Efficacy and safety of a selective partial agonist for nociception/orphanin‐FQ peptide (NOP) receptors in patients with insomnia disorder

Abstract

Aims

Insomnia is a common sleep disorder, affecting up to 20% of the world population and adversely impacting productivity, health, and overall well‐being. Although pharmacologic options exist to treat insomnia, the health‐related quality of life for patients who are prescribed hypnotics is no higher than for those who are not, revealing a significant treatment gap.

Sunobinop, an oral, selective, potent, partial agonist of the nociceptin receptor (NOP), was evaluated for efficacy and safety in the treatment of Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM‐5) insomnia disorder.

Methods

In this randomized, double‐blind, repeat‐dose, crossover, Phase 1 study, 30 patients were assigned to treatment with sunobinop 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg and placebo; changes in sleep parameters, measured by polysomnography (PSG), in addition to subjective sleep measures and safety‐related measures were assessed. Twenty‐nine patients completed the study.

Results

Sunobinop demonstrated a dose‐dependent and significant increase in sleep efficiency compared with placebo. Sleep efficiency was statistically significantly increased by 12.1%, 14.7%, 17.6% and 19.0% over baseline at 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg, respectively (P ≤ 0.001) compared to placebo. Sunobinop improved sleep maintenance, measured by wakefulness after sleep onset, at all doses compared with placebo. Sunobinop resulted in a significant dose‐dependent change in time spent in N1 and N2 sleep with no effect on rapid eye movement (REM) latency, differentiating sunobinop from other hypnotics. Results from PSG measures correlated well with those from subjective assessments. Adverse events (AEs) that occurred in this study were rated by investigators as largely mild.

Conclusions

In this Phase 1 study of 30 patients, sunobinop was well tolerated by patients, with no study discontinuation due to AEs. Doses were identified that had a beneficial effect on sleep measures without eliciting next‐day residual effects (<3 mg). These data suggest that sunobinop has the potential to be developed as a therapeutic option for the treatment of sleep disturbances, including DSM‐5 insomnia; however, larger confirmatory studies are warranted.

What is already known about this subject

• Insomnia is a common sleep disorder that affects millions.

• Existing treatments have limitations, thus a treatment gap exists.

• Nociceptin/orphanin‐FQ (nociceptin), the endogenous ligand for the nociceptin receptor (NOP), is an inhibitory neurotransmitter. Sunobinop is a selective, partial NOP agonist that increases non‐REM (rapid eye movement) sleep and decreases wakefulness in animal models and at a single high dose in humans.

What this study adds

• This Phase 1 study evaluated the safety and efficacy of a range of doses of sunobinop in patients with DSM‐5 insomnia disorder.

• The results suggest that sunobinop improves sleep efficiency, maintenance and architecture at a broad range of doses, while being safe and well tolerated in patients exposed to the drug in this Phase 1 safety and efficacy study.

• Sunobinop therefore has the potential to be further developed as a novel and valuable treatment option for insomnia and related disorders.

1. INTRODUCTION

Insomnia is a common sleep disorder that affects millions of individuals worldwide and can have profound effects on both individual functioning and societal well‐being. Estimates of the true number of patients with insomnia vary widely across studies, depending on the parameters set for disturbed sleep, ranging from 5% to 50% of all adults. ¹ However, recent meta‐analyses of observational studies estimated that clinically defined insomnia affects >20% of adults worldwide, with females having a significantly higher prevalence of insomnia than males. ² Of further concern, although nearly half of patients who experience insomnia are prescribed hypnotics for relief, their health‐related quality of life is no different than those patients who do not receive pharmacologic treatment. ³

Many pharmacologic agents are available to treat insomnia, although each has its own risks and benefits. The most common target for prescription treatments is the inhibitory neurotransmitter γ‐aminobutyric acid (GABA ) and its membrane‐bound receptors (usually GABA _A subunits). ⁴ Most hypnotics augment GABA function in the central nervous system (CNS), reducing neuronal activity and promoting sleep. ⁵ Benzodiazepines, such as diazepam and alprazolam, are positive allosteric modulators of the GABA_A receptor subunits that enhance the function of GABA, increasing sleep time, reducing latency to sleep onset and wakefulness after sleep onset, and increasing sleep efficiency. ⁶ , ⁷ Zolpidem and related molecules, sometimes called Z‐drugs, also induce sleep via a positive modulatory effect on the GABA pathway. ⁶ , ⁷ , ⁸ New prescription hypnotics, such as suvorexant and lemborexant, block orexin type 1 and type 2 receptors, inducing somnolence through inhibition of wakefulness. ⁴ Ramelteon is a melatonin type 1A and 1B receptor agonist that mimics the effects of endogenous melatonin to initiate sleep. ⁶ Many antidepressants possess antihistaminic (e.g., doxepin) or serotonergic antagonist activity (e.g., trazodone) and have been used due to their sedative effects. ⁹ Over‐the‐counter antihistamines (e.g., diphenhydramine) are commonly used to induce sleep. ⁸ Unfortunately, the therapeutic agents commonly used to treat insomnia have significant limitations, including insufficient efficacy, ¹⁰ no improvement of health‐related quality of life, ³ disruption of rapid eye movement (REM) sleep and other sleep‐architecture disturbances, ¹¹ potential for abuse and/or dependence, ⁷ withdrawal/discontinuation syndrome, ¹² cardiac arrhythmias, ¹³ respiratory depression, ⁶ , ⁷ anticholinergic side effects, ¹⁰ next‐day cognitive effects or impairment, ⁴ , ¹¹ insomnia rebound, ¹² and limitations for use in patients with severe hepatic impairment. ¹²

Nociceptin/orphanin‐FQ (nociceptin ) is the endogenous ligand for the nociceptin receptor (NOP ) and most commonly functions as an inhibitory neurotransmitter, reducing neuronal activity and inhibiting the release of other neurotransmitters. However, the role of nociceptin is complex and not fully elucidated. ¹⁴ NOP is widely expressed across the CNS and peripheral nervous system, showing expression in multiple brain regions involved in critical neurologic processes, such as pain perception, learning, memory and neuroendocrine control. ¹⁵ , ¹⁶ NOP shares structural similarities with μ , κ, and δ opioid receptors. However, nociceptin has no measurable affinity for μ or δ receptors and displays a 1000‐fold lower affinity for κ receptors than for NOP. ¹⁴ Furthermore, the endogenous opioids do not bind to NOP (Video S1). ¹⁷ , ¹⁸ Early studies of NOP identified it as a possible therapeutic target for several disorders, with agonists of the receptor explored for use against chronic cough, pain, anxiety, ¹⁴ hypertension ¹⁵ and addiction. ¹⁴ , ¹⁵ NOP modulators are among the National Institutes of Drug Abuse's top 10 list of most needed pharmacologic mechanisms for the development of therapeutics in response to the opioid crisis. ¹⁹ Chronic urologic conditions such as interstitial cystitis, bladder pain syndrome and overactive bladder are also potential treatment targets for compounds that interact with the NOP system. ¹⁷ , ²⁰

