SLEEPJ, 2021, 1–11

doi: 10.1093/sleep/zsaa275 Advance Access Publication Date: 11 December 2020 Original Article

Original Article Downloaded from https://academic.oup.com/sleep/article/44/6/zsaa275/6030922 by guest on 24 September 2021 Effect of the new dual receptor antagonist daridorexant on nighttime respiratory function and sleep in patients with mild and moderate obstructive sleep apnea Marie-Laure Boof1,*, , Jasper Dingemanse1, , Katharina Lederer2, , Ingo Fietze2 and Mike Ufer1,

1Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland and 2Advanced Sleep Research GmbH, Berlin, Germany

*Corresponding author. Marie-Laure Boof, Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123 Allschwil, Switzerland. Email: [email protected].

Abstract In this randomized, double-blind, placebo-controlled, two-period crossover study, the effect of the dual antagonist daridorexant was evaluated on nighttime respiratory function and sleep in 28 patients with mild and moderate obstructive sleep apnea (OSA). In each period, 50 mg daridorexant or placebo was administered every evening for 5 days. The primary endpoint was apnea/hypopnea index (AHI) during total sleep time (TST) after the last dosing. Other

endpoints included peripheral oxygen saturation (SpO2), sleep duration, latency to persistent sleep (LPS), wake after sleep onset (WASO), and sleep efficiency index (SEI). Pharmacokinetics, safety, and tolerability were also assessed. The mean treatment difference for AHI during TST (i.e. daridorexant − placebo) after the last dosing was 0.74 events/hour (90% confidence interval [CI]: –1.43, 2.92). The corresponding treatment difference for SpO during TST was 0.16% [90% CI: –0.21, 0.53]. 2021 2 Overall, there was no clinically relevant effect of daridorexant on AHI or SpO2-related data after single and repeated dosing irrespective of sleep phase (i.e. rapid eye movement [REM] vs non-REM). Moreover, after single and repeated dosing, daridorexant prolonged TST by 39.6 minutes (90% CI: 16.9, 62.3) and 38.8 minutes (19.7, 57.9), respectively, compared with placebo and favorably modulated other sleep-related endpoints (i.e. increased SEI, decreased WASO, and shortened LPS). It attained expected plasma concentrations and was well tolerated in patients with mild and moderate OSA.

These results indicate that single and repeated doses of 50 mg daridorexant do not impair nighttime respiratory function and improve sleep in patients with mild and moderate OSA.

Clinical Trial Registration: ClinicalTrials.gov NCT03765294. A study to investigate the effects of ACT-541468 on nighttime respiratory function in patients with mild to moderate obstructive sleep apnea. https://clinicaltrials.gov/ct2/show/ NCT03765294.

Statement of Significance Obstructive sleep apnea (OSA) is highly prevalent and often associated with -related symptoms. However, many sleep impair nighttime respiration and, therefore, require cautionary use in respiratory-depressed patients. Daridorexant is a new dual orexin receptor antagonist under development for the treatment of insomnia with presumably limited respiratory effects. This randomized, double-blind, placebo-controlled, two-period crossover study evaluated the effect of daridorexant on nighttime respiratory function in patients with mild and moderate OSA. At the highest phase-3 dose of 50 mg, daridorexant did not impair nighttime respiratory function based on apnea/hypopnea index and peripheral oxygen saturation data regardless of OSA severity. In addition, daridorexant improved sleep characteristics in this population that did not present insomnia symptoms at baseline.

Key words: obstructive sleep apnea; dual orexin receptor antagonist; daridorexant; pharmacokinetics; polysomnography; nighttime respiration; safety

Submitted: 26 June, 2020; Revised: 30 October, 2020 © Sleep Research Society 2020. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail [email protected].

