A phase 1 double‐blind, placebo‐controlled study of zuranolone (SAGE‐217) in a phase advance model of insomnia in healthy adults

1 INTRODUCTION

Approximately 30% of the adult United States (US) population experiences issues with the quality and quantity of their sleep (National Institutes of Health, 2005; National Sleep Foundation, 2002, 2005), and approximately 10% of the US adult population reports sleep problems severe enough to be considered insomnia disorder (American Psychiatric Association, 2013; LeBlanc et al., 2009; National Institutes of Health, 2005). In addition, approximately 60%–80% of patients with insomnia experience comorbid psychiatric conditions (Ford & Kamerow, 1989; Ohayon et al., 2000; Stewart et al., 2006; Weissman et al., 1996), and sleep disruptions can lead to significantly lower positive mood (Finan et al., 2015). In particular, people with self-reported sleep disruptions have been reported as 9.82 times more likely to have comorbid major depressive disorder (MDD) and 17.35 times more likely to experience clinically significant anxiety (Taylor et al., 2005). Insomnia can be chronic (i.e., lasting longer than three months) or short-term (i.e., lasting less than 3 months) and is defined in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition based on a variety of sleep-related symptoms, including difficulty in falling asleep, difficulty in maintaining sleep, and early waking, accompanied with clinically significant distress or functional impairment (American Psychiatric Association, 2013; National Institutes of Health, 2005). Insomnia symptoms—especially difficulty in initiating sleep—in adults and adolescents, are associated with reduced quality of life and increased mortality (Paiva et al., 2015; Parthasarathy et al., 2015; Scalo et al., 2014), and individuals who report difficulty returning to sleep after awakening (i.e., longer mean durations of awakenings [mDURAWs]) in the presence of other insomnia symptoms, are more likely to report daytime impairment and seek treatment for their sleep disorder (Ohayon, 2009; Ohayon et al., 2010).

Sleep disruptions and general insomnia are linked to greater brain metabolism and hyperactivity of neural circuits during normal sleep architecture (Nofzinger et al., 2004). Gamma-aminobutyric acid (GABA) is the primary mediator of inhibitory neurotransmission in the central nervous system and is intimately associated with the regulation of sleep and wake cycles (Wisden et al., 2017). Synaptic GABAA receptors (GABAARs) have rapid kinetics, low sensitivity to GABA, and prompt desensitization, enabling them to conduct fast inhibitory postsynaptic events that are typical for phasic inhibition (Brickley et al., 1999). Extrasynaptic GABAARs are activated by low concentrations of GABA neurotransmitter, which mediate persistent tonic inhibition (Stell & Mody, 2002). Tonic inhibition represents a large fraction of GABA signaling and can approach 80% of total GABA-mediated transmission in regions such as the thalamus (Belelli et al., 2005). Previous studies have reported a relationship between GABA activity in the hypothalamus and maintenance of wakefulness (Lin et al., 1989; Nitz & Siegel, 1996), and sleep-active GABAergic neurons in the brain inhibit wake-active neurons to promote sleep (Chung et al., 2017; Lin et al., 1989; Nitz & Siegel, 1996; Sherin et al., 1998; Uygun et al., 2016). The involvement of GABA signaling in sleep suggests that positive allosteric modulation of GABAAR presents a potential mechanism of action for insomnia pharmacotherapies (Wisden et al., 2017).