Sunobinop is an investigational, oral, potent, selective, partial agonist of NOP that is mainly excreted unchanged in urine. ²¹ , ²² Sunobinop has a high affinity for NOP receptors and a low affinity for classic μ‐, κ‐, and δ‐ opioid receptors. It has no agonist effect at μ‐ or κ‐ and only weak agonist activity at δ‐ receptors. ²² Given NOP's role in inhibiting neuronal activity, agonists such as sunobinop are potential candidates for treating sleep disorders. In animal models, sunobinop effectively increased non‐REM sleep and decreased wakefulness. ²² Additionally, supratherapeutic doses of sunobinop did not affect respiration, ventilation, or general physical condition in animal studies. ²² In Phase 1 single‐ and multiple‐ascending dose studies, oral sunobinop displayed dose proportional exposure up to 2 mg (less than proportional at 3 mg and above), maximal plasma concentrations (T _max) at a median 1.5 h, mean t _1/2 of 2.4–2.7 h (single dose), no accumulation following multiple doses and with the majority of drug eliminated unchanged in the urine at 8 h post dose. ²¹ In the Phase 1 safety and pharmacokinetic study, the tolerability of sunobinop was established among approximately 70 healthy subjects. Across the range of doses up to 30 mg, most AEs were mild with only one severe AE of somnolence. The most prominent AE was dose‐dependent somnolence. ²¹ Next‐day residual effects were studied in healthy subjects following administration of sunobinop doses of 0.2, 0.6, 2 and 6 mg at bedtime. ²³ A dose‐dependent effect on pharmacodynamic (PD) measures, including the digit symbol substitution test (DSST), Karolinska sleepiness scale (KSS) and body sway, was noted with no significant difference from placebo at doses of <2 mg and with significant next‐day residual effects noted at the highest, 6 mg dose. ²³ These earlier studies support the continued evaluation of a range of sunobinop doses in the DSM‐5 insomnia population. To date, completed studies in healthy subjects and ongoing and completed studies in patients with insomnia and other disorders have included dosing of approximately 400 participants with sunobinop.

This Phase 1 study aimed to assess the efficacy and safety of sunobinop as a novel therapeutic in a small number of patients with DSM‐5 insomnia disorder. The primary endpoint in the study was the effect of sunobinop on sleep efficiency (SE) in patients with insomnia as measured by polysomnography (PSG).

2. METHODS

2.1. Study design

The efficacy and safety of sunobinop were assessed through a randomized, double‐blind, 5‐period, repeat‐dose, crossover study (Figure 1).

FIGURE 1.

Study schema. This study had three phases: screening, treatment and follow‐up. A total of 106 patients were screened with 30 patients (enrolment target) eligible for randomization. Patients were randomized to one of five unique treatment sequences such that each patient was exposed to each sunobinop dose (0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg) and placebo. At each treatment period (no sooner than 5 days apart) patients were studied overnight via polysomnography for two consecutive nights. Sleep diary and next‐day residual assessments were performed in the morning after each overnight. EOS, end of study; PSG, polysomnography; S, study drug; TC, telephone call.

All patients provided written informed consent. Before patient screening, the protocol and informed consent forms were reviewed and approved by BioMed IRB (July 2017) and Chesapeake IRB (MOD00210395; May 2017). This study was conducted using standard operating procedures to ensure adherence to Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. The work was performed at Clinilabs, Inc. and Pacific Research Network.

2.2. Screening and baseline parameters

Screening occurred within 28 days before randomization. Screening procedures included a collection of the following: written consent; physical examination, including body weight, height, and BMI; demographic data; testing for alcohol, nicotine, opiates, amphetamines, cannabinoids, benzodiazepines, cocaine, barbiturates, phencyclidine and methadone; 12‐lead electrocardiogram (ECG); and vital signs, including blood pressure, pulse rate, respiratory rate, body temperature (oral) and oxygen saturation (SpO₂). Medical, sleep, psychiatric and medication histories were collected from all participants. Clinical laboratory testing was conducted on all participants, including urinalysis, serology for hepatitis, haematology and serum chemistries. Female patients received serum pregnancy testing and follicle‐stimulating hormone tests for those self‐reported as postmenopausal. Participants also completed the Columbia‐Suicide Severity Rating Scale (C‐SSRS) to monitor for self‐harming behaviours and/or thoughts. Patients kept sleep diaries for ≥7 consecutive days before the first PSG screening to determine median habitual bedtime. On nights 6 and 7 prior to randomization, PSG screenings were performed. The screening PSG results were also used as a baseline measurement for patients and compared to results following sunobinop and placebo treatments.

2.3. Study population

The enrolment goal for this Phase 1 study was 30 patients to allow for the completion of a minimum of 24 patients. Patients were males and non‐pregnant and post‐menopausal females with insomnia who were otherwise healthy; they were between the ages of 18 and 64 years, with body weight and BMI ranging from 50 kg to 100 kg and 18 kg/m² to 32 kg/m², respectively. Qualifying patients presented with an insomnia disorder as defined by DSM‐5 criteria. Patients had to have reported habitual bedtime between 10:00 PM and 12:00 AM with typical total nightly sleep <6.5 h. On PSG screening, eligible patients had mean latency to persistent sleep (LPS) and wakefulness after sleep onset (WASO) > 20 min with neither night <15 min, nor total sleep time (TST) < 420 min. Exclusion criteria included night or rotating shift workers, subjects with disturbed sleep attributable to other disorders (e.g., sleep apnoea, restless leg syndrome), and those with an apnoea/hypopnea index >10 or a period limb movement index >10 on the first screening PSG. Subjects with a history of premenstrual dysphoric disorder, frequent nausea or emesis, seizures, or drug or alcohol abuse were also excluded. Use of any medication, vitamins or herbal/mineral supplements during the 14 days preceding the initial dose and throughout the study was not permitted.

2.4. Endpoints

The primary efficacy endpoint for this Phase 1 study was a change from baseline in SE (defined as total sleep time as a percentage of time in bed) for each sunobinop dose level compared with placebo on night 2 as measured by PSG. Secondary efficacy endpoints included the change from baseline in LPS, TST, number of awakenings (NAW) and WASO for each sunobinop dose level compared with placebo and total stage N1, N2, N3 and REM sleep minutes. A post‐sleep questionnaire was administered to measure key subjective sleep secondary endpoints (subjective sleep latency (sSL), subjective total sleep time (sTST), sleep quality, depth of sleep and subjective wake after sleep onset (sWASO). Secondary pharmacodynamic (PD) endpoints included next‐day residual effects, as measured by the KSS, Profile of Mood States questionnaire (POMS), DSST, psychomotor vigilance test (PVT), and body sway postural stability tests.

2.5. Safety assessment in study participants

Safety and tolerability were assessed in all patients in the randomized safety population (defined as patients who were randomized, received at least one dose of the study drug, and had at least one post dose safety assessment) using investigator‐recorded AEs, clinical laboratory test results, vital signs, SpO₂, physical examinations, 12‐lead ECGs, neurological examinations (i.e., Romberg test for balance, heel‐to‐toe test, gait evaluation) and C‐SSRS. A follow‐up call occurred 7–10 days after the last administration of study drug (which is greater than 50 times the half‐life of sunobinop) to assess for AEs and concomitant medications taken since last study visit.

2.6. Treatment period

All patients were randomized in a balanced manner to one of five unique treatment sequences (as shown in Table 1), such that each patient was exposed to each drug dose level of sunobinop (0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg) and placebo. For each of the five separate treatment periods, patients arrived at the clinical study sites in the afternoon or evening for check‐in. During each treatment period, patients received one of four sunobinop doses or placebo on two consecutive evenings, with a minimum washout period of 5 days separating each successive treatment period.