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Introduction maximum recommended daily dose. However, due to the high inter- and intra-individual variability observed in the study, Obstructive sleep apnea (OSA) is a sleep-related breathing dis- should be used with caution in patients with com- order characterized by repeated reduction (i.e. hypopnea) or ces- promised respiratory function and at the lowest effective dose sation (i.e. apnea) of breathing due to the temporary obstruction [35]. At the highest approved dose of 10 mg, did of the upper airway during sleep [1, 2]. A close association be- not impair nighttime respiratory function in patients with mild tween OSA and the occurrence of cardiovascular diseases such OSA, while data for patients with moderate OSA have not been as systemic hypertension, coronary artery disease, heart failure generated [36]. [3, 4], or type 2 diabetes [5] has been reported. Furthermore, Daridorexant (ACT-541468) is a new DORA with favorable OSA has also short-term effects, mainly increased daytime pharmacokinetic (PK) and pharmacodynamic (PD) properties, sleepiness, leading to an increased risk of car accidents [6, 7] that is, quick absorption (median time to reach maximum con- and impaired quality of life [8]. Despite approximately one bil- centration 0.8–1.0 hours), short terminal half-life (5.9–8.8 hours lion patients with OSA worldwide and a prevalence exceeding across the tested doses), no relevant accumulation, and no ap- Downloaded from https://academic.oup.com/sleep/article/44/6/zsaa275/6030922 by guest on 24 September 2021 50% in some countries [2, 9, 10], it often remains undiagnosed parent next-day residual PD effects after evening administra- in more than 70% of population at high risk of developing OSA tion in adults or elderly healthy participants [37, 38]. In phase-2 [11], as associated symptoms (e.g. excessive daytime sleepiness, studies, daridorexant demonstrated dose-dependent efficacy in- tiredness, and reduced performance) that usually trigger con- dicated by a significant reduction of the objective sleep param- sultation in a sleep clinic are often not prominent [12]. eters wake after sleep onset (WASO) and latency to persistent OSA tends to coexist with insomnia [13–17], leading to chal- sleep (LPS) [39, 40]. After repeated dosing, daridorexant was safe lenges in the therapeutic approach for the treatment of both and well tolerated in both healthy participants (up to 75 mg) and disorders. Although continuous positive airway pressure (CPAP) patients with insomnia (up to 50 mg) [37–41]. therapy is an effective treatment for moderate to severe OSA, it is The present study evaluated the effect of single and repeated not well tolerated by patients with coexisting insomnia [17–19]. dosing with 50 mg daridorexant (i.e. the highest dose used in the Benzodiazepines, “Z-drugs,” and melatonin receptor agonists are phase-3 program) on nighttime respiratory function, and sleep at present the most commonly used approved drugs for short- characteristics, in patients with mild and moderate OSA. term treatment of insomnia [20]. Some of these drugs might im- pair nighttime respiratory function in patients with OSA, which is of safety relevance particularly when OSA is undiagnosed. Methods Benzodiazepines (e.g. triazolam or flurazepam) or “Z-drugs” (e.g. zolpidem or zaleplon) are suspected to decrease oxygen satur- Study design ation during nighttime in patients with OSA [21–26]. Only a few This randomized, double-blind, placebo-controlled, two-period sleep medications do not seem to impair nighttime respiratory crossover study aimed to investigate the effects of daridorexant function in patients with OSA such as the gamma-aminobutyric on nighttime respiratory function and sleep characteristics in acid (GABA)-A receptor agonist eszopiclone or the melatonin re- patients with mild and moderate OSA. It was approved by the ceptor agonist ramelteon [26–28]. German health authority (Bundesinstitut für Arzneimittel und Based on the above, there is a need for a safe sleep Medizinprodukte, BfArM) and by the local Ethics Committee that does not impact nocturnal breathing in patients primarily (Ethik-Kommission des Landes Berlin, Berlin, Germany). The treated for insomnia symptoms who present comorbid OSA study was conducted at a single site in accordance with the whether or not diagnosed. It is, therefore, of safety relevance to Declaration of Helsinki principles, International Council for investigate the effect of novel sleep agents on nighttime respira- Harmonisation Good Clinical Practice guidelines, and applicable tory function in patients with OSA. In recent years, orexin recep- regulations and laws. All patients provided written informed tors have evolved as a new promising target for the treatment consent prior to any screening procedures. of insomnia [29, 30]. Neurons synthesizing the After a screening period, 28 patients were enrolled and ran- orexin A and orexin B, originating from the hypothalamus, pro- domized in a 1:1 ratio to receive 50 mg daridorexant followed by ject in various brain areas, including the forebrain, corticolimbic matching placebo or vice versa. Daridorexant and placebo were structures, and brainstem involved in the regulation of the sleep– orally administered at nighttime for five consecutive days. Both wake cycle. They promote alertness/wakefulness by interacting study periods were separated by an in-between period lasting with both the orexin-1 and orexin-2 receptors [31]. Dual orexin 1 to 2 weeks. A time frame of 1 to 2 weeks was also applied be- receptor antagonists (DORAs) have, therefore, been proposed tween the last administration and the end-of-study visit. as a new treatment paradigm for insomnia. As orexin neurons The selected dose of 50 mg corresponds to the highest dose also project to brainstem regions influencing breathing, a role of used in the phase-3 program. In previous clinical studies, it was DORAs in the regulation of respiration as well as chemorecep- confirmed to be safe and well tolerated in healthy participants tion has been suggested [32, 33]. In mice, orexin indeed and patients with insomnia [39–41]. promote respiratory activity under conditions of stress such as hypercapnia without impacting basic ventilatory volume [34]. Suvorexant (Belsomra) and lemborexant (Dayvigo) are Study population two DORAs approved for the treatment of insomnia charac- terized by difficulties with sleep onset and/or sleep mainten- Male and female adults (i.e. >18 years) with mild or moderate ance. Suvorexant did not have clinically important respiratory OSA were enrolled. OSA severity was determined based on med- effects during sleep in patients with mild to moderate OSA at ical history within the last 3 years and confirmed by a diagnostic a supratherapeutic dose of 40 mg, that is, twice the approved night polysomnography (PSG, screening night) according to the Boof et al. | 3

American Academy of Sleep Medicine (AASM) guidelines, that is, defined as pauses of respiration for at least 10 seconds, while an average of 5 ≤ apnea/hypopnea index (AHI) < 15 events/hour hypopneas were defined as a reduction of airflow by at least 30%

(mild) and 15 ≤ AHI < 30 events/hour (moderate) during total for ≥10 seconds accompanied by an absolute decrease in SpO2 sleep time (TST) [42, 43]. by ≥4% (i.e. 4 units) compared with corresponding data prior to Respiratory disorders other than OSA and comorbidities with the hypopnea event. a potential impact on sleep, motor performance, or cognition (i.e. psychiatric disease, including suicidal ideation, neurological Secondary PD endpoint disorder, or severe insomnia) were exclusionary. Other key ex- The secondary respiratory PD endpoint was the treatment dif- clusion criteria included previous OSA-related surgical inter- ference between daridorexant and placebo for SpO2 during TST vention and peripheral oxygen saturation (SpO2) < 90% during after repeated dosing. wakefulness or <85% for >5 minutes during the screening night. Finally, the use of CPAP or dental appliance device (i.e. standard Exploratory PD endpoints of care treatment) was also prohibited to ensure proper evalu- Downloaded from https://academic.oup.com/sleep/article/44/6/zsaa275/6030922 by guest on 24 September 2021 The treatment difference between daridorexant and placebo ation of nighttime respiratory function (i.e. no modulation of after single and repeated dosing was further investigated with the incidence of apneas/hypopneas), whereas stopping of CPAP respect to respiratory function based on several exploratory PD treatment prior to study participation was not considered feas- endpoints including AHI during rapid eye movement (REM) and ible due to a potential safety risk. non-REM sleep, SpO2 during awake time, non-REM, and REM Pregnant or lactating women were also excluded, while sleep, time spent with SpO2 < 90%, <85%, and <80% (expressed women of childbearing potential had to use a highly effective as %TST). method of contraception during the entire study. Exploratory PD endpoints related to sleep characteristics included duration of the different nighttime phases (TST, non- REM, and REM sleep time), arousal index (total, respiratory, and Study procedures spontaneous), LPS, WASO, and sleep efficiency index (SEI). The PSG recordings were performed in each patient on night 1 (i.e. percentage of TST in the three different non-REM stages (N1, N2, after the first dosing) and night 5 (i.e. after the last dosing) of and N3) was also evaluated. The arousal indices were calculated each period using MiniScreen PRO v5.19.0 (Löwenstein Medical, by determining the number of arousals during TST and are ex- Rheinland-Pfalz, Germany). In addition, each patient underwent pressed as the number of arousals/hour TST.