Zuranolone (SAGE-217; 3α-hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1ʹ-yl)-19-nor-5β-pregnan-20-one) is a rationally designed, orally bioavailable, investigational neuroactive steroid, and like other members of the neuroactive steroid family, such as allopregnanolone, it is a positive allosteric modulator (PAM) for both synaptic and extrasynaptic GABAAR, making it pharmacologically distinct from current insomnia pharmacotherapies, including benzodiazepines and “Z-drugs,” which target only synaptic GABAARs (Hosie et al., 2006; Martinez Botella et al., 2017). Neuroactive steroid sites on GABAARs are distinct from and do not overlap with the binding sites for the benzodiazepines and barbiturates (Laverty et al., 2017; Löscher & Rogawski, 2012). The pharmacokinetics of zuranolone are suitable for once daily dosing (Hoffmann et al., 2019), and zuranolone has previously been examined in Phase 2 (Gunduz-Bruce et al., 2019) and Phase 3 (Clayton, 2020) trials for MDD and a Phase 3 trial in postpartum depression (Deligiannidis et al., 2021). Zuranolone represents an opportunity to examine the role that positive allosteric modulation of both synaptic and extrasynaptic GABAAR plays in the regulation of sleep as well as implications for the treatment of insomnia and sleep disruptions.

Acute sleep disturbance can be studied using the 5-h phase advance model of transient insomnia in healthy participants. The overall size of the phase advance increases wakefulness and allows for the reduction of steady sleep pressure while the circadian rhythm for wakefulness is strong, and prior studies have demonstrated that this insomnia model can be modulated pharmacologically (Horoszok et al., 2014; Rosenberg et al., 2014). In the 5-h phase advance model, multiple sleep parameters, including wake after sleep onset (WASO), total sleep time (TST), and sleep efficiency (SE) are negatively affected, and these disruptions can be mitigated by sedative and hypnotic agents, such as nonbenzodiazepines (e.g., lorediplon) and Z-drugs (e.g., zolpidem) (Horoszok et al., 2014). Furthermore, physiological similarities between insomnia disorder and phase advance transient insomnia models have been reported (Bonnet & Arand, 2003).

This Phase 1, double-blind, randomized trial in healthy adults used a 5-h phase advance model to evaluate the effects of zuranolone compared with placebo on transient insomnia.

2 METHODS 2.1 Study design

This randomized, double-blind, single-dose, placebo-controlled study (Clinicaltrials.gov identifier: NCT03284931) was conducted at a certified sleep laboratory in the US. The procedures of this study were in compliance with the ethical principles from the Helsinki Declaration of 1975, as revised in 1983, and was consistent with the International Council on Harmonization of Technical Requirements for Pharmaceuticals for Human Use and Good Clinical Practice guidelines, as well as all applicable regulatory requirements. The study was approved by an institutional review board. Written informed consent was obtained at screening and was required for enrollment.

2.2 Study population

Eligible participants were healthy, ambulatory, men and women between the ages 18 and 64, with body weight ≥50 kg and a body mass index (BMI) between 18 and 32 kg/m2. Participants were required to have a Pittsburgh Sleep Quality Index score of ≤5 and an Epworth Sleepiness Scale score of ≤10, indicating normal sleep quality (SQ) and lack of excessive daytime sleepiness. All participants completed a sleep diary for a minimum of six consecutive days between screening and qualification polysomnography (PSG), confirming habitual bed and rise times within 1-h time frames and a routine time in the bed of 7–9 h. During the PSG qualification visit (5-h, phase advanced), participants were required to have a PSG-assessed WASO of more than 45 min, an apnea-hypopnea index of less than 10, and a periodic limb movement arousal index of less than 10.

Participants agreed to adhere with behavioral restrictions, including abstinence from using tobacco, alcohol, and recreational drugs; maintenance and documentation of normal sleep habits; and refraining from working night shifts, napping, or flying more than 1 time zone away from the study site (full details in Supporting Information Methods S1). Female participants were required to use an approved form of contraception (full list in Supporting Information Methods S2) during the study and for 30 days following the last dose of the study drug.

Exclusion criteria included: a clinically significant abnormal finding during the physical examination at the screening visit; a positive drug and/or alcohol test at screening or the PSG qualification visit; consumption of excessive amounts of caffeine (defined as >500 mg/day) within 30 days prior to the screening visit; use of strong inhibitors and/or inducers of cytochrome P450 3A4 within the prior 14 days or 5 half-lives (whichever is longer); consumption of grapefruit juice, grapefruit, Seville oranges, St. John's Wort, or products containing these within 30 days prior to the screening visit; night shift work and flying more than 1 time zone within 30 days prior to the screening visit. Full exclusion criteria are provided in the Supporting Information Methods S3.

