The pipeline for moderate to severe obstructive sleep apnea (OSA) therapy is robust, ranging from new hypoglossal nerve stimulators (HGNS) and other implanted devices to drugs that target upper airway muscle tone and other functions that are involved in the underlying causes of the disorder.
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August 2024When it comes to drug therapy, however, most of the recent buzz has been triggered by data on tirzepatide (Zepbound, Eli Lilly), released on June 21 at the American Diabetes Association (ADA) 84th Scientific Sessions, suggesting that the drug may obviate the need for continuous positive airway pressure (CPAP) in nearly half of OSA patients. To gauge how the glucagon-like peptide-1 (GLP-1) receptor agonist fits in with existing therapies, and to assess the overall OSA treatment pipeline, ENTtoday spoke with several experts in the sleep disorders field.
The tirzepatide data “are particularly exciting,” said Thomas M. Kaffenberger, MD, an assistant professor in the department of otolaryngology-head and neck surgery at the University of Pittsburgh School of Medicine. “It’s important to remember that when you lose weight, you don’t just lose it in your hips and belly; you lose it in the airway as well. As that happens, upper airway fat deposits that we know contribute to OSA decrease, and OSA symptoms often improve significantly [Sleep. 2014;37:1639-1648].”
Anecdotally, he said, “We’ve already seen the effect of GLP-1s in our clinical practice, and we have many new surgical consultations for patients who are already taking semaglutide [Ozempic and Mounjaro, Novo Nordisk]. In fact, many of these patients would not meet the weight criteria for surgical consultation without these drugs. To have the symptom improvements confirmed by the tirzepatide trial data is quite impressive.”
Dr. Kaffenberger cautioned, however, that one of the challenges of the new GLP-1 therapies will be maintaining the weight loss when the therapy stops.
The SURMOUNT-OSA Trial
The tirzepatide data emerged from the SURMOUNT-OSA phase 3 clinical trial, which Atul Malhotra, MD, a professor and research chief of pulmonary, critical care, and sleep medicine at UC San Diego Health, presented during a session at the ADA meeting. The results were also published online ahead of print in The New England Journal of Medicine (DOI: 10.1056/NEJMoa2404881).
SURMOUNT-OSA included two parallel, double-blind, randomized, placebo-controlled multicenter international trials. Patients who were not treated with CPAP at baseline were included in trial 1 (120 on placebo; 114 on tirzepatide). Patients who were given CPAP therapy at entry were enrolled in trial 2 (115 on placebo; 120 on tirzepatide). The mean body mass index (BMI) of participants in both trials was over 38 at baseline, and approximately 60% had severe OSA based on their apnea-hypopnea index (AHI), which tracks the number of apnea and hypopnea events during an hour of sleep.
The study’s primary endpoint was the mean change in AHI at 52 weeks. In trial 1, the mean change was −25.3 events per hour with tirzepatide and −5.3 events per hour with placebo. That equated to an estimated treatment difference of −20.0 events per hour (95% CI, −25.8 to −14.2) (P<0.001). In trial 2, the mean change in AHI at week 52 was −29.3 events per hour with tirzepatide and −5.5 events per hour with placebo, for an estimated treatment difference of −23.8 events per hour (95% CI, −29.6 to −17.9) (P<0.001).
Patient-reported outcomes told a similar story. Pooled PROMIS sleep disturbance scores, for example, were nearly twice as improved in the tirzepatide group (-5.7) when compared with the placebo group (-2.7; P<0.001).
This is a breakthrough trial in the treatment of obesity and sleep apnea. — Louis Aronne, MD
“This is a breakthrough trial in the treatment of obesity and sleep apnea,” said Louis Aronne, MD, a professor of clinical medicine and Sanford I. Weill Professor of Metabolic Research at Cornell University in Ithaca, N.Y., during the ADA session. He noted that more than half of the patients in the study who were using CPAP “would no longer need one” based on their significant responses to tirzepatide.