PSG during the screening period to determine the baseline char- In addition, treatment differences for AHI- and SpO2-related acteristics for AHI, SpO2, and objective sleep parameters. data as well as the duration of nighttime phases (TST, non-REM, Each PSG recording included electroencephalogram, and REM) and the objective sleep parameters LPS, WASO, and SEI electrooculogram, chin and leg electromyogram, measurement were also evaluated after first dosing (i.e. on night 1). of respiratory efforts and nasal airflow, and pulse oximetry. PSG All variables were scored according to the current AASM recording lasted 8 hours and was started within 1 hour of indi- criteria [42], at the study site by a single somnologist, who was vidual usual bedtime as determined by patient’s self-reporting unaware of the randomization schedule and not otherwise in- during screening. This approach was applied in order not to dis- volved in the study. turb individual sleep habits.

SpO2 was continuously measured as part of PSG recording by Daytime sleepiness finger pulse oximetry and initiated within 20 minutes prior to Patients were requested to rate their feelings about daytime the start and stopped at the end of the PSG recording. sleepiness, which included morning sleepiness (very vs not at In both study periods, the patients were admitted to the all sleepy), daytime alertness (very sleepy vs wide awake and study site on day 1 and received the first dose of daridorexant or alert), and daily ability to function (poor vs excellent) by means placebo in the evening of day 1 (i.e. 30 minutes before the start of visual analog scale (VAS) data ranging from 0 to 100 mm. of PSG recording and at least 2 hours after the evening meal). Morning sleepiness was assessed in the morning, the day after Each patient was discharged in the morning of day 2 followed each administration. Daytime alertness and daily ability to func- by self-administration of study treatment at home from day 2 tion were assessed in the evening, the day following previous to day 4. Patients were instructed to record time of treatment administration. administration, interval between evening meal and dosing, and bedtime in a diary, and study staff contacted the patients every Pharmacokinetics day to ensure adherence to treatment intake. Each patient was Blood samples were collected in ethylenediaminetetraacetic readmitted on day 5 and received the last dose of daridorexant acid (EDTA) tubes in each period at pre-dose on day 1, trough or placebo in the evening of day 5. (pre-dose) on day 5, and on days 2 and 6 in the morning (9 hours post-dose) for the determination of daridorexant plasma con- centrations. After centrifugation, plasma was transferred to poly- Assessment of PD, PK, safety, and tolerability propylene tubes and stored at −20°C or below. Concentrations of Primary PD endpoint daridorexant in plasma were measured using a previously de- The primary respiratory PD endpoint was the treatment differ- scribed validated liquid chromatography method with tandem ence between daridorexant and placebo for AHI during TST after mass spectrometry [44]. The lower limit of quantification was repeated dosing for 5 days (i.e. after the last dosing). 0.5 ng/mL. Inter-batch precision expressed as coefficient of vari- The AHI was calculated as the sum of apneas and hypopneas ation was ≤7.9%, and inter-batch accuracy expressed as a rela- divided by TST and expressed as events per hour. Apneas were tive deviation from nominal value ranged from 0.5% to 7.5%. 4 | SLEEPJ, 2021, Vol. 44, No. 6

