Daytime Neuromuscular Electrical Stimulation for Treatment of Mild OSA

Since the early 1980s when the first patients with severe obstructive sleep apnea (OSA) were successfully treated by a prototype continuous positive airway pressure (CPAP) device made from a vacuum cleaner motor, the field of sleep medicine has been dominated by device-based therapies that aim to open the airway mechanically during sleep. Whether they work by using pressurized air as a splint, pulling the lower jaw forward, stimulating the tongue to move and stiffen with each breath or prevent sleep in the supine position, existing OSA treatment devices have one thing in common: they only work while they are used during sleep. While countless users have experienced the life-changing benefits of treating their OSA, many have wondered whether they could train their body to breathe normally without the use of a nighttime device. Now, for the first time, a device designed to do just that is commercially-available for people suffering from primary snoring and mild OSA.

In 2015, the co-founders of a London-based start-up - Signifier Medical Technologies - came together with one goal in mind: to develop a treatment that targets an underlying cause of OSA, thereby freeing patients from their overnight devices. Akhil Tripathi, cofounder and CEO, had an established track record of successful medical device development, while Anshul Sama, cofounder and otolaryngologist, brought his extensive understanding of upper airway anatomy, physiology and the landscape of existing OSA treatments. Together, they and their team studied the history of upper airway neuromuscular electrical stimulation (NMES) - what worked, what didn't work - and designed and tested what would eventually become eXciteOSA.

An Overview on Upper Airway Strength and Endurance in OSA

Before reviewing how eXciteOSA works, it's worth revisiting the role of the upper airway musculature in OSA. As is the case with all skeletal muscles, the genioglossus (tongue) muscle contains a mix of slow-twitch and fast-twitch fibers. Slow-twitch fibers contain more mitochondria, which produce energy aerobically; they contract slowly, and are suited to sustained, long-duration activity as they are resistant to fatigue. In contrast, fast-twitch fibers produce energy anaerobically, and are involved with short-burst power activities. Put simply, the skeletal muscles of marathon runners tend to have more slow-twitch (high endurance) fibers, while sprinters tend to have more fast-twitch (high strength) fibers. Studies have shown that patients with OSA have a greater proportion of fast-twitch muscle fibers in their tongue, and therefore a lower proportion of slow-twitch fibers compared to controls.^1,2 When stimulated with a platinum electrode, biopsies taken from the tongues of patients with OSA demonstrate greater fatiguability compared with biopsies taken from controls,¹ particularly amongst those who are not obese.²

Consistent with this in vitro evidence, multiple studies have found that patients with OSA are able to generate significantly greater force with their tongue, but also exhibit significantly less tongue muscle endurance, compared with controls.^3,4 Given that each apnea/hypopnea is typically terminated by a rapid activation of upper airway muscles in order to re-open the occluded airway, it has been hypothesized that untreated OSA is a form of strength training resulting in a shift from slow-twitch to fast-twitch muscle fiber composition in the genioglossus and surrounding muscles.⁵ Thus, although in lay terms we often hear OSA referred to as being associated with muscle weakness, evidence suggests that muscle endurance is the most likely contributor to the development of OSA.

Applying the Known Concept of Neuromuscular Electrical Stimulation to the Tongue

The proportion of slow-twitch versus fast-twitch muscle fiber proportions varies from person to person, and is largely determined by genetics, although modifiable through training. NMES has been used in sports medicine, rehabilitation and physiotherapy for decades, with different stimulation patterns targeting endurance versus strength training.⁶ For example, eight to 10 weeks of low-frequency NMES is associated with a fast-to-slow twitch muscle fiber transition in the knee extensor, hamstring and quadricep muscles.^7,8 Given that the genioglossus is the same muscle type as the limbs, it is logical to assume that the same shift would result from NMES applied to the tongue. Indeed, a 2007 study applied electrical stimulation to the genioglossus of New Zealand white rabbits and found that the proportion of slow-twitch fibers almost doubled over a period of seven days.⁹ The evidence indicates that OSA is associated with reduced slow-twitch muscle fibers, combined with the knowledge that low-frequency NMES is associated with a phenotype shift from fast-twitch to slow-twitch fibers in other skeletal muscles, therefore presents a promising alternative therapy option.

The first assessment of NMES applied to the genioglossus took place in the 1990s, resulting in a published case study demonstrating that stimulation applied both externally (beneath the chin) and internally (beneath the tongue) was associated with an apnea-hypopnea index (AHI) reduction from 13.2 to 3.9 events/hour.¹⁰ In the first clinical trial of low-frequency (6.5 pulses per second) NMES for OSA, a modest but statistically-significant reduction in the AHI of 8 events/hour was observed, alongside significantly improved daytime sleepiness.¹¹ Finally, a 2004 clinical trial of high-frequency (50 pulses per second) NMES found a reduction in objectively-measured snoring but no change in the AHI.¹²

Designing eXciteOSA

These early trials indicated that electrical stimulation of the genioglossus may result in an improved upper airway muscle response amongst patients with OSA. In order to design a viable treatment device however, the co-founders at Signifier Medical Technologies faced many important decisions. For example, given the evidence that skeletal muscles respond differently to high- versus low-frequency stimulation,⁶ what is the appropriate frequency (pulses per second) to apply to the tongue? How often should therapy be applied, and over what duration? Which patients with OSA are most likely to respond to NMES? What is the best way of directing stimulation to the genioglossus?