TABLE 1.

Summary of patient demographics and baseline characteristics in the randomized safety population.

Variable	Treatment sequence					Overall (N = 30)
	ABCDE (n = 6)	BCDEA (n = 6)	CDEAB (n = 6)	DEABC (n = 6)	EABCD (n = 6)
Age (years)
Mean (SD)	55.2 (3.4)	54.0 (3.0)	45.3 (14.9)	41.0 (16.5)	42.8 (13.5)	47.7 (12.5)
Median	55.5	53.5	44.0	41	41.5	52.5
Minimum, maximum	50, 60	50, 58	29, 64	22, 60	22, 60	22, 64
Age group, n (%)
≤ 60 years	6 (100)	6 (100)	5 (83)	6 (100)	6 (100)	29 (97)
18–39 years	0	0	3 (50)	3 (50)	3 (50)	9 (30)
40–60 years	6 (100)	6 (100)	2 (33)	3 (50)	3 (50)	20 (67)
61–64 years	0	0	1 (17)	0	0	1 (3)
Sex, n (%)
Male	2 (33)	2 (33)	4 (67)	4 (67)	3 (50)	15 (50)
Female	4 (67)	4 (67)	2 (33)	2 (33)	3 (50)	15 (50)
Race, n (%)
White	4 (67)	3 (50)	3 (50)	0	2 (33)	12 (40)
Black or African American	2 (33)	2 (33)	3 (50)	6 (100)	4 (67)	17 (57)
Other	0	1 (17)	0	0	0	1 (3)
Ethnicity, n (%)
Hispanic or Latino	2 (33)	0	2 (33)	0	1 (17)	5 (17)
Not Hispanic or Latino	4 (67)	6 (100)	4 (67)	6 (100)	5 (83)	25 (83)
Screening weight (kg)
Mean (SD)	70.2 (16.4)	70.4 (12.8)	81.5 (9.8)	83.9 (9.5)	76.3 (14.1)	76.5 (13.2)
Median	69.2	63.6	81.9	83.3	71.1	74.3
Minimum, Maximum	52.1, 99.3	61.0, 93.6	66.7, 94.0	70.8, 99.7	59.8, 99.5	52.1, 99.7
Body mass index (kg/m 2 )
Mean (SD)	25.0 (3.0)	25.3 (3.5)	26.8 (3.8)	28.4 (3.4)	26.3 (2.5)	26.3 (3.3)
Median	25.0	24.4	27.8	29.4	26.5	26.7
Minimum, maximum	20.8, 29.4	21.1, 30.9	20.8, 31.9	21.9, 31.4	21.7, 28.9	20.8, 31.9

Note: Demographics by treatment sequence are shown with treatment A = sunobinop 0.5 mg; B = sunobinop 1 mg; C = sunobinop 3 mg; D = sunobinop 6 mg; E = placebo.

Abbreviation: SD, standard deviation.

Doses were administered each evening 2 h after eating and 30 min prior to the subject's median habitual bedtime, with lights‐out approximately 30 min later. Following lights‐out, participants were monitored via PSG for 8 h until lights‐on, at which point they completed a post‐sleep questionnaire. Tests for next‐day residual effects of treatment were administered in the morning following each PSG. Daytime napping between the two consecutive PSG tests was prohibited.

Laboratory tests, including serum chemistry, haematology and urinalysis, were conducted prior to treatment period 1 only. Urine pregnancy tests for female subjects, vital signs, SpO₂, ECG, and alcohol, nicotine, and urine drug screens were performed immediately before each of the five treatment periods. Participants also completed the C‐SSRS since the last treatment period and reported concomitant medications and AEs.

2.7. Statistical methods

The enrolled population consisted of all patients who provided informed consent. The full analysis population (FAP) for efficacy and PD analyses consisted of patients who received at least one dose of study drug and had at least one post‐dose efficacy or PD measurement. With a crossover study design, a sample size of 24 subjects had 90% power to detect a difference in SE means of approximately 7%, assuming a standard deviation (SD) of differences of 10, using a two‐group t‐test (crossover analysis of variance) with a 0.05 two‐sided significance level.

Following treatment, SE was assessed from PSGs collected and scored by a central reader, with sleep stages scored following the American Academy of Sleep Medicine standard criteria. Mean SE data was obtained from PSG on nights 1 and 2 at baseline and in each treatment period. Baseline, post‐baseline and change from baseline in mean sleep efficiency (in addition to night 2 only data for SE) were summarized by treatment. Statistical analysis for pairwise treatment comparisons was performed using a mixed model approach that included period, sequence and treatment as fixed effects, subject within the sequence as a random effect, and baseline SE as a covariate. A two‐sided significance level of 0.05 was used to compare baseline and post‐treatment, and differences between compared treatments and corresponding 95% confidence interval (CI) were calculated.

For secondary efficacy variables, the average for nights 1 and 2 per treatment period or baseline was used for summary and analysis. Baseline, post‐baseline and change from baseline for secondary efficacy variables were summarized by treatment using descriptive statistics using the same mixed model approach used in the primary efficacy variable analysis.

Sleep quality was recorded in the post‐sleep questionnaire on a scale of 1 to 10, with 1 being “poor” and 10 being “excellent,” and was analysed as a continuous variable. In addition, sleep quality was summarized categorically for each scale by treatment and overall.

Tests for next‐day residual effects were based on results from the FAP. The baseline was defined as the average of the assessments 5–6 days prior to the first treatment period. Descriptive statistics (mean, SD, coefficient of variation, median and minimum and maximum values) were tabulated at baseline and post‐baseline time points for each treatment. The statistical analysis was performed using a mixed model for repeated measures approach, with sequence, treatment, period, time point and the interaction of treatment by time as fixed effects, baseline as a covariate, and time as a repeated measure. The model was applied on the average of the two visit days in each treatment period for each scheduled time point. The pairwise treatment comparison difference of the least squares (LS) means (having controlled for baseline as the covariate) and corresponding 95% CI were analysed for each time point.

All safety data (AEs, clinical laboratory results, vital signs, SpO2, 12‐lead ECGs, C‐SSRS and neurologic test results) were recorded for enrolled or randomized safety population. Summary statistics (n, mean, SD and minimum and maximum values) for baseline, each scheduled time point, end of study and changes from baseline were calculated. All AEs were categorized into preferred terms (PTs) and associated system organ class (SOC) using the Medical Dictionary for Regulatory Activities (MedDRA) version 20.0. ²⁴ All treatment‐emergent AEs (TEAEs) were summarized by presenting the incidence of AEs for each treatment by the MedDRA SOC and PTs for the randomized safety population.

Statistical programming and analyses were performed using SAS® software version 9.3 (SAS Institute, Cary, NC).

2.8. Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY, and are permanently archived in the Concise Guide to PHARMACOLOGY 2023/24. ²⁵ , ²⁶

3. RESULTS

3.1. Population

A total of 106 patients were screened to reach the predefined target enrolment of 30 patients. Of the 76 patients that did not progress beyond screening, 56 did not meet inclusion/exclusion criteria, the largest percentage of whom failed PSG sleep criteria for insomnia. The 30 enrolled patients were randomly assigned to a five‐period treatment sequence and included in the randomized safety population. In total, 29 patients completed the study with one discontinuation due to failure to meet inclusion/exclusion criteria (positive test for prohibited substances) prior to the last treatment period. Patient demographics are summarized in Table 1.