Safety and tolerability were assessed based on vital signs, arousal indices, LPS, WASO, and SEI) were evaluated by linear 12-lead electrocardiogram (ECG), physical examination, clinical mixed-effects modeling, which included treatment, period, and chemistry, hematology, and adverse event (AE) data. baseline (i.e. data from PSG performed at screening) as fixed effects and patient as a random effect. The mean square error from the model was used to calculate the two-sided 90% CI for Statistical analysis the true mean difference (daridorexant − placebo). Treatment Primary PD endpoint analysis difference was considered statistically significant when the 90% An increase in AHI during TST of 5 events/hour was the prede- CI did not include 0. Study results are reported as LSM differ- fined minimum change considered clinically meaningful based ence, associated standard error (SE) or two-sided 90% CI, and on the findings from longitudinal population-based studies p-value for treatment difference with reference to 0. that suggest that OSA may be a risk factor for developing comorbidities [3, 5]. This criterion was also used in previous Analysis of daytime sleepiness clinical studies [28, 35]. To evaluate whether 50 mg daridorexant Daytime sleepiness data were analyzed by mixed-effects Downloaded from https://academic.oup.com/sleep/article/44/6/zsaa275/6030922 by guest on 24 September 2021 induces such effect, it was hypothesized that the treatment dif- modeling with the VAS score as a dependent variable. Study ference between daridorexant and placebo for AHI during TST treatment and night as well as the interaction between both after repeated dosing was ≥5 events/hour (null hypothesis). variables were included as fixed effects and participant as a Assuming a variance of 14.6 for the primary endpoint and a random effect. For each of the three endpoints, the quantile true treatment difference ≤1.5, based on previous studies [27, 28, plot did not deviate from the normality of the weighted resid- 35], with a type one error of 0.05 and 90% power, a minimum of uals confirming the validity of a parametric model. As there was 24 evaluable patients were required to identify a treatment dif- no interaction between study night and treatment, results are ference for AHI during TST < 5 events/hour. provided as global LSM treatment difference (daridorexant – Individual values of AHI during TST were statistically evalu- placebo) with the associated two-sided 90% CI and p-value for ated by linear mixed-effects modeling, which included treat- treatment difference with reference to 0. ment, period, and baseline (i.e. data from PSG performed at screening) as fixed effects and patient as a random effect. Mean square error from the model was used to calculate the two- Results sided 90% confidence interval (CI), for the true mean difference Disposition and demographics (daridorexant − placebo) for AHI during TST. Study results are reported as least square mean (LSM) difference, associated two- Twenty-eight (28) patients were enrolled in the study. Of these, sided 90% CI, and p-value for “treatment difference” with refer- 25 completed study treatment and had evaluable PSG data, while ence to the clinically meaningful threshold of 5 events/hour. To 3 patients were discontinued and thus excluded from the pri- reject the null hypothesis, the upper limit of the two-sided 90% mary analysis, due to an AHI increase from baseline > 10 events/ CI for treatment difference (daridorexant – placebo) was to be <5 hour in period 1 (N = 2 after placebo and N = 1 after daridorexant events/hour (alpha = 0.01). administration). These patients were included in the sensitivity A sensitivity analysis of primary endpoint data was per- analysis. formed to include discontinued patients. To this end, missing Of the 28 enrolled patients, 16 had mild OSA and 12 moderate values under daridorexant were imputed with the worst ob- OSA. There were 18 male and 10 female patients with a mean served value under active treatment, and values missing under age of 60.1 years and a mean body mass index of 28.6 kg/m2 placebo were imputed with respective baseline values, that is, (Table 1). Overall, baseline characteristics were well balanced assuming no effect of placebo. across both treatment sequences. Only 1 of the 28 enrolled pa- The least square approach was used for linear regression tients presented a comorbid mild insomnia per medical history. analysis of AHI during TST at baseline (i.e. OSA severity) and treatment difference for AHI after single and repeated dosing. The same approach was also used for linear regression analysis Effect on nighttime respiratory-related endpoints of treatment difference for AHI on night 1 vs night 5. The effect of single (night 1) and repeated (night 5) dosing with 50 mg daridorexant on nighttime respiratory function is pro- Secondary PD endpoint analysis vided in Table 2. Individual treatment differences for AHI during The same approach as used for the primary endpoint analysis TST are shown in Figure 1. was used for the analysis of SpO2-related data. To this end, a In the 25 evaluable patients, no effect of 50 mg daridorexant decrease of more than 2% in SpO2 was predefined as clinic- was observed on the primary endpoint (AHI during TST after ally meaningful as previously reported [35]. Study results are repeated dosing) as the mean (90% CI) treatment difference reported as LSM difference, associated two-sided 90% CI, and (daridorexant – placebo) was 0.74 events/hour (–1.43, 2.92) p-value for “treatment difference” with reference to the clinic- (Table 2, Figure 1). The treatment difference (daridorexant – ally meaningful threshold of –2%. To reject the null hypothesis, placebo) was significantly lower than the threshold of clinical the lower limit of the two-sided 90% CI for treatment difference meaningfulness, that is, 5 events/hour (p = 0.001). As the upper (daridorexant – placebo) was to be >–2%. bound of the 90% CI was lower than the value of 5 events/hour, the null hypothesis was rejected indicating that daridorexant Exploratory PD endpoints analysis had no clinically meaningful effect on AHI during TST in pa- Individual values of each exploratory respiratory- and sleep- tients with mild and moderate OSA. This was confirmed by the related PD endpoint (i.e. duration of the nighttime phases, sensitivity analysis including all 28 enrolled patients, as the Boof et al. | 5

Table 1. Demographic and baseline characteristics

50 mg Daridorexant → Placebo → 50 mg Overall Characteristics Placebo (N = 14) daridorexant (N = 14) (N = 28)

Mean age (range) [y] 59.9 (40.0, 79.0) 60.2 (45.0, 78.0) 60.1 (40.0, 79.0) ≥18 to <65, n (%) 8 (57.1%) 8 (57.1%) 16 (57.1%) ≥65, n (%) 6 (42.9%) 6 (42.9%) 12 (42.9%) Mean body mass index (range) [kg/m2] 28.7 (23.4, 33.6) 28.5 (24.8, 34.0) 28.6 (23.4, 34.0) Sex, n (%) Male 9 (64.3%) 9 (64.3%) 18 (64.3%) Female 5 (35.7%) 5 (35.7%) 10 (35.7%) Race, n (%) White 13 (92.9%) 14 (100%) 27 (96.4%) Hispanic or Latino 1 (7.10%) 0 (0.00%) 1 (3.60%) Downloaded from https://academic.oup.com/sleep/article/44/6/zsaa275/6030922 by guest on 24 September 2021 OSA severity, n (%) Mild 7 (50.0%) 9 (64.3%) 16 (57.1%) Moderate 7 (50.0%) 5 (35.7%) 12 (42.9%) Mean AHI during TST (SD) [events/h] 17.4 (9.51) 16.6 (7.67) 17.0 (8.49)

Mean SpO2 during TST (SD) [%] 94.1 (1.27) 93.5 (1.43) 93.8 (1.36) TST (SD) [min] 386 (71.8) 372 (74.2) 382 (72.4) LPS (SD) [min] 32.2 (53.9) 26.0 (33.2) 28.2 (43.6) WASO (SD) [min] 74.1 (52.5) 83.5 (61.7) 77.1 (56.7) SEI (SD) [%] 80.4 (14.9) 77.3 (15.4) 79.4 (15.1)