‘These Are Important Benefits’
Eric Kezirian, MD, MPH, sleep apnea surgeon and professor of head and neck surgery at the David Geffen School of Medicine at UCLA, in Calif., underscored the significance of the SURMOUNT-OSA trial. “The improvements seen in AHI and secondary endpoints such as the Epworth Sleepiness Scale suggest that 40% to 50% of study participants received adequate clinical benefit with tirzepatide, compared to 15% with placebo,” he said. “These are important benefits.”
Dr. Kezirian stressed, however, that the data do not support using tirzepatide prior to starting CPAP. Rather, they “suggest that tirzepatide should be considered complementary to CPAP or a second-line approach in those with obesity (BMI >=30) and moderate to severe OSA.” That strategy is needed because “any approach to weight loss, including tirzepatide, takes time,” he explained. “So, typically, you would want to start a patient with obesity and OSA on CPAP even if you are also starting the GLP-1.”
Dr. Kaffenberger agreed that such a combined approach is key. But he noted that, given the persistent compliance problems with CPAP—up to 60% of patients are nonadherent, according to one literature review (J Otolaryngol Head Neck Surg. 2016;45:43)—newer treatment choices are needed. He pointed to HGNS as a particularly promising area of research. These surgically implanted systems send an electric pulse to the hypoglossal nerve, which has been shown to maintain lingual motor tone and restore upper airway patency by preventing the tongue from prolapsing into the pharynx during sleep (Chest. 2018;154:1435-1447).
One of the investigational HGNS systems is Nyxoah’s Genio 2.1 HGNS, which includes an implantable stimulator that targets both the left and the right hypoglossal nerve branches. The Genio 2.1 system recently achieved several key efficacy scores in the DREAM trial. The multicenter prospective study enrolled 115 patients with moderate to severe OSA. Participants had a mean baseline AHI of 28.0, a mean oxygen desaturation index (ODI) responder rate of 27.0, and a mean BMI of 28.5. At 12 months, 73 patients (63%) were deemed to be AHI responders, based on Sher criteria, which include a decrease in AHI of ≥50% and an AHI <20 events per hour (P=0.002); 82 subjects (71.3%) were deemed ODI responders (P<0.001), the investigators reported.
Dr. Kaffenberger noted that Genio 2.1 requires only one surgical incision for placement of the implant and sensor. Inspire—the first HGNS entrant, approved by the FDA in 2014—requires two incisions: one under the patient’s chin to reach the hypoglossal nerve controlling the tongue, and another in the upper chest where the implant and breathing sensor are placed, according to the manufacturer’s website.
Genio 2.1 “has a really good chance of getting FDA approval in the next year or two,” he said, adding that the system is also being studied as an OSA treatment for patients who have complete concentric collapse of their soft palate. “These patients typically aren’t candidates for Inspire, and there is a clinical trial underway evaluating Genio 2.1 for these challenging-to-treat patients” (ClinicalTrials.gov Identifier: NCT05592002).
Aura 6000 (ImThera) is another HGNS that sleep disorders specialists should keep an eye on, Dr. Kaffenberger noted. A recent randomized trial, known as THN3, of 138 patients with moderate to severe OSA who were treated with the Aura 6000 system documented significant improvements in AHI, ODI, and several sleep quality scales. In the case of AHI, at four months, response rates were substantially greater in the patients treated with the HGNS system versus those in the control group (52.3% versus 16.6%, respectively) (JAMA Otolaryngol Head Neck Surg. 2023;149:512-520).
“This system has a few things that potentially set it apart from the other HGNS entrants,” Dr. Kaffenberger said. For example, while other systems such as Inspire stimulate the entire distal hypoglossal nerve, the Aura 6000 system selectively targets sectors of the proximal nerve. “The investigators of the JAMA study claim that this approach has some benefits,” he said. “Specifically, they note that distal stimulation primarily activates tongue protruders. The multi-contact array that Aura 600 uses, in contrast, has the ability to stimulate lingual protruders and retractors, to varying degrees. This concept is the ‘lingual hydrostat’ model, which describes the stiffening of the tongue in order to prevent the upper airway tissue collapsing during sleep.”