3.2. Efficacy

3.2.1. Objective endpoints from PSG

Sleep efficiency (SE)

SE increased from baseline (71.3% SD 8.8%) following administration of all treatments. Sunobinop treatment was associated with an increase in mean SE at all doses tested compared to placebo and the increase was greater with higher dose (findings from night 2 only mirrored those that were the mean of nights 1 and 2, as such all subsequent data is presented as the mean of nights 1 and 2 in order to consider all collected data). The increase in the LS mean from baseline with placebo was 7.9% (standard error of the mean [SEM] 1.02%) and with sunobinop 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg was 12.1% (SEM 1.02%), 14.7% (SEM 1.02%), 17.6% (SEM 1.03%) and 19.0% (SEM 1.02%), respectively. The increase over placebo was 4.1% (95% CI 1.7, 6.6%; P = 0.001), 6.7% (95% CI 4.3, 9.2%; P < 0.001), 9.7% (95% CI 7.2, 12.1%; P < 0.001) and 11.0% (95% CI 8.6, 13.5%; P < 0.001) at 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg, respectively, and was statistically significantly different from placebo at each dose level. Each successive dose level was statistically significantly different (P < 0.05) as compared to the next lower dose except for 6.0 mg which, while producing a numerically larger effect than 3 mg, did not reach the level of statistical significance as compared to 3.0 mg. (Figure 2 shows mean SE in minutes ± SD.)

FIGURE 2.

Mean (night 1 and night 2) with standard deviations of objective sleep efficiency measured by polysomnography as percentage (time asleep/time in bed) at baseline and for each treatment. Horizontal lines represent analysis of statistical significance of each treatment compared to placebo (upper) and between each successive dose level (lower). NS, non‐significant (P < 0.05).

Latency to persistent sleep (LPS)

LPS decreased from baseline (57.6 min; SD 32.8 min) following sunobinop administration of all treatments. Sunobinop treatment was associated with a decrease in LPS at 1 mg, 3 mg and 6 mg compared to placebo; the largest decrease was observed at the highest dose tested. The decrease in the LS mean from baseline with placebo was −28.5 min (SEM 2.78 min) and with sunobinop 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg was −25.9 min (SEM 2.78 min), −29.9 min (SEM 2.78 min), 29.0 min (SEM 2.82 min) and 31.7 min (SEM 2.78 min), respectively. The change over placebo was 2.6 min (95% CI −4, 9.2, min; P = 0.436), −1.4 min (95% CI −8, 5.2 min; P = 0.674), −0.5 min (95% CI −7.2, 6.1 min; P = 0.872) and −3.2 min (95% CI −9.8, 3.3 min; P = 0.333) at 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg, respectively, and was not statistically significantly different from placebo at any dose level. (Figure 3A shows mean LPS in minutes ± SD.)

FIGURE 3.

Mean (night 1 and night 2) with standard deviations of objective latency to persistent sleep in minutes at baseline and for each treatment by polysomnography (A) and subjective sleep latency in minutes by patient diary (B). Horizontal lines represent analysis of statistical significance of each treatment compared to placebo (upper) and between each successive dose level (lower). min, minutes; NS, non‐significant (P < 0.05).

Total sleep time (TST)

TST increased from baseline (342.1 min; SD 42.4 min) following sunobinop administration of all treatments. Sunobinop treatment was associated with an increase in TST greater than that achieved by placebo at all doses; the increase was greater with higher dose. The increase in the LS mean from baseline with placebo was 38.1 min (SEM 4.88 min) and with sunobinop 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg was 57.9 min (SEM 4.88 min), 70.3 min (SEM 4.88 min), 84.5 min (SEM 4.96 min) and 91.0 min (SEM 4.88 min), respectively (data not shown). The increase over placebo was 19.8 min (95% CI 8.0, 31.5 min; P = 0.001), 32.3 min (95% CI 20.5, 44.0 min; P = < 0.001), 46.4 min (95% CI 34.6, 58.3 min; P < 0.001) and 52.9 min (95% CI 41.2, 64.6 min; P < 0.001) at 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg, respectively, and was statistically significantly different from placebo at each dose level. Each successive dose level was statistically significantly different (P < 0.05) as compared to the next lower dose except for 6 mg which, while producing a numerically larger effect than 3 mg, did not reach the level of statistical significance as compared to 3 mg.

Wake after sleep onset (WASO)

WASO decreased from baseline (89.4 min; SD 37.9 min) following sunobinop administration of all treatments. Sunobinop treatment was associated with a decrease in wake after sleep onset greater than that achieved by placebo at all doses; the decrease was greater with higher dose. The decrease in the LS mean from baseline with placebo was −12.7 min (SEM 4.54 min) and with sunobinop 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg was −37.1 min (SEM 4.54 min), −44.5 min (SEM 4.54 min), −59.1 min (SEM 4.60 min) and −63.5 min (SE 4.54 min), respectively. The decrease over placebo was −24.3 min (95% CI −34.5, −14.2 min; P < 0.001), −31.8 min (95% CI −41.9, −21.6 min; P < 0.001), −46.4 min (95% CI −56.6, −36.2 min; P < 0.001) and −50.8 min (95% CI −60.9, −40.7 min; P < 0.001) at 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg, respectively, and was statistically significantly different from placebo at each dose level. A dose of 3 mg was statistically significantly different from 1 mg (P < 0.05) while 1 mg did not differ significantly from 0.5 mg nor did 6 mg differ significantly from 3 mg. (Figure 4 shows mean WASO in minutes ± SD.) A post hoc analysis found a strong treatment effect on WASO in the second half of the night compared with placebo. The decrease over placebo was −15.6 min (95% CI −24.6, −6.7 min; P < 0.001), −27.7 min (95% CI −36.7, −18.8 min; P < 0.001), −35.3 min (95% CI −44.3, −26.3 min; P < 0.001) and −39.6 min (95% CI −48.6, −30.7 min; P < 0.001) at 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg, respectively, and was statistically significantly different from placebo at each dose level. (Figure 5A and B show mean WASO during the first and second half of the night ± SD.)

FIGURE 4.

Mean (night 1 and night 2) with standard deviations of objective wake after sleep onset in minutes at baseline and for each treatment by polysomnography (A) and subjective wake after sleep onset in minutes by patient diary (B). Horizontal lines represent analysis of statistical significance of each treatment compared to placebo (upper) and between each successive dose level (lower). min, minutes; NS, non‐significant (P < 0.05).

FIGURE 5.

Mean (night 1 and night 2) with standard deviations of objective wake after sleep onset in minutes by polysomnography at baseline and for each treatment in the 1st half (A) and 2nd half (B) on the night. Horizontal lines represent analysis of statistical significance of each treatment compared to placebo (upper) and between each successive dose level (lower). min, minutes; NS, non‐significant (P < 0.05).