2.3 Procedures

The study utilized a double-blind, placebo-controlled, six-sequence, three-way crossover design (Figure 1), with a 7-day washout period between treatments. Participants arrived at the clinic approximately 7 h prior to their habitual bedtime. Eligibility criteria were confirmed, and participants were randomized (1:1:1:1:1:1) to 1 of 6 possible study drug administration sequences.

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Study design. The study used a randomized, six-sequence, crossover design in 45 participants. QHS, quaque hora somni (i.e., nightly at bedtime)

A single dose of double-blind study drug (zuranolone 30 mg, zuranolone 45 mg, or matching placebo) was administered as three capsules to the participant, at the site, on Days 1, 8, and 15. Zuranolone blinded study drug or placebo was administered with food 30 (±15) min prior to lights out.

Lights out and PSG recording began 5 h (±30 min) before the participants’ habitual bedtime. Participants were required to remain in bed for 8 h, after which the lights were turned on, and they were awakened, if asleep. Following lights on, PSG recording continued for 5 (±1) min of quiet wakefulness, and participants completed a postsleep questionnaire 30 min after the end of the recording. Discharge from the clinic occurred at or after 6:00 a.m. when the safety assessments did not reveal evidence of impairment and at the investigator's discretion. Participants resumed normal sleep patterns and maintained a sleep diary during the 1-week washout periods between treatments. A follow-up visit was conducted 7 days (±1 day) after the final administration of study drug, and a follow-up telephone call (Visit 8) occurred 7 days (±1 day) after the follow-up visit.

2.4 Assessments 2.4.1 Safety and tolerability

The Safety Set included all participants (n = 45) administered study drug. Postwaking safety and tolerability assessments and next day effect assessments were performed, including reporting of treatment-emergent adverse events (TEAEs), vital signs, 12-lead electrocardiograms, and the Columbia Suicide Severity Rating Scale. Next day effect assessments included the Karolinska Sleepiness Scale (KSS), the Digit Symbol Substitution Test (DSST) data, Romberg's test, and heel-to-toe walking. Both the KSS and DSST were completed within 30 min (±15) before initiation and after completion of PSG.

2.4.2 Efficacy

The Efficacy Set was based on a modified intent-to-treat (ITT) population and included all participants in the Safety Set who had at least one postdose PSG datapoint. The primary endpoint was objective SE, defined as the percentage of time in bed spent asleep, determined by an 8-h overnight PSG recording. Secondary endpoints consisted of both objective (i.e., by PSG) and subjective (i.e., by postsleep questionnaire) measurements, including WASO (objective and subjective); TST (objective and subjective); latency to persistent sleep (LPS; objective) and sleep latency (SL; subjective); SQ (subjective); number of awakenings (NAW; objective) and mDURAWs (objective); time spent in sleep stages (i.e., N1, N2, N3, and R), and latency to stage R sleep.

2.5 Statistical methods

Assuming a two-sided t-test at an alpha level of 0.05, a sample size of 31 evaluable participants would provide 80% power to detect a difference of 8 percentage points between zuranolone and placebo for SE. The trial was planned to recruit 42 participants to obtain at least 31 evaluable participants assuming a nonevaluability rate of 20%. Forty-five participants were enrolled.

The primary and secondary efficacy endpoints were both analyzed using a mixed effects model for repeated measures. The model included treatment, treatment sequence, period, and screening SE as fixed effects and participant nested within the sequence as random effect. An unstructured covariance structure was used to model within-participant errors. The residuals from the mixed-effect model were then tested for normality using the Shapiro–Wilk W-test. If the normality assumption was met, the model-based point estimates (least-squares [LS] means) of zuranolone 30 mg versus placebo and zuranolone 45 mg versus placebo together with the 95% confidence intervals, and p values from the mixed-effect model for repeated measures were reported. If the normality assumption was not met, nonparametric tests were used. Friedman's test was used to test the overall treatment effect among the three treatment groups and treatment comparisons (zuranolone 30 mg vs. placebo and zuranolone 45 mg vs. placebo) were assessed using the Wilcoxon signed-rank test on the within-participant differences. No multiplicity adjustment for the efficacy analyses was performed. Nominal p values with confidence intervals are presented.

