Benjamin Clemenson, PharmD; Coborn's
Background: “Obstructive sleep apnea (OSA) is caused by the interaction between impaired pharyngeal anatomy and inadequate dilator muscle function during sleep.” This leads to people with OSA having a narrow or collapsed upper airway. If left untreated, OSA can increase the patient's risk of serious adverse health events including cardiovascular disease, diabetes, and stroke. Recently, topical application of the TASK-1/3 potassium (K+) channel antagonist, BAY2586116, was investigated and shown to be safe and tolerable. In addition, the medication provided sustained improvement to upper airway collapsibility as patients who responded to the drug had an average of approximately 2cmH2O reduction in closing pressure. However, clinical improvement from BAY2586116 such as apnea-hypopnea index (AHI) has yet to be determined. Additionally, prior studies only assessed nasal breathing and have not studied the impact of oronasal breathing, a mechanism known to alter surface tension forces and lead to an increase in pharyngeal collapsibility. Therefore, it is not known if the type of breathing with BAY2586116 impacts airway function differently.
Objective: BAY2586116 nasal spray was compared to placebo to determine if physiological response to the medication led to clinical improvement in OSA severity. Patients were defined as having a physiological response to the novel medication if the patient’s critical closing pressure (Pcrit) improved upper airway collapsibility by ≥2 cmH₂O reduction in closing pressure. OSA severity was assessed for clinical improvement utilizing AHI and oxygen desaturation index (ODI). It was also hypothesized that nasal breathing will have a more pronounced reduction in AHI for Pcrit responders.
Study Design: Ten participants completed three overnight polysomnography sleep studies with approximately one week between each visit. The three overnight polysomnography sleep studies were done in a randomized order for each patient with patients receiving 160 μg of BAY2586116, a placebo nasal spray, or 160 μg of BAY2586116 in addition to a chinstrap or mouth tape to ensure nasal-only breathing. Sleep scoring was calculated utilizing American Academy of Sleep Medicine 2012 guidelines and were evaluated by a sleep scorer. The study was double blinded during the two interventions when the patient only received nasal spray as an intervention. The third intervention in which the patient also utilized a chin strap or mouth tape as part of the intervention was not blinded to investigators or the patient. However, the study sleep scorer was blinded during each of the three sleep studies. The patient’s placebo dose was compared to their BAY2586116 dose with unrestricted breathing as well as their BAY2586116 dose with nasal breathing only. The assessment of clinical improvement looked at the ten patients' collective response. Further analysis was done on the five physiological responders and the five non-physiological responders separately to determine if physiological response impacted the clinical improvement of the medication. The measures assessing OSA severity including ODI and AHI were evaluated for group response. Additionally, AHI and ODI were assessed during non-rapid eye movement (NREM) and rapid eye movement (REM). Hypopnea events were defined as a reduction in airflow by at least 30% that lasted ten seconds or longer and led to either a three second or greater increase in electroencephalogram frequency or a reduction of oxygen saturation by at least 3%. Additionally, vitals including the following days morning and evening blood pressure as well as heart rate were captured.
Results: Five men and five women completed all three polysomnography studies. Participants were on average diagnosed with severe OSA, were obese with an average BMI of 35, and did not have insomnia. Patients who received BAY2586116 and had unrestricted breathing had a statistically significant reduction in morning blood pressure compared to their blood pressure following placebo. No changes occurred in evening blood pressure or heart rate. Additionally, patients who were physiological responders had reductions of 10mmHg (P = 0.005) and 9mmHg (P = 0.04) for systolic and diastolic readings, respectively, compared to the placebo drug. In contrast, patients who were not physiologic responders were found to have no significant differences in morning blood pressure compared to their placebo dose. Additionally, no serious drug-related side effects were reported. Collectively the ten patients as a group had no significant differences between AHI and ODI when comparing BAY2586116 to the placebo. However, when comparing physiological responders to non-responders, patients who responded to BAY2586116 were found to have statistically significant improvements in AHI and ODI. In contrast, BAY2586116 non-responders saw no change between placebo and drug. Furthermore, statistically significant improvements were seen in the Pcrit responder group with reductions of 22 to 46% in markers of OSA severity overall for ODI and AHI as well as for ODI and AHI during REM and NREM sleep. The hypothesis of nasal only breathing improving with BAY2586116 was not supported. Both physiological responders and non-responders were not statistically significant when comparing AHI and ODI between their placebo dose and the BAY2586116 dose with nasal breathing only. However, there is concern that the intervention of the chin strap may worsen upper airway function and OSA severity by retrusion of the mandible.
Conclusions: The trial indicated that topical application of a TASK 1/3 K+ channel antagonist was able to reduce OSA severity along with systolic and diastolic blood pressure the next morning in patients who had a physiological response to upper airway collapsibility. However, as the study only included ten patients, further investigation is needed utilizing larger populations to establish a better understanding of the physiological factors that impact the medication.
Key Point: BAY2586116 is a novel TASK 1/3K+ channel antagonist nasal spray that was found to reduce sleep apnea severity in patients who showed physiological response to the medication. Further investigation is needed within larger populations. However, this medication may provide a promising therapeutic approach to improving sleep apnea in patients who respond to the therapy.
Reference:
- Osman AM, Toson B, Naik GR, et al. A novel TASK channel antagonist nasal spray reduces sleep apnea severity in physiological responders: a randomized, blinded, trial. Am J Physiol Heart Circ Physiol. 2024;326(3):H715-H723. doi:10.1152/ajpheart.00541.2023
- Patil SP, Billings ME, Bourjeily G, et al. Long-term health outcomes for patients with obstructive sleep apnea: placing the Agency for Healthcare Research and Quality report in context-a multisociety commentary. J Clin Sleep Med. 2024;20(1):135-149. doi:10.5664/jcsm.10832