Number of awakenings (NAW)

NAW decreased from baseline (12.1; SD 3.5) following sunobinop administration of all treatments. Sunobinop treatment was associated with a decrease in NAW at all doses tested which is greater than that achieved by placebo; the decrease was greater with higher dose. The change in the LS mean from baseline with placebo was 0.5 (SEM 0.75) and with sunobinop 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg was −2.8 (SEM 0.75), −2.3 (SEM 0.75), −4.6 (SEM 0.76) and −6.0 (SEM 0.75), respectively (data not shown). The decrease over placebo was −3.3 (95% CI −4.7, −1.9; P < 0.001), −2.8 (95% CI −4.2, −1.3; P < 0.001), −5.1 (95% CI −6.5, −3.7; P < 0.001) and −6.5 (95% CI −7.9, −5.1; P < 0.001) at 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg, respectively, and was statistically significantly different from placebo at each dose level. Sunobinop 3.0 mg was statistically significantly different from 1.0 mg (P < 0.05) while 1.0 mg was not significantly different from 0.5 mg nor was 6.0 mg as compared to 3.0 mg. Sunobinop 1.0 mg, 3.0 mg and 6.0 mg also showed, in a post hoc analysis, a significant, dose‐related reduction in the duration of wake bouts compared with placebo. The decrease in average wake time per bout over placebo was −0.9 min (95% CI −2.2, 0.5 min; P = 0.202), −1.4 min (95% CI −2.8, −0.1 min; P = 0.037), −2.5 min (95% CI −3.8, −1.1 min; P < 0.001) and −1.7 min (95% CI −3.0, −0.3 min; P = 0.016) at 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg, respectively (data not shown).

Sleep architecture (N1, N2, N3 and REM)

Time spent in N1 decreased from baseline (32.3 min; SD 12.9 min) following administration of all treatments. Sunobinop treatment was associated with a decrease in time spent in N1 greater than that achieved by placebo at all doses; the decrease was greater with dose increase. The change in the LS mean from baseline with placebo was −0.0 min (SEM 1.97 min) and with sunobinop 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg was −5.1 min (SEM 1.97 min), −6.0 min (SEM 1.97 min), −15.0 min (SEM 1.99 min), and −18.5 min (SEM 1.97 min), respectively (data not shown). The decrease over placebo was −5.1 min (95% CI −9.4, −0.8 min; P = 0.020), −5.9 (95% CI −10.2, −1.7 min; P < 0.007), −15.0 min (95% CI −19.3, −10.7 min; P < 0.001) and −18.5 min (95% CI −22.7, −14.2 min; P < 0.001) at 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg, respectively, and was statistically significantly different from placebo at each dose level. Sunobinop 3.0 mg was statistically significantly different from 1.0 mg (P < 0.05) while 1.0 mg was not significantly different from 0.5 mg nor was 6.0 mg as compared to 3.0 mg.

Time spent in N2 increased from baseline (191.5 min; SD 38.9 min) following administration of all treatments. Sunobinop treatment was associated with an increase in time spent in N2 greater than that achieved by placebo at all doses; the increase was greater with dose increase. The change in the LS mean from baseline with placebo was 23.5 min (SEM 5.53 min) and with sunobinop 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg was 57.1 min (SEM 5.53 min), 69.2 min (SEM 5.53 min), 132.1 min (SEM 5.61 min) and 146.3 min (SEM 5.53 min), respectively (data not shown). The increase over placebo was 33.6 min (95% CI 20.2, 46.9 min; P < 0.001), 45.7 (95% CI 32.3, 59.0 min; P < 0.001), 108.5 min (95% CI 95.1, 122.0 min; P < 0.001) and 122.8 min (95% CI 109.5, 136.2 min; P < 0.001) at 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg, respectively, and was statistically significantly different from placebo at each dose level. Sunobinop 6.0 mg was statistically significantly different from 3.0 mg and 3.0 mg was statistically significantly different from 1.0 mg (P < 0.05) while 1.0 mg was not significantly different from 0.5 mg.

Time spent in N3 decreased from baseline (54.5 min; SD 29.0 min) following administration of all treatments. Sunobinop treatment was associated with a decrease in time spent in N3 greater than that achieved by placebo at all doses; the decrease was greatest at the 3.0 mg dose level. The change in the LS mean from baseline with placebo was −1.0 min (SEM 3.66 min) and with sunobinop 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg was −4.8 min (SEM 3.66 min), −4.7 min (SEM 3.66 min), −16.6 min (SEM 3.70 min) and −10.6 min (SEM 3.66 min), respectively (data not shown). The decrease over placebo was −3.8 min (95% CI −11.1, 3.5 min; P = 0.308), −3.7 min (95% CI −11.0, 3.7 min; P = 0.324), −15.6 min (95% CI −23.0, −8.2 min; P < 0.001) and −9.5 min (95% CI −16.9, −2.2 min; P = 0.011) at 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg, respectively, and was statistically significantly different from placebo at the 3.0 and 6.0 mg dose levels. Sunobinop 3.0 mg was statistically significantly different from 1.0 mg (P = 0.002) while 1.0 mg was not significantly different from 0.5 mg nor 6.0 mg as compared to 3.0 mg.

Time spent in REM changed from baseline (63.7 min; SD 21.7 min) following administration of all treatments. Placebo, 0.5 and 1.0 mg produced an increase in time spent in REM while 3.0 and 6.0 mg produced a decrease in time spent in REM from baseline levels. Sunobinop treatment was associated with a decrease in time spent in REM greater than that achieved by placebo only at the two highest doses tested of 3.0 and 6.0 mg; the decrease was greatest at the 6.0 mg dose level. The change in the LS mean from baseline with placebo was 15.6 min (SEM 3.92 min) and with sunobinop 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg was 10.7 min (SEM 3.92 min), 11.8 min (SEM 3.92 min), −15.8 min (SEM 3.97 min), and −26.3 min (SEM 3.92 min), respectively (data not shown). The decrease over placebo was −4.9 min (95% CI −13.2, 3.3 min; P = 0.237), −3.8 (95% CI −12.1, 4.4 min; P = 0.356), −31.4 min (95% CI −39.7, −23.1 min; P < 0.001) and −41.9 min (95% CI −50.1, −33.7 min; P < 0.001) at 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg, respectively, and was statistically significantly different from placebo only at the 3.0 mg and 6.0 mg dose. A dose of 6.0 mg was statistically significantly different from 3.0 mg and 3.0 mg was statistically significantly different from 1 mg (P < 0.001) while 1 mg was not significantly different from 0.5 mg. (Figure 6 shows time spent in each sleep state as a percentage of TST).

FIGURE 6.

Percent of time spent in each sleep phase (N1, N2, N3 or REM) across the total sleep time by polysomnography at baseline and for each treatment. REM, rapid eye movement; TST, total sleep time.

REM latency changed from baseline (64.2 min; SD 22.1 min) following administration of all treatments. Placebo, 0.5, 3.0 and 6.0 mg produced an increase in REM latency while 1.0 mg produced a decrease in REM latency from baseline levels. The change in the LS mean from baseline with placebo was 1.5 min (SEM 11.0 min) and with sunobinop 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg was 3.4 min (SEM 11.01 min), −4.9 min (SEM 11.01 min), 13.8 min (SEM 11.18 min) and 34.8 min (SEM 11.01 min), respectively (data not shown). The change as compared to placebo was 1.9 min (95% CI −24.4, 28.2 min; P = 0.885), −6.4 min (95% CI −32.7, 19.9 min; P = 0.630), 12.3 min (95% CI −14.2, 38.9 min; P = 0.359) and 33.3 min (95% CI 7.1, 59.6 min; P 0.013) at 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg, respectively, and was statistically significantly different from placebo only at the 6.0 mg dose. Each successive dose level was not statistically significantly different (P > 0.05) as compared to the next lower dose (data not shown).

