already in this space are readily apparent. Clearly, the more we learn about the basic mechanisms of action underlying bioelectronic medicine approaches to treating HF, the more likely it will be that more effective therapies emerge down the road.