Cryolipolysis Comes to OSA Therapy
Dr. Kaffenberger cited another pipeline HGNS. Developed by Cryosa, Inc., the system “uses a controlled cooling process to selectively treat oral tissue and open the airway without the need for masks, hoses, incisions, or implants,” according to a company press release. The ARCTIC-3 trial is currently evaluating the Cryosa System for the treatment of moderate to severe OSA (ClinicalTrials.gov Identifier: NCT06008626).
The system’s mechanism of action is not that dissimilar to the cryolipolysis treatments that some aesthetic centers use to shrink fat cells in different parts of the body, Dr. Kaffenberger said. “The Cryosa System takes that idea and applies it to the upper airway,” he said. “Cooling probes are placed on the back of the tongue and soft palate to try to shrink down the fat cells within this area. There have been some really nice MRI studies done showing that fat deposits are a common contributor to OSA [Sleep. 2014;37:1639-1648], so this company has taken that idea and is trying to build on it.”
The Cryosa System “is a one-time treatment right now, and it’s being tested in a couple of centers across the U.S.,” he added. “We are preparing to treat patients with it at our practice.”
In addition to conservative approaches, positive airway pressure therapy will likely remain the first-line option. That being said, for patients who do not tolerate CPAP well, multimodal approaches will continue to be important.” —Eric Kezirian, MD, MPH
Asked to comment on the HGNS therapies highlighted by Dr. Kaffenberger, Dr. Kezirian focused his observations solely on Aura 6000 because he is a consultant for the other systems. “We would not expect that the Aura 6000 does a better job of controlling the causes of OSA,” he said. “The results of THN3 are not better than Inspire’s STAR trial [N Engl J Med. 2014;370:139-149]. However, this device has a second trial (OSPREY) that is now in data collection stages. Its advantage may be a simpler implantation procedure and smaller implanted components” (ClinicalTrials.gov ID NCT04950894).
The OSA Horizon
As for how the next three to five years may play out in the OSA therapy arena, Dr. Kezirian said, “In addition to conservative approaches, positive airway pressure therapy will likely remain the first-line option. That being said, for patients who do not tolerate CPAP well, multimodal approaches will continue to be important. This can include the combination of surgery (whether neurostimulation or another procedure) with weight loss. I expect there will be more than one neurostimulation technology in the market, with the choices dictated by scientific research, patient preferences, and surgeon input (the triad of evidence-based medicine).”
Dr. Kezirian’s mention of evidence-based medicine is an echo of cautions he made in a 2020 review article he co-authored on proposed alternatives to OSA treatments (Am J Respir Crit Care Med. 2020;202:1503-1508). Although several of the treatments at the time of the study were deemed to have enough solid published evidence to recommend them, such as positional therapy devices, others, such as orthodontic devices aimed at correcting teeth and tongue positioning to improve or even “cure” OSA, were found to have little basis in solid science.
“And that’s a problem,” he said, “because we have seen, as we noted in the paper, many patients stop or delay effective OSA therapy based on false hopes offered by unproven therapies.” That is occurring at least in part “because many of these products are being aggressively marketed to patients with OSA without supportive data. So, it’s time to let the evidence guide us.”
This is a sea change in how we are viewing future treatments of OSA.” — Kathleen L. Yaremchuk, MD
Dr. Kaffenberger disclosed he is a consultant for Inspire and Nyxoah and has institutional research support from Cryosa Medical. Dr. Kezirian disclosed he is a consultant for Berendo Scientific, Cryosa, and Nyxoah and previously conducted research supported by Inspire provided to his institution, and consulted for huMannity Medtec. Dr. Yaremchuk disclosed she is a consultant for Nyzoah and Stryker.