3.2.2. Subjective endpoints from sleep questionnaire

sSL

Sunobinop also affected patients' self‐reported sSL, with patients reporting shorter sSL with increasing dose. The change in the LS mean from baseline (72.6 min; SD 48.6 min) with placebo was −19.4 min (SEM 6.5 min) and with sunobinop 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg was −17.5 min (SEM 6.5 min), −30.9 min (SEM 6.5 min), −32.0 min (SEM 6.6 min) and −37.7 min (SEM 6.5 min), respectively. The change as compared to placebo was 1.9 min (95% CI −12.3, 16.1 min; P = 0.789), −11.5 min (95% CI −25.7, 2.7 min; P = 0.111), −12.5 min (95% CI −26.9, 1.8 min; P = 0.086) and −18.2 min (95% CI −32.4, −4.1 min; P = 0.012) at 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg, respectively, and was statistically significantly different from placebo at the 6.0 mg dose. (Figure 3B shows mean sSL ± SD.)

sWASO

The subjective sWASO findings were consistent with the objective data with a decrease in sWASO following administration of all treatments. The change in the LS mean from baseline (99.8 min; SD 58.6 min) with placebo was −20.0 min (SEM 9.4 min) and with sunobinop 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg was −23.9 min (SEM 9.4 min), −45.4 min (SEM 9.4 min), −63.8 min (SEM 9.5 min), and −66.1 min (SEM 9.4 min), respectively. The change as compared to placebo was −3.9 min (95% CI −23.2, 15.3 min; P = 0.686), −25.4 min (95% CI −44.7, −6.2 min; P = 0.010), −43.8 min (95% CI −63.2, −24.3 min; P < 0.001) and −46.2 min (95% CI −65.4, −26.9 min; P < 0.001) at 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg, respectively, and was statistically significantly different from placebo at 1.0, 3.0 and 6.0 mg dose levels. (Figure 4B shows mean sWASO ± SD.)

sTST

The sTST findings were consistent with the objective data with an increase in sTST following administration of all treatments as compared with baseline. The change in the LS mean from baseline (296.8 min; SD 61.2 min) with placebo was 27.6 min (SEM 16.1 min) and with sunobinop 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg was 24.7 min (SEM 16.1 min), 78.3 min (SEM 16.1 min), 87.9 min (SEM 16.2 min) and 94.5 min (SEM 16.1 min), respectively. The change as compared to placebo was −2.9 min (95% CI −34.4, 28.7 min; P = 0.857), 50.6 (95% CI 19.1, 82.2 min; P = 0.002), 60.3 min (95% CI 28.4, 92.1 min; P < 0.001) and 66.9 min (95% CI 35.3, 98.4 min; P < 0.001) at 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg, respectively, and was statistically significantly different from placebo at 1.0, 3.0 and 6.0 mg dose levels (data not shown).

Sleep quality

Sleep quality increased from baseline following administration of all treatments. Sunobinop treatment was associated with an increase in sleep quality greater than that achieved by placebo at all doses; the increase was greater with dose increase. The increase in the LS mean from baseline (3.9; SD 1.6) with placebo was 1.6 (SEM 0.33) and with sunobinop 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg was 2.0 (SEM 0.33), 2.5 (SEM 0.33), 3.0 (SEM 0.33) and 3.4 (SEM 0.33), respectively (data not shown). The increase over placebo was 0.4 (95% CI −0.2, 1.0; P = 0.161), 0.9 (95% CI 0.3, 1.5; P = 0.002), 1.5 (95% CI 0.9, 2.0; P < 0.001) and 1.8 (95% CI 1.3, 2.4; P < 0.001) at 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg, respectively, and was statistically significantly different from placebo at each dose level except 0.5 mg.

Depth of sleep

Depth of sleep (self‐reported number of awakenings) decreased from baseline following administration of all treatments. Sunobinop treatment was associated with a decrease in depth of sleep greater than that achieved by placebo at all doses; the increase was greater with dose increase. The increase in the LS mean from baseline (4.4; SD 2.1) with placebo was −1.0 (SEM 0.23) and with sunobinop 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg was −1.7 (SEM 0.23), −2.1 (SEM 0.23), −2.6 (SEM 0.23) and −2.5 (SEM 0.23), respectively (data not shown). The decrease over placebo was −0.7 (95% CI −1.3, −0.1; P = 0.020), −1.1 (95% CI −1.6, −0.5; P < 0.001), −1.6 (95% CI −2.1, −1.0; P < 0.001) and −1.5 (95% CI −2.1, −0.9; P < 0.001) at 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg, respectively, and was statistically significantly different from placebo at each dose level.

3.2.3. Pharmacodynamics endpoints for assessment of next day residual effects

DSST

There was no statistically significant difference (P > 0.05) between sunobinop and placebo in the total number of correct answers (averaged across both testing days) at 0.5 mg at any timepoint. (Figure 6 shows mean total number correct ± SD; baseline 52.2; SD 9.9.) Statistically significant lower scores were evident following 1 mg at a single timepoint (12 h post dose) and 3.0 mg and 6.0 mg at multiple timepoints with the largest decrease following 6.0 mg. The LS means for placebo varied from 56.9 (SEM 1.9) to 61.1 (SEM 1.9) over the time course of measurement and with sunobinop 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg varied from 56.8 (SEM 1.9) to 61.9 (SEM 1.9), 56.3 (SEM 1.9) to 60.7 (SEM 1.9), 50.8 (SEM 1.9) to 56.2 (SEM 1.9) and 43.4 (SEM 1.9) to 50.5 (SEM 1.9), respectively. The maximum decrease over placebo was −2.3 (95% CI −6.0, 1.4; P = 0.220; 14 h post dose), −4.8 (95% CI −8.5, −1.0; P = 0.012; 12 h post dose), −8.8 (95% CI −12.6, −5.1; P < 0.001; 12 h post dose) and −17.7 (95% CI −21.4, −14.0; P < 0.001; 12 h post dose) at 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg, respectively. As such the effect of sunobinop on number of correct answers peaks at 12 h post dose and recovers at subsequent timepoints. (Figure 7 shows mean DSST ‐ # answered correct ± SD.)

FIGURE 7.

Mean (night 1 and night 2) with standard deviations of digit symbol substitution test (# of correct responses) at baseline and for each treatment over the 8 h after awakening (9–16 h post dose). The table shows the statistical significance for the least squares mean difference from placebo and from the next lower sunobinop dose at each measured timepoint. NS, non‐significant (P > 0.05). [Correction added on 25 September 2025, after first online publication: Figure 7 has been updated in this version.]

Karolinska sleepiness scale

There was no statistically significant difference (P > 0.05) between sunobinop and placebo in KSS (averaged across both testing days) at 0.5 mg and 1 mg at any timepoint (baseline 4.7; SD 2.1; data not shown). Statistically significant higher scores were evident following 3 mg and 6 mg at multiple timepoints with the largest increase following 6 mg. The LS means for placebo varied from 3.3 (SEM 0.3) to 4.2 (SEM 0.3) over the time course of measurement and with sunobinop 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg varied from 3.6 (SEM 0.3) to 4.5 (SEM 0.3), 3.6 (SEM 0.3) to 4.3 (SEM 0.3), 4.5 (SEM 0.31) to 5.4 (SEM 0.31) and 4.9 (SEM 0.3) to 6.1 (SEM 0.3), respectively. The maximum increase over placebo was 0.4 (95% CI −0.2, 1.0; P = 0.199; 10 h post dose), 0.4 (95% CI −0.3, −1.0; P = 0.261; 10 h post dose and 95% CI −0.2, 1.0: P = 0.199; 13 h post dose), 1.6 (95% CI 1.0, 2.2; P < 0.001; 10 h post dose and 95% CI 0.9, 2.2; P < 0.001; 12 h post dose) and 2.4 (95% CI 1.8, 3.0; P < 0.001; 13 h post dose) at 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg, respectively. As such, the effect of sunobinop on KSS peaks at 10–13 h post dose and recovers at subsequent timepoints.