Age, body mass index, AHI, SpO2, TST, LPS, WASO, and SEI data are presented as arithmetic means. upper bound of the 90% CI for the treatment difference was also When compared with placebo, daridorexant significantly pro- <5 (2.38 events/hour [90% CI: –0.22, 4.97]; p = 0.048). longed mean (SE) TST by 39.6 minutes (13.2; p = 0.007) and 38.8 min- Mean AHI values were comparable between daridorexant and utes (11.1; p = 0.002) after single and repeated dosing, respectively. placebo irrespective of sleep phase, that is, treatment difference of Accordingly, non-REM sleep was also prolonged compared 0.48 events/hour (90% CI: –1.72, 2.69; p = 0.71) and 1.31 events/hour with placebo by 40.6 ± 13.7 minutes (p = 0.007) and 31.2 ± 10.3 (90% CI: –2.65, 5.26; p = 0.58) during non-REM and REM sleep phases, minutes (p = 0.006) without changes in the proportion of N1, N2, respectively. Treatment differences for AHI during TST, non-REM, and N3 sleep stages indicated by mean (SE) treatment difference and REM sleep phases were also similar after single and repeated for N1, N2, and N3 of –2.06 minutes (2.27; p = 0.37), 2.48 minutes dosing (Table 2). (2.62; p = 0.35), and –1.70 minutes (1.13, p = 0.15), respectively. By AHI at baseline as a marker of OSA severity did not correlate contrast, no statistically significant treatment difference com- with the treatment difference for AHI indicated by an r2 of 0.014 pared with placebo was observed for REM sleep indicated by (p = 0.57) and 0.003 (p = 0.78) after single and repeated dosing, mean (SE) treatment differences of –0.98 minutes (5.42; p = 0.86) respectively (Figure 2). and 6.21 minutes (4.70; p = 0.20) after single and repeated dosing There was no association between the individual treatment with daridorexant, respectively (Table 3). differences on night 1 vs night 5 as determined by linear regres- After repeated dosing, no statistically significant treatment sion analysis (Supplementary Figure S1). difference compared with placebo was observed for the total Similarly, no effect of 50 mg daridorexant was observed on arousal indices indicated by mean (SE) treatment difference the secondary endpoint (SpO2 during TST after repeated dosing) of 0.52 arousals/hour TST (0.71; p = 0.47). Accordingly, statistic- as the mean (90% CI) treatment difference (daridorexant – pla- ally significant treatment differences compared with placebo cebo) was 0.16% (–0.21, 0.53) (Table 2, Figure 3). The treatment were also not observed in respiratory and spontaneous arousal difference (daridorexant – placebo) was significantly above the indices indicated by mean (SE) treatment difference of 0.35 threshold of clinical meaningfulness, that is, –2% (p < 0.0001). As arousals/hour TST (0.97; p = 0.72) and 0.32 arousals/hour TST the lower bound of the 90% CI was above the value of –2%, the (0.30; p = 0.31), respectively. null hypothesis was rejected indicating that daridorexant had Repeated administration of daridorexant significantly in- no clinically meaningful effect on SpO2 during TST in patients creased mean (SE) SEI by 8.04% (2.33; p = 0.002) (Table 3) and with mild and moderate OSA. reduced mean (SE) WASO by 31.0 minutes (9.52; p = 0.004). LPS

SpO2 data were similar after single and repeated dosing with was also shortened but the treatment difference did not reach daridorexant and placebo (Table 2). Overall, time spent with statistical significance with mean (SE) treatment difference of

SpO2 < 90%, <85%, and <80% was also comparable after single –19.8 minutes (10.7; p = 0.12) (Table 3). and repeated dosing with daridorexant and placebo indicating Results of the sleep-related endpoints were similar after the the absence of oxygen desaturation induced by daridorexant first dosing (Table 3). (Table 2).

Effect on daytime sleepiness Effect on sleep-related endpoints The time course of daytime sleepiness data is provided as mean The effect of single and repeated dosing with 50 mg daridorexant change-from-baseline over time (Supplementary Figure S2) and on the duration of nighttime phases and objective sleep param- as individual VAS scores over time (Supplementary Figures S3– eters is provided in Table 3. S5) profiles. There was no difference between daridorexant and 6 | SLEEPJ, 2021, Vol. 44, No. 6

Table 2. Effect of daridorexant on nighttime respiratory function

Night 1 Night 5

Daridorexant Treatment difference Daridorexant Treatment difference (50 mg) Placebo (daridorexant – placebo) (50 mg) Placebo (daridorexant – placebo)

AHI during (events/h) TST 16.7 (14.2, 19.2) 15.5 (13.0, 18.0) 1.18 (−1.70, 4.07) 15.0 (12.5, 17.6) 14.3 (11.8, 16.8) 0.74 (−1.43, 2.92) [0.49] [0.001]* Non-REM 16.5 (13.8, 19.2) 14.5 (11.8, 17.2) 1.97 (−1.29, 5.24) 14.3 (11.7, 16.9) 13.8 (11.2, 16.4) 0.48 (−1.72, 2.69) [0.31] [0.71] REM 17.2 (11.7, 22.7) 21.6 (16.2, 26.9) −4.35 (−10.3, 1.59) 18.0 (13.2, 22.8) 16.7 (11.9, 21.6) 1.31 (−2.65, 5.26) [0.22] [0.58]

Mean SpO2 during (%) Downloaded from https://academic.oup.com/sleep/article/44/6/zsaa275/6030922 by guest on 24 September 2021 TST 93.7 (93.3, 94.1) 94.0 (93.6, 94.4) −0.34 (−0.66, −0.02) 93.9 (93.5, 94.3) 93.7 (93.3, 94.2) 0.16 (−0.21, 0.53) [0.084] [<0.0001]** Awake time 93.6 (93.2, 94.0) 94.0 (93.7, 94.5) 0.42 (−0.78, −0.06) 93.4 (92.8, 93.9) 93.5 (93.0, 94.1) −0.18 (−0.70, 0.34) [0.058] [0.57] Non-REM 93.7 (93.3, 94.0) 94.0 (93.6, 94.4) −0.36 (−0.66, −0.06) 93.9 (93.4, 94.3) 93.7 (93.2, 94.1) 0.19 (−0.19, 0.56) [0.052] [0.41] REM 94.1 (93.5, 94.7) 94.1 (93.6, 94.7) −0.02 (−0.39, 0.71) 94.1 (93.5, 94.7) 94.0 (93.3, 94.6) 0.16 (−0.39, 0.71) [0.95] [0.62]