3 RESULTS 3.1 Participants and treatment

Forty-five participants were randomized to this trial. Demographic and baseline characteristics are provided in Table 1. Thirty-six participants (80%) completed all periods of the study. Nine participants discontinued at the following periods for the stated reasons: four participants during the double-blind period (scheduling conflicts [n = 3], positive cotinine drug test [n = 1]), five participants completed all treatment periods, but did not return for the follow-up visit (lost to follow-up).

TABLE 1. Participant demographics Baseline characteristics All participants (n = 45) Age in years, mean (SD) 37.1 (11.17) Female 18 (40%) Male 27 (60%) Race Asian 2 (4.4%) Black or African American 25 (55.6%) Native Hawaiian or other Pacific Islander 1 (2.2%) White 8 (17.8%) Other 8 (17.8%) Multiple 1 (2.2%) Ethnicity Hispanic or Latino 16 (35.6%) Mean body mass index 26.8 (3.08) Baseline measurements Mean (SD) Epworth Sleepiness Scale 2.9 (1.61) Pittsburgh Sleep Quality Index 1.2 (0.81) Wakefulness After Sleep Onset 145.83 (67.934) Apnea-Hypopnea Index 2.82 (2.480) Periodic Limb Movement Arousal Index 0.26 (0.480) Note: Data for participants in the study are listed as mean (SD) or n (%). 3.2 Objective assessments by PSG

Both zuranolone doses (30 or 45 mg) significantly improved objective SE (measured by PSG) with medians of 84.6% and 87.6%, respectively, compared to 72.9% for placebo (p < 0.001 for both doses). Secondary endpoints measured by PSG are summarized in Table 2, including WASO, TST, LPS, NAW, and mDURAW. In addition to the effects on SE, zuranolone (30 and 45 mg) reduced median WASO to 55.0 and 42.5 min, respectively, compared to 113.0 min for placebo (p < 0.001 for each dose). Furthermore, TST was higher with zuranolone treatment (a median of 406.3 min for the 30-mg group and 420.3 min for the 45-mg group, compared with a median of 350.0 min in placebo; both p < 0.001). Zuranolone reduced mDURAWs with medians of 4.3 min (p < 0.001; 30 mg) and 3.7 min (p = 0.001; 45 mg) compared with 7.4 min for placebo. No significant differences between zuranolone treatment at either dose and placebo were observed for LPS and NAW.

TABLE 2. Efficacy outcomes Measure Baseline (median) Placebo (n = 41) Zuranolone 30 mg (n = 44) Zuranolone 45 mg (n = 42) Median (min, max) Median (min, max) Diff. versus placebo p Value Median (min, max) Diff. versus placebo p Value median (Q1, Q3) median (Q1, Q3) SE 66.04 72.92 (7.7, 92.6) 84.64 (45.8, 97.4) 11.35 (1.98, 26.15) <0.001 87.55 (54.1, 98.0) 12.61 (3.65, 33.13) <0.001 WASO (min) 134.00 113.00 (16.0, 304.0) 55.00 (10.0, 250.5) −22.00 (−118.00, −6.00) <0.001 42.50 (5.0, 208.0) −55.50 (−105.00, −14.00) <0.001 TST (min) 317.00 350.00 (37.0, 444.5) 406.25 (220.0, 467.5) 54.50 (9.50, 125.50) <0.001 420.25 (259.5, 470.5) 60.50 (17.50, 159.00) <0.001 LPS (min) 28.50 12.50 (0.0, 305.0) 13.25 (0.0, 91.5) −1.50 (−14.50, 5.00) 0.208 14.25 (1.0, 71.5) −1.00 (−13.50, 8.50) 0.264 NAW 9.00 8.0 (1, 41) 8.0 (1, 21) −1.00 (−4.00, 4.00) 0.963 7.0 (0, 32) −2.00 (−5.00, 2.00) 0.352 mDURAW (min) 9.36 7.38 (1.5, 169.5) 4.23 (1.4, 92.5) −3.43 (−15.10, 0.88) <0.001 3.67 (0.0, 30.5) −1.50 (−13.41, 0.86) 0.001 Note: Treatment versus placebo comparisons of polysomnography (PSG) data was assessed using a Wilcoxon signed-rank test on the within-participant difference. SE was the primary efficacy endpoint. p values are not adjusted for multiplicity. Abbreviations: LPS, latency to persistent sleep; mDURAW, mean duration of awakening; NAW, number of awakenings; SE, sleep efficiency; TST, total sleep time; WASO, wakefulness after sleep onset.