PVT

There was no statistically significant difference (P > 0.05) between sunobinop and placebo in mean response time (averaged across both testing days) at 0.5 mg and 1.0 mg at any timepoint (baseline 324.7 msec; SD 88.7 msec; data not shown). Statistically significantly higher times were evident following 3 mg and 6 mg at multiple timepoints with the largest increase following 6 mg. The LS means for placebo varied from 442.2 msec (SEM 130.05 msec) to 542.2 msec (SEM 130.05 msec) over the time course of measurement and with sunobinop 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg varied from 432.6 msec (SEM 130.05 msec) to 607.4 msec (SEM 130.05 msec), 494.5 msec (SEM 130.05 msec) to 590.1 msec (SEM 130.05 msec), 595.2 msec (SEM 131.7 msec) to 983.0 msec (SEM 131.7 msec) and 733.3 msec (SEM 130.05 msec) to 1175.9 msec (SEM 130.05 msec), respectively. The maximum increase over placebo was 131.9 msec (95% CI −168.4, 432.2 msec; P = 0.389; 12 h post dose), 125.7 msec (95% CI −174.7, 426.0 msec; P = 0.412; 12 h post dose), 523.3 msec (95% CI 220.2, 826.4; P < 0.001; 10 h post dose) and 711.4 msec (95% CI 411.1, 1011.8 msec; P < 0.001; 12 h post dose) at 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg, respectively. As such the effect of sunobinop on mean response time peaks at 10–12 h post dose and recovers at subsequent timepoints.

Body sway

There was no statistically significant difference (P > 0.05) between sunobinop and placebo in sway (averaged across both testing days) at 0.5 mg and 1.0 mg at any timepoint (baseline 39.4; SD 23.1; data not shown). Statistically significant effects on postural stability (1/3 angle of arc, cumulative total over 60 s) were evident following 3.0 mg and 6.0 mg at multiple timepoints with the largest increase following 6 mg. The LS means for placebo varied from 31.2 (SEM 4.5) to 34.9 (SEM 4.5) over the time course of measurement and with sunobinop 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg varied from 32.5 (SEM 4.5) to 35.5 (SEM 4.5), 31.2 (SEM 4.5) to 35.7 (SEM 4.5), 40.8 (SEM 4.6) to 56.1 (SEM 4.6) and 47.6 (SEM 4.5) to 64.8 (SEM 4.5), respectively. The maximum increase over placebo was 2.8 (95% CI −8.9, 14.4; P = 0.642; 9 h post dose), 3.6 (95% CI −8.0, 15.2; P = 0.539; 9 h post dose), 24.1 (95% CI 12.3, 35.8; P < 0.001; 9 h post dose) and 32.8 (95% CI 21.1, 44.4; P < 0.001; 9 h post dose) at 0.5 mg, 1.0 mg, 3.0 mg and 6.0 mg, respectively. As such, the effect of sunobinop on mean response time peaks at 9 h post dose and recovers at subsequent timepoints.

POMS

No statistically significant differences (P < 0.05) in the subdomains of the POMS assessment scale of “anger”, “tension”, or “depression” were observed. Lower doses of sunobinop (≤1.0 mg) were not statistically significantly different from placebo in the subdomains for “confusion”, “total mood disturbance”, and “vigour”. Doses ≥3.0 mg were associated with statistically significantly higher scores in the subdomains for “confusion” (max increase over placebo of 0.8; 95% CI 0.3, 1.3; P = 0.002 at 3.0 mg at 9 h post dose and 1.6; 95% CI 1.1, 2.1; P < 0.001 at 6.0 mg at 14 h post dose) and “total mood disturbance” (max increase over placebo of 2.7; 95% CI 0.2, 5.2; P = 0.033 at 3.0 mg at 9 h post dose and 7.0; 95% CI 4.5, 9.4; P < 0.001 at 6.0 mg at 14 h post dose) and significantly lower for “vigour” (max decrease over placebo of −1.8; 95% CI −2.8, −0.8; P < 0.001 at 3.0 mg at 14 h post dose and −2.8; 95% CI −3.8, −1.8; P < 0.001 at 6.0 mg at 14 h post dose). A statistically significant effect on subdomain of “fatigue” was only noted at the 6.0 mg dose (max increase over placebo of 2.3; 95% CI 1.2, 3.3; P < 0.001 at 14 h post dose).

3.3. Safety

A summary of TEAEs reported for ≥2 patients and organized by MedDRA Version 20.0 ²⁴ system organ classification (SOC), preferred term (PT), and maximum severity are presented in Table 2. No deaths or serious AEs were reported in this study. A total of 89 TEAEs were reported, and 25 of 30 patients (83%) experienced at least one TEAE. The majority of reported TEAEs were mild (77%), and no patients discontinued the study due to AEs. AEs experienced by two or more patients following any dose level of sunobinop included somnolence (most frequently reported, 70% of patients), dizziness, headache and irritability. Apart from infrequent hypotension (two patients) and bradycardia (one patient), no changes in clinical laboratory values, vital signs, neurologic tests. SpO2 measurements, or ECG and C‐SSRS results were reported during the study. The instances of hypotension and bradycardia, although considered reasonably related to the study drug, were mild and resolved without treatment.

TABLE 2.

Summary of TEAE by MEDRA 20.0 SOC, PT, and severity in the randomized safety population.

TEAE/severity	Placebo (N = 30)	Sunobinop 0.5 mg (N = 30)	Sunobinop 1 mg (N = 30)	Sunobinop 3 mg (N = 29)	Sunobinop 6 mg (N = 30)	Overall (N = 30)
	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)
Any TEAE
Mild	4 (13)	6 (20)	7 (23)	14 (48)	17 (57)	21 (70)
Moderate	0	1 (3)	1 (3)	3 (10)	1 (3)	4 (13)
Severe	0	0	0	0	0	0
Nervous system disorders
Somnolence
Mild	2 (7)	3 (10)	2 (7)	13 (45)	16 (53)	18 (60)
Moderate	0	1 (3)	1 (3)	2 (7)	1 (3)	3 (10)
Dizziness
Mild	0	0	1 (3)	1 (3)	2 (7)	2 (7)
Headache
Mild	1 (3)	0	2 (7)	0	0	2 (7)
Psychiatric disorders
Irritability
Mild	1 (3)	0	0	1 (3)	2 (7)	2 (7)

Note: TEAEs are reported for ≥2 patients following any treatment by system organ class, preferred term and maximum severity.

Abbreviations: TEAE, treatment‐emergent adverse events; MEDRA, Medical Dictionary for Regulatory Activities; SOC, system organ classification; PT, preferred term.

