Abstract
BAY 2253651 is a nasally applied genioglossus muscle activatorviapharyngeal mucosal receptor stimulation (potassium channel blocker) aimed to treat obstructive sleep apnoea. Although well-tolerated and safe, there was no significant therapeutic effect.https://bit.ly/3zDbyia
To the Editor:
For obstructive sleep apnoea (OSA), few mechanical treatment options are available and no pharmacotherapy is approved [1–3]. However, safe and efficacious pharmacotherapy would have substantial appeal for many people with OSA.
A promising target is pharmacological treatment increasing upper airway stability by activating the genioglossus muscle. Its activation by the central respiratory control system is importantly modified by mechanoreceptive reflex mechanisms operating locally in the upper airways and modulated by changes in pharyngeal pressure [4–6]. It has been shown that genioglossus muscle activity and reflex modulation to changes in airway pressure are sleep stage dependent [7–9]. Many OSA patients have apnoea-free intervals in which genioglossus muscle activity is only 25–40% higher compared with sleep phases with frequent obstructive apnoeas [10].
Based on an animal model, one promising pharmacological agent which targets genioglossus muscle activation by amplifying upper airway reflex activity is BAY 2253651 [11]. This agent is a potent TASK-1 and TASK-3 potassium channel blocker with a high selectivity. The degree to which BAY 2253651 increases genioglossus muscle activity and thus improves OSA severity in humans is unknown. Accordingly, we performed a first-in-patient randomised, multicentre, double-blind, placebo-controlled, parallel group-comparison study to investigate the efficacy and safety of BAY 2253651 for the treatment of OSA.
Adults currently on treatment for OSA with continuous positive airway pressure (CPAP) (≥3 months), with an apnoea–hypopnoea index (AHI) of 15–50 h−1after 48 h of CPAP withdrawal documented by polysomnography (PSG; night 1) (table 1) and at least 4 h of sleep time, were eligible to participate in the study. As genioglossus muscle activation alone in very severe and multifactorial OSA (i.e.AHI >50 h−1)不太可能有效,这些典型个体als were not enrolled.
Exclusion criteria included neck circumferences ≥44 cm, known severe respiratory tract allergies and known allergies or hypersensitivity to the study drugs, severely impaired breathing/nasal congestion within 2 days prior to randomisation, intake of a nasal decongestant during the intervention time, use of any topical medication containing local anaesthetics for nose and throat within 7 days before first investigational medicinal product administration, intake of medication for insomnia within 24 h prior to each PSG, history of severe heart failure or severe COPD, heavy smoking, and regular daily consumption of more than 1 L of xanthine-containing beverages.
All participants provided informed consent and were investigated at tertiary centres by an experienced investigator. The trial was registereda priori(ClinicalTrials.gov identifier:NCT03603678; EudraCT-number 2017-001851-29) and an independent data monitoring committee was delegated.
Part A had a multicentre, randomised, parallel, double-blind, placebo-controlled, group comparison design with a single nasal dose (100 µg) of BAY 2253651. Participants were randomised to either 100 µg of BAY 2253651 intranasally or to a placebo nose spray and then went to sleep (night 2).
Part B was an open-label follow-up with 100 µg BAY 2253651 applied at home over 5 consecutive nights. Data from home pulse oximetry for the parameters “oxygen desaturation index (ODI) ≥3%, all night”; “ODI ≥4%, all night”; and “mean peripheral oxygen saturation (SpO2)” were collected.
Participants were stratified (1:1) according to OSA severity (moderate OSA with AHI 15–30versussevere OSA with AHI 31–50 events per h sleep) after the first PSG using an interactive voice/web response system (IxRS). For part A, the nasal sprays containing BAY 2253651 or corresponding placebo were identical in appearance (size, colour and shape). The packaging and labelling were designed to maintain blinding to the site staff as well as to the participants. The study data remained blinded until all clinical assessments have been completed, database lock and authorisation of data release according to standard operating procedures.
PSG was conducted and scored according to the recommendations from the American Academy of Sleep Medicine from 2007 (AASM 2007 Version B) and endophenotypes (“treatable traits”) were determined [12–15].
应答率(由应答器the reduction of the AHI (0–4 h) from baseline ≥50%) of the placebo and active arm were compared using a Bayesian approach. This study was planned to fulfil the go criterion if the posterior probability that the responder rate in the active arm is larger than the responder rate under placebo exceeds 0.95. On the assumption of a response rate of 0.10 to placebo and 0.40 to the active drug, 30 participants per treatment arm were needed to provide 87% probability to go. The sponsor terminated the trial for futility after data review of the first 30 subjects randomised.
34 participants (mean±sdage 63.4±8.5 years, 64.7% males) with recurrent moderate to severe OSA were randomised. Recruitment started on 13 August, 2018 and the last follow-up was at the 23 May, 2019. Craniofacial phenotyping presented no relevant differences between AHI strata for parameters with strong relationship to OSA severity.
The responder rate was 1 (6.3%) for BAY 2253651 and 1 (6.7%) for placebo. There were no differences in any of the standard PSG parameters (all p>0.05) (table 1). The posterior probability that the responder rate under BAY 2253651 is larger than the responder rate under placebo equals 0.476. There were no overall group differences in endophenotype traits, but the mean of the peak inspiratory airflow during sleep was higher at baseline in those who had an improvement in their AHI with BAY 2253651 (defined as any reduction in AHI from baseline)versusthose who did not (0.92±0.10versus0.74±0.12% wakefulness; p=0.005).
Due to early termination only nine subjects proceeded with the open label multiple dose study part B (5 nights), where no relevant changes from baseline were observed for the parameters “ODI ≥3%, all night”; “ODI ≥4%, all night”; and “meanSpO2”.