TST with SpO2 (%) <90% 3.13 (1.95, 4.30) 2.15 (0.98, 3.33) 0.98 (−0.28, 2.23) 2.04 (−1.86, 5.93) 5.46 (1.56, 9.36) −3.42 (−7.84, 0.99) [0.20] [0.20] <85% 0.22 (0.11, 0.34) 0.11 (−0.00, 0.23) 0.11 (−0.02, 0.24) 0.20 (0.01, 0.38) 0.14 (−0.04, 0.32) 0.06 (−0.14, 0.26) [0.16] [0.63] <80% 0.03 (0.01, 0.05) 0.00 (−0.02, 0.03) 0.02 (−0.00, 0.05) 0.10 (−0.04, 0.23) 0.02 (−0.11, 0.15) 0.08 (−0.08, 0.23) [0.15] [0.39]

Data are displayed as LSM (95% CI) for treatments and 90% CI (p-value) for treatment difference. Study treatments were administered once daily in the evening. *Primary endpoint: upper bound of 90% CI was below the clinically meaningful threshold of 5 events/h. P-value was determined for treatment difference (daridorexant – placebo) with reference to the clinically relevant threshold of 5 events/h. **Secondary endpoint: upper bound of 90% CI was above the clinically meaningful threshold of –2%. P-value was determined for (daridorexant – placebo) with refer- ence to the clinically relevant threshold of –2%. Other p-values were determined for treatment difference (daridorexant – placebo) with reference to the value 0.

placebo as indicated by mean (90% CI) treatment differences of of placebo during period 1). Cystitis (one event on daridorexant –0.99 mm (–4.37 to 2.39; p = 0.62), –1.58 mm (–4.86 to 1.69; p = and two events on placebo) and hangover (two events on 0.42), and 1.51 mm (–1.58 to 4.60; p = 0.41) for next-day morning daridorexant and one event on placebo) were the most common sleepiness, daytime alertness, and daily ability to function, re- AEs occurring in three patients each, while all other AEs oc- spectively. This indicates the absence of daridorexant-induced curred in single patients only. None of the AEs required con- next-day sleepiness in any of these subjective assessments. comitant therapy, and there were no clinically relevant effects of daridorexant on vital signs, ECG, or laboratory variables.

Pharmacokinetics In the morning of days 2 and 6, the arithmetic mean (95% CI) of Discussion daridorexant was 445 ng/mL (393–497) and 628 ng/mL (532–724), This randomized, double-blind, placebo-controlled study shows respectively. Comparison of plasma concentrations obtained that daridorexant at the highest phase-3 dose of 50 mg does not on days 6 and 2 revealed an accumulation ratio of approxi- impair nighttime respiratory function in patients with mild and mately 1.4 (standard deviation: 0.4). The arithmetic mean (95% moderate OSA. CI) trough concentration obtained at pre-dose on night 5 was AHI is considered as the gold standard for the diagnosis of 312 ng/mL (241–383). OSA and classification of its severity [45] and has been utilized as a primary endpoint in many of the respiratory safety studies in patients with OSA [26]. Longitudinal population-based studies Safety and tolerability have suggested that an increase by ≥5 events/hour in AHI is as- AEs that occurred during the study are summarized in Table 4. sociated with an increased risk for developing hypertension [3] There were no serious AEs and no discontinuations due to an or type 2 diabetes [5]. In the safety respiratory studies conducted AE. Overall, the incidence of AEs was similar following the ad- with ramelteon [28] and the two other DORAs, suvorexant [35] ministration of daridorexant and placebo (N = 4 [15.4%] vs N = 6 and lemborexant [36], the threshold of 5 events/hour was used for [22.2%] patients, respectively). the definition of a clinically meaningful effect of study treatment. All AEs were of mild intensity except for a single moderate Using the same threshold of 5 events/hour in the present AE of asymptomatic thrombocytopenia (after administration study for the analysis of the primary endpoint, daridorexant did Boof et al. | 7

20 Night1 20 15 acebo) pl 10 10 ce t- [events/h] en er f vents/h] f e 5 di orexan t placebo) T[

n 0 t- arid TS me t

(d 0 ea r T -10 during -5 HI Downloaded from https://academic.oup.com/sleep/article/44/6/zsaa275/6030922 by guest on 24 September 2021 (daridorexan difference rA t -10 fo -20 0510 15 20 25 30 -15 AHIduringTST at baseline [events/h] Treatmen r2:0.0141 -20 p-value: 0.5716 Night1 Night5 Equation:Y=0.1248*X-0.7568 Mean +/-90%CI Mean +/-90%CI Night5 Figure 1. Individual treatment differences for AHI during TST on night 1 and night 5. Data are provided as treatment differences (daridorexant – placebo) and 20

LSM ± 90% CI for treatment difference after single dosing (night 1) and repeated ] h / s

dosing (night 5). t en e v 10 [e not affect AHI during TST after repeated dosing for 5 days in the

25 evaluable patients. The robustness of the primary results was ifferenc acebo) l td further confirmed by a sensitivity analysis that included all 28 p 0 - t enrolled patients. Finally, mean AHI values after repeated dosing n with daridorexant were also comparable to baseline data, fur- Treatmen ther supporting the primary conclusion on the absence of rele- -10 ridorexa vant AHI changes. a (d