The potential of zuranolone to affect sleep architecture was also examined via PSG (Table 3a). The LS mean time spent in Stage N2 and Stage N3 significantly increased with zuranolone treatment at both 30 mg (N2: 258.2 min, p < 0.001; N3: 68.4 min, p = 0.004) and 45 mg (N2: 266.8 min, p < 0.001; N3: 74.7 min, p < 0.001) doses compared with placebo treatment (N2: 192.3 min; N3: 56.1 min). No significant difference in the time spent in N1 or stage R sleep was observed at either zuranolone dose compared with placebo. Latency to stage R sleep was determined from the number of non-R stage sleep epochs from lights off to the first epoch of stage R sleep. A significant increase in latency to stage R sleep was observed in both zuranolone groups, with median values of 159.0 min (p = 0.025) and 220.5 min (p < 0.001) for the 30- and 45-mg doses, respectively, compared with 120.0 min for placebo.

TABLE 3a. Time spent in each sleep stage determined by polysomnography Measure Placebo (n = 41) Zuranolone 30 mg (n = 44) Zuranolone 45 mg (n = 42) LS mean (SE) LS mean (SE) Diff. vs. placebo LS mean (95% CI) p Value LS mean (SE) Diff. vs. placebo LS mean (95% CI) p Value Stage N1 (min) 20.67 (1.762) 20.11 (1.712) −0.56 (−3.76, 2.64) 0.727 19.58 (1.743) −1.09 (−4.29, 2.11) 0.499 Stage N2 (min) 192.30 (7.890) 258.16 (7.579) 65.86 (47.16, 84.57) <0.001 266.79 (7.776) 74.49 (55.71, 93.27) <0.001 Stage N3 (min) 56.12 (4.982) 68.38 (4.861) 12.26 (4.06, 20.47) 0.004 74.71 (4.937) 18.59 (10.40, 26.78) <0.001 Stage R (min) 50.59 (3.278) 50.15 (3.151) −0.45 (−8.01, 7.11) 0.906 43.54 (3.232) −7.05 (−14.63, 0.53) 0.068 Median (range) Median (range) Diff. vs. placebo p Value Median (range) Diff. vs. placebo p Value median (Q1, Q3) median (Q1, Q3) Latency to stage R (min) 120.0 (3, 429) 159.0 (4, 528) 55.00 (−30.00, 92.00) 0.025 220.5 (11, 508) 95.00 (17.00, 211.00) <0.001 Note: Stages N1, N2, N3, and stage R least-squares means and p- values were calculated from a mixed model for repeated measures. Latency to stage R sleep are presented as median (range) or median difference (Q1 − Q3 difference), with a statistical comparison to placebo using a Wilcoxon signed-rank test on the within-participant differences. p Values are not adjusted for multiplicity. Abbreviations: CI, confidence interval; LS mean, least-squares mean.