In all three trials described above, stimulation was applied submentally using at least one electrode placed externally underneath the chin. While testing various eXciteOSA prototypes, investigators at Signifier found that applying stimulation from beneath the chin resulted in inadequate recruitment of the extrinsic rather than intrinsic musculature. As a result, they developed a mouthpiece that relies entirely on intraoral stimulation by placing electrodes directly on the conductive wet surface of the tongue, ensuring both vertical and diagonal patterns of stimulation of the intrinsic muscles.

eXciteOSA was developed by taking what is known about the role of the genioglossus in OSA pathophysiology and developing a version of NMES that can be delivered directly to the tongue muscles intraorally. The product was launched commercially in 2021 as the first daytime device designed to deliver NMES to the genioglossus, with the aim of increasing muscle endurance to promote airway patency.

How eXciteOSA Works

The product consists of four components:

1. A rechargeable control unit that attaches to the mouthpiece via a USB-C connection;
2.  A washable, flexible mouthpiece with an electrode array that fits onto the tongue;
3.  A smartphone app that pairs with the control unit to control therapy via Bluetooth, which
   allows the user to initiate therapy sessions and adjust the intensity; and
4. A physician portal for remote monitoring and long-term patient management.

To initiate a session, the user connects the mouthpiece to the control unit, then places the mouthpiece onto their tongue. When placed correctly, two electrode pads make contact with the anterior surface of the tongue and two additional electrodes contact the lateral surfaces of the tongue near the molars.

Once the user begins a session within the app, electrical impulses are delivered for periods of six seconds interspersed by four-second rest periods. Over the course of each 20-minute therapy session, electrical impulses are delivered at 3 Hz, 10 Hz and 20 Hz frequencies (pulses per second) in five-minute sequences. The intensity (electrical current) of the stimulation is adjustable within the app on a scale of 1-15; users are instructed to apply stimulation at their maximum tolerated level, which for most people increases over time as they become accustomed to the sensation. The app will prevent a second therapy session from being initiated within a single day. Further, if a therapy session is aborted before completion or paused for >3 minutes, the app will prevent initiation of a new session for a period of 30 minutes.

Clinical Evidence Supporting eXciteOSA

eXciteOSA was first tested in a proof-of-concept trial of n=13 participants with primary snoring or mild OSA, which resulted in a significant reduction in bed-partner reported snoring intensity over six weeks.¹³ Subsequently, a multi-center, single-arm trial was undertaken amongst participants with primary snoring (n=50) or mild OSA (n=65).^14,15 Across the full study sample, the average percentage of total sleep time spent snoring above 40 decibels - the threshold commonly used to define nighttime noise pollution - dropped by 41% (p<0.01) over the six-week treatment period. In the subset of patients with mild OSA, the AHI reduced from 10.2 to 6.8 events/hour on average (p<0.01), alongside significant improvements in the 4% oxygen desaturation index (ODI), Epworth Sleepiness Scale and Pittsburgh Sleep Quality Index.¹⁶ Adherence to therapy was 85%, meaning participants completed an eXciteOSA therapy session on average 85% of days. In a subset of 51 participants identified as responders (representing 78% of the sample), the AHI dropped from 10.4 to 5.0 events/hour. A post-hoc analysis found that 46% (n=30 of 65) experienced a complete treatment response over six weeks, defined as a follow-up AHI of <5 events/hour.

As a new-to-world therapy, Signifier Medical supported a 2022 investigatorinitiated study conducted at University of California San Diego (UCSD) in order to learn more about the eXciteOSA mechanism of action.¹⁷ A sample of n=20 patients with primary snoring or mild OSA underwent measurements of tongue strength and endurance using the IOPI device (IOPI Medical; Woodinville WA USA), followed by an in-lab polysomnography (PSG) at baseline, which included wires placed in the tongue to measure genioglossus electromyography (EMG). These procedures were repeated after one month of eXciteOSA. No change in genioglossus EMG was observed, indicating that the impact of eXciteOSA is mediated through an alternative pathway. Importantly, and consistent with prior studies,^3,4 the investigators observed a significant improvement in genioglossus endurance (time to task failure increased from 22 to 37 seconds on average; p=0.03). The investigators also observed a significant improvement in PSG-determined sleep efficiency (75% to 84%; p<0.01), and in the subset of patients with mild OSA at baseline, the AHI reduced from 17.4 to 7.4 events/hour (n=11; p>0.05 but not statistically powered; post-hoc analysis).

Accessing eXciteOSA

eXciteOSA was granted marketing authorization by the Food and Drug Administration (FDA) as a Class II medical device through the de novo pathway in early 2021, and is indicated for the treatment of adults (aged >=18 years) suffering from primary snoring or mild OSA (AHI <15 events/hour). In a prior clinical trial,¹⁴ adverse events were limited to 15% of patients, and included excessive salivation, tingling sensation on the tongue and tooth sensitivity. No serious adverse events were reported.

As of mid-2022, eXciteOSA is commercially available in the United States, Canada, the United Kingdom and Germany, with more regions coming soon. To date, over 6,000 patients have begun therapy worldwide. CMS established two new Level II Healthcare Common Procedures Coding System (HCPCS) codes to describe eXciteOSA that went into effect April 1, 2022. Signifier Medical Technologies is committed to broad patient access for this new therapy and has educated health insurance payors on the value of eXciteOSA, and will continue to share the evidence required to achieve widespread coverage.

Future Directions

As a new-to-world therapy, there remains much to learn about how best to integrate eXciteOSA intraoral NMES into the OSA care pathway. Signifier Medical Technologies is dedicated to engaging with the sleep research community to produce high-quality evidence from rigorous clinical trials. Four clinical trials are currently underway, with further studies and real-world evidence protocols under development.

The team at Signifier is eager to learn from the experiences of patients and clinicians as they begin and continue their journey with eXciteOSA. Sleep professionals and patients can learn more at exciteosa.com or contact the team using the form at signifiermedical.
com/contact/.

References

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