SpO2 represents another clinically relevant commonly used endpoint in respiratory safety studies [26]. Here, a lack of treat- -20 ment effect after repeated dosing was also observed. While 0510 15 20 25 30 AHIduringTST at baseline [events/h] mean basal nocturnal SpO2 in healthy participants is ≥96% [46], it typically ranges from approximately 91% to 94% in patients r2:0.0034 with OSA and is even lower in obese patients with OSA [47–49]. p-value:0.7809

Therefore, a decrease of 2% in SpO2 is considered clinically rele- Equation:Y=0.0510*X -0.0503 vant in mild to severe OSA patients as it would lead to hypox- emia. This threshold was used in the respiratory safety study Figure 2. Relationship between treatment difference for AHI during TST and OSA severity at baseline on night 1 and night 5. Scatter plot and simple linear re- with suvorexant [35] in which no effect was observed after gression relationship between the treatment difference (daridorexant – placebo) single or repeated dosing. for AHI during TST and OSA severity (AHI during TST at baseline). The gray area Using the same threshold, no clinically meaningful effect of indicates the 95% CI of the regression line. r2: correlation coefficient. daridorexant on SpO2 during TST after repeated dosing was de- termined. Another relevant endpoint concerns %TST with SpO2 Except for AHI during REM sleep after repeated dosing, the < 90%, which has increasingly been used in sleep studies as an 90% CI of all endpoints did not contain the threshold for clinical indicator of oxygen desaturation [50]. In the present study, no relevance suggesting the absence of an effect of daridorexant treatment difference for time spent with SpO2 < 90% was de- also in specific sleep stages.

termined comparing daridorexant and placebo. This was also In terms of AHI- and SpO2-related endpoints, also no treat-

applicable to %TST with SpO2 < 85% and <80% (due to the low ment differences between daridorexant and placebo were number of patients presenting such events) confirming the ab- obtained after first dosing, in line with the results after repeated sence of marked overnight oxygen desaturation. dosing. Consistent results after first and repeated dosing were Irrespective of OSA diagnosis, more apnea and hypopnea anticipated based on minimal PK accumulation observed in pre- events are observed during REM sleep compared with non-REM vious clinical studies [37, 38]. sleep [51–53], which is explained by a reduction of the pharyn- The full spectrum of mild to moderate OSA intensity was geal muscle activity [54] and a reduced chemoreceptor sensi- covered in this study as AHI at baseline ranged from 5.5 to 29.9 tivity [55–57]. It is thus also of relevance to evaluate the effect of events/hour. There was no association between AHI at baseline a sleep medication during REM and non-REM sleep. Importantly, (i.e. OSA severity) and the treatment effect of daridorexant on

no treatment difference for AHI and SpO2 during non-REM and AHI after single and repeated dosing (Figure 2). Conceptually, REM sleep phases was observed. this would be suggestive of limited AHI changes also in patients 8 | SLEEPJ, 2021, Vol. 44, No. 6

5 the upper bound of the 90% CI for treatment difference ex- ceeded 5 events/hour. This was mainly due to intra- and

o) inter-variability [35], which led to a specific warning in the eb

c suvorexant labeling information for patients with comprom- a ] pl ised respiratory function [60]. In the same study, suvorexant h

t- improved TST, but without relevant improvement of other ob- nts/

ve jective sleep parameters. [e

orexan In patients with mild OSA, lemborexant did not impact

ST nighttime respiration [36]. Due to the lack of data in patients arid d gT 0 with moderate or severe OSA, a warning was included in the la- in e(

r beling information of lemborexant regarding its use in patients nc du e with compromised respiratory function [61]. 2 er f Downloaded from https://academic.oup.com/sleep/article/44/6/zsaa275/6030922 by guest on 24 September 2021