When sleep stage was assessed by percentage of time asleep, zuranolone administration at either dose was associated with significant increases in the percentage of time (Table 3b) spent in stage N2 (LS means: placebo = 60.0%, zuranolone 30 mg = 65.2%, and zuranolone 45 mg = 66.0%; p < 0.001 for either dose vs. placebo). Non-significant increases were observed in stage N3 (medians: placebo 17.0%, zuranolone 30 mg = 17.9%, and zuranolone 45 mg = 18.5%). Corresponding decreases were observed in the time spent in stages N1 (medians: placebo 5.7%, zuranolone 30 mg = 3.8%, and zuranolone 45 mg = 4.7%; p < 0.05 for either dose vs. placebo) and R (LS means: placebo = 16.2%, zuranolone 30 mg 12.6%, and zuranolone 45 mg = 10.7%; p < 0.001 for either dose vs. placebo).

TABLE 3b. Percentage of time spent in each sleep stage as determined by polysomnography Placebo (n = 41) Zuranolone 30 mg (n = 44) Zuranolone 45 mg (n = 42) Measure Median (range) Median (range) Diff. versus placebo p Value Median (range) Diff. versus placebo p Value median (Q1, Q3) median (Q1, Q3) Stage N1, % 5.674 (0.945, 15.733) 3.784 (0.219, 14.545) −1.37 (−2.43, 0.17) 0.014 4.681 (0.789, 11.364) −1.28 (−2.84, 0.03) 0.001 Stage N3, % 16.968 (0.000, 39.365) 17.915 (0.000, 34.308) −0.59 (−2.99, 1.87) 0.475 18.497 (0.173, 35.547) 1.00 (−2.18, 5.18) 0.309 LS mean (SE) LS mean (SE) Diff. vs. placebo p Value LS mean (SE) Diff. vs. placebo p Value LS mean (95% CI) LS mean (95% CI) Stage N2, % 60.00 (1.169) 65.17 (1.128) 5.17 (2.73, 7.61) <0.001 66.00 (1.154) 6.01 (3.57, 8.45) <0.001 Stage R, % 16.15 (0.782) 12.61 (0.753) −3.54 (−5.28, −1.80) <0.001 10.70 (0.772) −5.45 (−7.20, −3.71) <0.001 Note: Stages N1 and N3 are presented as median (range) or median difference (Q1 − Q3 difference), with a statistical comparison to placebo using a Wilcoxon signed-rank test on the within-participant differences. Stage N2 and stage R least-squares (LS) means and p values were calculated from a mixed model for repeated measures. p Values are not adjusted for multiplicity. Abbreviation: LS Mean, least-squares mean. 3.3 Subjective assessments

Subjective WASO (sWASO), TST (sTST), SL (sSL), and SQ (sSQ) were also measured using a postsleep questionnaire. All measures improved significantly, supporting the objective PSG-generated data (Table 4). Both zuranolone 30 mg (11.7 min median difference, p = 0.026) and 45 mg (15.0 min median difference, p = 0.001) groups showed significant improvement in sTST versus placebo. Each zuranolone dose group also had a −10.0 min (p < 0.001) median difference in sWASO and a 1 point (p < 0.001) median difference in sSQ score compared with placebo. A significant decrease in sSL was also observed for the 45-mg group, with a 5 min median difference from placebo (p < 0.001).

TABLE 4. Subjective efficacy measures Placebo (n = 41) Zuranolone 30 mg (n = 44) Zuranolone 45 mg (n = 42) Measure Median (range) Median (range) Diff. vs. placebo p Value Median (range) Diff. vs. placebo p Value median (Q1, Q3) median (Q1, Q3) sWASO (min) 20.0 (0, 300) 10.0 (0, 120) −10.0 (−40.0, 0.0) <0.001 5.0 (0, 300) −10.0 (−40.0, −5.0) <0.001 sTST (min) 424.8 (60, 540) 450.0 (40, 555) 11.7 (−4.8, 65.1) 0.026 465.0 (0, 510) 15.0 (0.0, 60.0) 0.001 sSL (min) 15.0 (4, 400) 15.0 (2, 240) 0.0 (−5.0, 0.0) 0.288 10.0 (1, 60)

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