4. DISCUSSION

In this Phase 1 study of 30 patients with DSM‐5 insomnia disorder, sunobinop was well tolerated at the doses tested. There were no deaths or serious AEs and no patient discontinuations due to TEAEs. As expected with a pharmacotherapy for insomnia, somnolence was the most commonly reported AE. All AEs reasonably attributed to the study drug resolved by the conclusion of the study period and no noteworthy findings occurred during the follow‐up period.

Using PSG, considered the gold standard for sleep research, ²⁷ sleep efficiency, the primary endpoint for this study, was significantly higher (12%–19% increase over baseline) following each sunobinop dose level as compared separately with placebo. Improvement in SE increased with escalating doses. Additionally, all sunobinop dose levels showed statistically significantly improved sleep maintenance, as measured by WASO, compared with placebo. When treated with any dose of sunobinop, patients were awake for less total time (26–52 min) than when receiving a placebo (77 min). The effect on WASO was greater in the second half of the night. Sleep onset, as measured by LPS, was similar for all treatments. At each dose level, sunobinop was associated with a statistically significant increase in TST and decrease in NAW when compared to placebo.

Considering self‐reported subjective endpoints; sSL, sWASO, sTST, sleep quality and depth of sleep, all showed a dose‐dependent improvement with increasing dose of sunobinop. Statistical significance for sSL was achieved only at the highest dose likely due to variability in this endpoint; however, for sWASO, sTST and sleep quality, statistical significance was achieved at all dose levels of sunobinop greater than 0.5 mg and for depth of sleep significance was achieved at all doses including 0.5 mg. Overall, the subjective measures correlated well with the objective PSG measures except in the case of sleep onset; this may be due to a large placebo effect on LPS in the current study which was greater than observed in a prior study from our group. ²²

Sleep architecture is frequently altered in sleep disorders, with disruption to the proportion of time spent in phases N1, N2, N3 and REM sleep during the night's rest. This study saw a significant dose‐dependent decrease in N1 and increase in N2 sleep with sunobinop treatment with no effect on REM latency, while REM duration was significantly reduced by sunobinop only at 3 and 6 mg. An increase in N2 is considered potentially beneficial, ²⁸ while a decrease in REM duration from normal levels has been associated with long‐term negative outcomes. ²⁹ However, this may vary. Common antidepressant drugs are known to reduce REM when used to treat depressive disorder and without adversity. ³⁰ If REM duration is abnormally increased, as is the case in alcohol use disorder patients, ³¹ then a normalization of REM duration would likely be considered a benefit; as such, the sleep architecture changes noted in this study should be taken into consideration for dose selection in future studies. The notable effect of increase in N2, as well as preservation of REM sleep cycles, differentiates sunobinop from other hypnotics. Relatedly, sunobinop also showed a dose‐dependent and significant decrease in NAW per night, increase in sleep depth (a self‐reported assessment of number of awakenings) and a reduction in the duration of wake bouts.

This is the first study to report the effect of a range of doses of sunobinop in patients with insomnia and the first detailed clinical study of the effect of any NOP receptor agonist in sleep. Comparison with studies using other insomnia drugs are challenging due to differences in design; however, studies with zolpidem have shown effects on LPS, TST, WASO, SE and NAW as measured by PSG; LPS was decreased by 9–12 min, TST was increased by 29 min, WASO was reduced by 13–25 min, SE increased by 6% and NAW decreased by 0.95 occurrences at doses 6.25–12.5 mg. ³² Likewise the more recently approved orexin type 1 and type 2 antagonist, suvorexant has shown effects on LPS, TST and WASO; LPS increase by 2–22 min, TST increased by 22–50 min and WASO decreased by 17–31 min at doses of 10–20 mg. Interestingly, suvorexant did not have an effect on NAW. ³² It is important to note that much of this data resulted from dose levels greater than the recommended starting dose for zolpidem and suvorexant. ³² The efficacy results from sunobinop compare favourably, particularly for WASO and NAW, which in addition to TST and SE, reach the threshold for clinical significance. ³² Perhaps more importantly the American College of Physicians guidelines note that there is insufficient evidence to determine efficacy or benefit: risk ratio of many available therapies ¹² and all specific recommendations from the American Academy of Sleep Medicine, including for zolpidem and suvorexant, are classified as weak based on confidence in/quality of available efficacy data and potential risks. ³² As such, newer pharmacotherapies with improved efficacy and safety profiles are needed.

Sunobinop has strong potential utility in treating DSM‐5 insomnia disorder in patients with comorbidities. Sunobinop shows no next‐day effects at doses <3.0 mg while statistically significant effects on sleep parameters are noted at all doses including the lowest dose tested of 0.5 mg. Furthermore, as sunobinop is primarily excreted unchanged in the urine (elimination half‐life is approximately 2.3 h) and does not adversely impact respiratory function, ²¹ it may be well‐suited for patients with comorbid disease, such as those at risk for hepatic disease and/or respiratory disorders. As such, sunobinop is currently undergoing evaluation as a possible treatment for insomnia associated with recovery from alcohol use disorder. ³³

The potential for pharmacological action of sunobinop in a variety of organs and tissues where NOP receptors are expressed could provide additional positive benefits but could also produce unwanted consequences depending on the population under study. The high concentration of unchanged sunobinop that is present in the urine ²¹ imparts a strong likelihood of target engagement of NOP receptors in the bladder. Given the inhibitory action of NOP agonists on the micturition reflex and pain transduction, ²⁰ the therapeutic potential of sunobinop in urologic disorders, in particular those with nighttime symptoms (e.g. nocturia) is worthy of clinical exploration. While these examples are potentially of therapeutic value, careful monitoring of unintended effects remains important.

One limitation of this Phase 1 study is the small sample size. Generalizing the safety and efficacy findings from the current Phase 1 study to the general insomnia population would require larger confirmatory studies. The short overall duration of the study is a further limitation; while we would not expect sunobinop's pharmacokinetics to change upon further repeat dosing, a longer‐term trial of the efficacy and safety of sunobinop in a population with DSM‐5 insomnia disorder is warranted.

In conclusion, in this Phase 1 study of 30 adult patients with DSM‐5 insomnia disorder sunobinop was well‐tolerated and all adverse events reported were considered mild and transient. This study suggests that sunobinop, at appropriate doses, effectively increases sleep efficiency and positively affects sleep architecture and NAWs, making it a novel and potentially valuable new treatment option for various sleep disorders.

AUTHOR CONTRIBUTIONS

All authors contributed substantially to the conception or design of the work and the data's acquisition, analysis or interpretation. All authors were involved in drafting or revising the manuscript critically for important intellectual content. They accept fully responsible for all content and editorial decisions and had final approval of the manuscript.

CONFLICT OF INTEREST STATEMENT

All authors were employees of Imbrium Therapeutics at the time of the study; Maha Ahmad holds stock at Johnson & Johnson.

DATA SHARING STATEMENT

The data used and/or analysed during the current study are available from the corresponding author on reasonable request.

Supporting information

Video S1. Nociceptin system and sunobinop mechanism of action.

Whiteside GT, He E, Shet MS, Zhou M, Ahmad M, Harris SC. Efficacy and safety of a selective partial agonist for nociception/orphanin‐FQ peptide (NOP) receptors in patients with insomnia disorder. Br J Clin Pharmacol. 2026;92(1):172‐185. doi: 10.1002/bcp.70193

DATA AVAILABILITY STATEMENT

The data that supports the findings of this study are available in the supplementary material of this article.