f Daridorexant at a dose of 50 mg was safe and well tol- pO di erated based on AE, vital signs, ECG, and clinical laboratory rS nt fo e data. No serious or severe AEs occurred, and none of the AEs m reported led to treatment or study discontinuation. The inci- at e dence of AEs was similar following daridorexant or placebo Tr administration. This is in line not only with the good safety -5 and tolerability profile of daridorexant obtained during clin- Night1 Night5 ical development but also with DORAs in general [62], al- Mean +/-90%CI Mean +/-90%CI though more clinical research and post-approval surveillance are needed with this still relatively new class of compounds in Figure 3. Individual treatment differences for SpO during TST on night 1 and 2 view of their potentially widespread use. night 5. Data are provided as treatment differences (daridorexant – placebo) and There was no indication of next-day residual effects elicited LSM ± 90% CI for treatment difference after single dosing (night 1) and repeated dosing (night 5). by daridorexant based on VAS data. This is in line with infor- mation regarding daytime sleepiness from AE data. Here, there were no AEs suggestive of morning or daytime sleepiness ex- with severe OSA (i.e. AHI > 30 events/hour). Yet, this would need cept for three participants with AEs of hangover that occurred to be confirmed in a dedicated nighttime respiratory safety both after daridorexant (n = 2) and placebo (n = 1). Accordingly, study in patients with severe OSA. there were also no next-day residual effects of daridorexant in In sleep studies, several aspects are evaluated to profile sleep the phase-2 study in patients with insomnia at the same dose of characteristics, among them sleep initiation and maintenance, 50 mg as used in the present study [39]. duration of sleep, and sleep efficiency. These are assessed ob- The 5-day exposure duration was considered sufficient to jectively using PSG by means of LPS, WASO, TST, and duration assess repeated-dose effects of daridorexant on nighttime re- of nighttime phases, as well as SEI [58]. No changes in the per- spiratory function, since steady-state exposure to daridorexant centage of N1 to N3 sleep stages during TST were observed after and its metabolites is reached after 3 days, given the negligible repeated dosing with daridorexant compared with placebo accumulation as previously determined in healthy participants suggesting that daridorexant does not modify the overall sleep [37, 38, 41]. architecture. The dose of 50 mg daridorexant selected for this study was Prolongation of TST, decrease in WASO, and increase in SEI the highest therapeutic dose tested in the phase-3 program. compared with placebo were observed after first-dose admin- Therefore, the results of the present study suggest that any istration and this was also applicable after repeated dosing, lower dose would also not lead to respiratory depressant effects despite the absence of changes in respiratory and spontaneous in patients with mild and moderate OSA as the AE incidence arousal indices. In addition, LPS was shortened although this was dose-dependent in studies with healthy participants [37, 38] was not statistically significant, which may be explained by the and similar between doses in patients [39, 40]. However, the lack population not having insomnia symptoms and an LPS within of a supratherapeutic dose in this study may be perceived as the accepted ranges for normal sleep initiation as per Diagnostic a study limitation precluding the definition of a safety margin and Statistical Manual of Mental Disorders-5 [59]. LPS values in with regard to respiratory depressant effects. this study with daridorexant were comparable to those observed Another study limitation concerns the administration of in respiratory studies conducted with ramelteon and suvorexant study treatments at home on days 2 to 4. To mitigate the risk [28, 35]. In addition, none of the participants presented sleep of nonadherence, patients had to document the time of drug onset insomnia as per medical history. By contrast, in phase-2 intake in a diary, and study staff contacted the patients each efficacy studies, patients with insomnia who were enrolled had day to ensure adherence. Pre-dose plasma concentrations of to present an LPS > 20 minutes at baseline PSG, and, here, 50 daridorexant obtained on day 5 were in line with concentrations mg daridorexant significantly reduced both LPS and WASO [39, at the same dosing regimen of 50 mg in previous studies arguing 40]. Taken together, these objective sleep parameter data results against nonadherence [44], and none of the individual plasma suggest that daridorexant can improve sleep characteristics also concentrations were sufficiently low to suggest nonadherence. in patients with OSA. In conclusion, daridorexant administered at the highest In the respiratory safety study conducted with suvorexant, phase-3 dose of 50 mg did not impair nighttime respiratory func- results did not suggest important respiratory effects during tion in patients with mild and moderate OSA and was well toler- sleep in patients with mild to moderate OSA, although ated. In addition, daridorexant favorably modulated sleep in this Boof et al. | 9

Table 3. Effect of daridorexant on the duration of sleep phases and objective sleep parameters

Night 1 Night 5

Daridorexant Treatment difference Daridorexant Treatment difference (50 mg) Placebo (daridorexant – placebo) (50 mg) Placebo (daridorexant – placebo)

Duration of sleep phases (min) TST 408 (387, 429) 369 (347, 390) 39.6 (16.9, 62.3) 409 (390, 427) 370 (351, 388) 38.8 (19.7, 57.9) [0.007] [0.002] Non-REM 358 (337, 379) 317 (297, 338) 40.6 (17.1, 64.1) 355 (340, 371) 324 (308, 340) 31.2 (13.6, 48.8) [0.007] [0.006] REM 50.1 (38.9, 61.2) 51.0 (39.9, 62.2) −0.98 (−10.3, 8.31) 53.9 (44.3, 63.5) 47.7 (37.9, 57.4) 6.21 (−1.86, 14.3) [0.86] [0.20]

Objective sleep parameters Downloaded from https://academic.oup.com/sleep/article/44/6/zsaa275/6030922 by guest on 24 September 2021 LPS (min) 21.6 (4.91, 38.3) 41.4 (24.8, 58.1) −19.8 (−41.1, 1.47) 15.7 (1.76, 29.6) 32.9 (19.0, 46.8) −17.3 (−35.5, 1.02) [0.12] [0.12] WASO (min) 56.2 (37.0, 75.4) 88.5 (69.3, 107) −32.3 (−53.3, −11.3) 55.5 (37.3, 73.8) 86.5 (68.3, 104) −31.0 (−47.3, −14.7) [0.01] [0.004] SEI (%) 85.0 (80.6, 89.3) 76.7 (72.3, 81.1) 8.25 (3.52, 13.0) 85.0 (81.2, 88.8) 77.0 (73.2, 80.8) 8.04 (4.05, 12.0) [0.007] [0.002]

Data are displayed as LSM (95% CI) for treatments and 90% CI (p-value) for treatment difference. P-value was determined for treatment difference (daridorexant – pla- cebo) with reference to the value 0. Study treatments were administered once daily in the evening.

Table 4. Incidence of AEs by treatment Vincent Lemoine (Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd) for statistical analysis of clinical data, as 50 mg Daridorexant Placebo (N = 26) (N = 27) well as Susanne Globig and Giancarlo Sabattini (Department of Preclinical Pharmacokinetics and Metabolism, Idorsia Any AE 4 (15.4) 6 (22.2) Pharmaceuticals Ltd) for the bioanalysis of daridorexant. The au- Cystitis 1 (3.8) 2 (7.4) thors would also like to thank the participants for volunteering Hangover not due to alcohol 2 (7.7) 1 (3.7) their time to participate in this research. Nasopharyngitis — 1 (3.7) Thrombocytopenia — 1 (3.7) ECG PR prolongation — 1 (3.7) Disturbance in attention 1 (3.8) — Hematuria 1 (3.8) — Author contributions M.-L.B., J.D., and M.U. designed the study. I.F., as principal inves- Data are displayed as the number (%) of patients with AEs in the descending tigator, and K.L., as sub-investigator, conducted the study and order of frequency. were responsible for data acquisition. M.-L.B. drafted the manu- script and J.D., K.L., I.F., and M.U. critically revised the manu- population despite the absence of coexisting insomnia symp- script. All authors gave the final approval of the manuscript to toms. Further studies are needed to evaluate if daridorexant is be published. also safe to be administered in patients with severe OSA inde- Conflict of interest statement. There are no conflicts of interest. pendent whether they are under CPAP treatment.

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