Considering potential cardiovascular side-effects of potassium channel blockers, no relevant changes or adverse events were observed for local side-effects, heart rate, blood pressure, and ECG rhythm. One participant had a temporarily increased QT-interval 6 days after last intake of BAY 2253651 while taking Citalopram (but not during the intervention night).
A single dose of 100 µg BAY 2253651, applied nasally, did not lead to a reduction in AHI in people with moderate to severe OSA off CPAP. A limitation of our trial is the small sample size, as the trial was terminated early due to futility. Another limitation is missing data on actual drug delivery. While an effect on polysomnographic parameters of OSA can be ruled out with confidence (based on part A and B data), the trial was non-informative from a mechanistic point of view. A proof of mechanism trial with a chemically altered follow-up compound is currently recruiting patients (NCT04236440).
Finally, there were no major discernible differences in other polysomnographic or pulse oximetric parameters between the BAY 2253651- and placebo-treated patient groups. However, similar to other non-CPAP interventions and consistent with OSA endophenotyping concepts, those who have less collapsible pharyngeal airways at baseline may be more likely to respond favourably to pharmacotherapy. Lastly, BAY 2253651 was safe and well-tolerated in the treated group of OSA patients.
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Acknowledgements
We thank all the participants who volunteered for this study. We also acknowledge the contributions of all colleagues which were involved in the recruitment and study processes, especially Tsogyal Latshang (Kantonsspital Graubünden), Sarosh Irani (Kantonsspital Aarau), Yvonne Nussbuamer (Kantonsspital Schaffhausen), Robert Thurnheer (Kantonsspital Münsterlingen), Jean-Luc Kurzen (Spital Männedorf), Marc Spielmanns (Zürcher RehaZentrum Wald), Alexander Turk and Patrick Schihin (Spital Horgen), Lungenliga Glarus (Thomas Brack and Alice Odermatt), The Oxford Centre for Respiratory Medicine (Kallirroi Lamprou and Blake Marsh), The Oxford Respiratory Trials Unit (Dushendree Sen, Tara Harris and Debby Nicoll) and Lunge Zürich (Michael Schlunegger, Dominic Karrer and Sylke Meier). We also thank the patients who committed to the study and often travelled long distances to participate. Without their effort, this project would not have been possible. The authors would like to thank Simone Steinbach (professional medical writer) for her contribution to the manuscript draft.
Footnotes
This study was registered at Clinicaltrials.gov with identifierNCT03603678. Original data are available from the corresponding author upon reasonable request.
作者的贡献:g . Weimann昂格尔,r .鳍ger and C. Xing had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: T. Gaisl, C.D. Turnbull, G. Weimann, S. Unger, R. Finger, C. Xing, P.A. Cistulli, D.J. Eckert, J.R. Stradling and M. Kohler. Acquisition, analysis or interpretation of data: all authors. Drafting of the manuscript: T. Gaisl, G. Weimann, M. Kohler and S. Steinbach (professional medical writer). Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: T. Gaisl and S. Unger. Administrative, technical or material support: T. Gaisl, G. Weimann, R. Finger, C. Xing, J.R. Stradling and M. Kohler. Study supervision: G. Weimann, R. Finger, C. Xing and M. Kohler. Independent supervision, compliance regulations, data management and monitoring: PRA Health Sciences.
利益冲突:这项工作是由Bayer (sponsor). G. Weimann, S. Unger, R. Finger and C. Xing are employees (including stock options) of the sponsor. T. Gaisl, C.D. Turnbull, P.A. Cistulli, S. West, D.J. Eckert, J.R. Stradling and M. Kohler report personal fees from Bayer during the conduct of the study. P.A. Cistulli, A.K.I. Chiang, D.J. Eckert, J.R. Stradling and M. Kohler report grants from Bayer (all through their respective employer) during the conduct of the study. P.A. Cistulli has an appointment to an endowed academic Chair at the University of Sydney that was created from ResMed funding. He receives no personal fees and this relationship is managed by an Oversight Committee of the University. He has received research support from ResMed, SomnoMed, and Zephyr Sleep Technologies, outside the submitted work. He is a consultant to Zephyr Sleep Technologies, Signifier Medical Technologies, SomnoMed, and ResMed and writer for Wolters Kluwer and Quintessence, outside the submitted work. He has a pecuniary interest in SomnoMed related to a previous role in R&D 2004, outside the submitted work. A.K.I. Chiang and D.J. Eckert report grants from Cooperative Research Centre Project Grant (Australian Government, Academia and Industry collaboration, Industry partner: Oventus Medical), outside the submitted work. D.J. Eckert reports research grants and personal fees from Apnimed and is member of the advisory board of Apnimed, outside the submitted work. J.R. Stradling reports personal fees from Resmed UK, outside the submitted work. M. Kohler reports personal fees from Novartis, grants and personal fees from GSK, grants and personal fees from Roche, personal fees from Boehringer Ingelheim, personal fees from Mundipharma, personal fees from OM Pharma, personal fees from AstraZeneca, all outside the submitted work; and he is a founder and board member of Deep Breath Intelligence Ltd, a company that provides services in the field of breath analysis.
Support statement: This work was supported by the study sponsor, Bayer HealthCare. J.R. Stradling and C.D. Turnbull acknowledge support from the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. C.D. Turnbull was supported by an NIHR Academic Clinical Lectureship. The views expressed are those of the authors and not necessarily of the NHS, the NIHR, or the Department of Health. Funding information for this article has been deposited with theCrossref Funder Registry.
- ReceivedJuly 2, 2021.
- AcceptedAugust 23, 2021.
- Copyright ©The authors 2021.
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