David Bronstein is a freelance medical writer based in New Jersey.
Why the ‘Take a Pill’ Approach Makes Sense for Some OSA Patients
Tirzepatide isn’t the only pharmacologic approach to treating obstructive sleep apnea (OSA). Several drugs are in development that promise to mitigate some of the root causes of the disorder.
“Patients often ask me whether there is a pill they could take for their sleep apnea—particularly those who can’t tolerate CPAP,” said Kathleen L. Yaremchuk, MD, chair of otolaryngology/head and neck surgery and a member of the division of sleep medicine at Henry Ford Health in Detroit. “In the past, I’d sort of laugh and explain that a pill can’t address an anatomic blockage of the upper airway. Well, in a year or two, my answer will be different, because we do in fact have medications that increase the tone of the upper airway.”
This development “reminds us that although we call this disorder obstructive sleep apnea, it’s also physiologic,” Dr. Yaremchuk said. “This is a sea change in how we are viewing future treatments of OSA.”
One example is AD109, a combination of the novel antimuscarinic agent aroxybutynin and the norepinephrine reuptake inhibitor atomoxetine. Dr. Yaremchuk participated in the phase 2 randomized, double-blind, placebo-controlled, parallel-group, Mariposa trial assessing the combination in 181 patients (Am J Respir Crit Care Med. 2023;208:1316-1327). The investigators reported significant improvement in several OSA markers. For example, AHI with a 4% desaturation criterion (primary outcome) was reduced from a median of 20.5 (12.3–27.2) to 10.8 (5.6–18.5) in a 2.5/75-mg drug combination arm (−47.1%), and from 19.4 (13.7–26.4) to 9.5 (6.1–19.3) in a 5/75 mg arm (−42.9%; both P<0.0001 versus placebo).
Subjectively, there was an improvement in fatigue with the 2.5/75 mg dosage (P<0.05 versus placebo and atomoxetine). The most common adverse events were dry mouth, insomnia, and urinary hesitancy.
Dr. Yaremchuk underscored why this pharmacologic approach “will be a game changer” for certain OSA patients. For some of them, she noted, “the upper airway muscles are incompetent. When an individual goes to sleep, their muscles relax and their upper airway collapses.” The atomoxetine component of AD109 “acts on the brainstem and increases muscle tone during sleep and keeps the airway open.” The antimuscarinic component is needed, she added, to ensure that patients aren’t stimulated during sleep with insomnia, because atomoxetine has been shown to increase heart rate—an adverse reaction observed in the Mariposa trial, although to a lesser degree than in previous studies (Drug Saf. 2003;26:729-740).
As for how AD109 and other drug therapies might ultimately fit into OSA treatments, Dr. Yaremchuk said a multimodal approach is most likely. It’s not unusual, she noted, for patients with diabetes, hypertension, or a host of other chronic conditions to require two different medications to control their disease. “OSA is no different,” she said. “Maybe they will need an oral mandibular device. Maybe they need CPAP or perhaps some form of surgery. Now, we have drugs in the pipeline that also can help—including a novel TASK channel antagonist nasal spray that reduces sleep apnea severity [Am J Physiol Heart Circ Physiol. 2024;326:H715-H723]. This gives us even more treatment options we can titrate until OSA symptoms are finally under control.”
Thomas M. Kaffenberger, MD, an assistant professor in the department of otolaryngology–head and neck surgery at the University of Pittsburgh School of Medicine, agreed that the AD109 results “are encouraging, but we don’t yet know whether OSA patients actually will be able to tolerate these medications long term.” If follow-up data confirm safety and efficacy, he noted, “Fantastic; maybe we can combine atomoxetine and oxybutynin with tirzepatide or some other weight loss options, which is great news for all of the OSA patients who we know can’t tolerate CPAP.”