Safety, Tolerability, and Pharmacokinetics of Single- and Multiple-Ascending Doses of Sunobinop in Healthy Participants

Abstract

Sunobinop is an investigational, potent, selective partial agonist at the nociceptin/orphanin FQ peptide receptor in vitro. Three phase 1 studies were conducted to evaluate the safety, tolerability, and pharmacokinetics (PK) of escalating single- and multiple-dose administration of sunobinop in healthy participants. Study 1 was a randomized, double-blind, placebo-controlled, single-ascending dose study. Study 2 was a randomized, double-blind, placebo-controlled, multiple-ascending dose study. Study 3 was a randomized, open-label, single-dose, 4-way crossover study of oral and sublingual sunobinop comparing morning (AM) and bedtime (PM) administration. Seventy participants were included. Systemic exposure (peak plasma concentration [C_max], area under the plasma concentration-time curve from time 0 to the time of last quantifiable concentration [AUC_0-t], and area under the plasma concentration–time curve from time 0 extrapolated to infinity [AUC_inf]) of sunobinop was characterized by dose proportionality from 0.6 to 2 mg and increased less than proportionally from 3 to 30 mg. The PKs of sunobinop were similar, regardless of AM or PM administration, for both the oral and sublingual formulations. The majority of absorbed sunobinop was excreted unchanged in the urine within 8 hours of dosing, thereby showing rapid elimination with no appreciable accumulation following 14 consecutive days of once-daily dosing and suggesting exclusive renal elimination. Most treatment-emergent adverse events (TEAEs) were mild in severity; 1 severe TEAE occurred and all TEAEs resolved by the end of the studies. Sunobinop was generally well-tolerated and safe across the range of doses evaluated and presents a clinical profile suitable for continued development.

Nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP) was first discovered and isolated from rat and porcine extracts in the 1990s by 2 distinct research groups.^{1, 2} Reverse pharmacology was then used to identify the endogenous ligand. Although the NOP shares structural similarity with mu, kappa, and delta opioid receptors, important differences in endogenous ligand selectivity, signal transduction, phosphorylation, desensitization, internalization, and trafficking have been observed.³ N/OFQ has no measurable affinity for mu- or delta-opioid receptors and displays 1000-fold lower affinity for kappa receptors⁴; likewise the endogenous opioids do not bind NOP.^{2, 5} N/OFQ functions as an inhibitory neurotransmitter, and it is important to note that through NOP, it can inhibit the effects of mu receptor agonists.⁶ As such, NOP modulators are among the National Institute on Drug Abuse's top 10 most important pharmacologic targets for the development of therapies in response to the opioid crisis.⁷

NOP is widely expressed in the central and peripheral nervous systems, and has been pursued as a potential therapeutic target for several disorders,⁹ including chronic cough,⁸ pain,^{8, 9} sleep,¹⁰ anxiety,^{8, 9} depression,^{8, 9} Parkinson's disease,⁸ addiction,^{8, 9} hypertension,⁸ interstitial cystitis/bladder pain syndrome (IC/BPS),⁵ and overactive bladder (OAB).⁵

Sunobinop (V117957; Imbrium Therapeutics/Purdue Pharma, Stamford, CT, USA) is an investigational, oral drug that is a potent and selective partial agonist at NOP in vitro. Sunobinop displays high affinity for human NOP receptors (K_i = 3 nM) with potent partial agonist activity (EC50 = 4 nM, E_max = 48%) and a low affinity for mu and kappa opioid receptors (K_i = 1630 and 2280 nM, respectively) without agonist activity (up to 10 µM) and is a weak agonist at delta receptors (K_i = 476 nM, EC50 = 2205 nM, E_max = 16%).¹⁰ Its structure is shown in Figure 1.¹¹ Prior to initiating human studies, sunobinop safety and pharmacokinetics (PKs) were extensively evaluated in nonclinical species (Imbrium Therapeutics, unpublished data, 2022). The absolute bioavailability of sunobinop ranges from 25% to 67% in rats, dogs, and monkeys. Absorption after a single oral dose of [¹⁴C]-sunobinop was relatively rapid, with peak plasma levels achieved within 5.33 hours. The calculated half-life (t_1/2) ranged from 3.25 to 5.45 hours across the same 3 species. Sunobinop displayed limited metabolism in vitro when incubated with human hepatocytes, as well as following oral single dosing with [¹⁴C]-sunobinop to rats, dogs, and monkeys. Unchanged sunobinop was the predominant radioactive peak in the plasma and urine of these species. No radioactive metabolites were detected in rats.

Figure 1

Sunobinop structure. 4-((endo)-9-((exo)-bicyclo[3.3.1]nonan-3-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-3-oxo-3,4-dihydroquinoxaline-2-carboxylic acid.

The present report describes the results of 3 phase 1 clinical studies conducted to evaluate the PK of escalating single-dose and multiple-dose administrations and establish the safety and tolerability of sunobinop in healthy participants.

Methods

Study Design

All 3 studies followed the principles of the Declaration of Helsinki and Good Clinical Practice. One study was approved by the Midlands Independent Review Board (IRB; now WCG IRB) in Overland, TX, and conducted at PRA Health Sciences in Lenexa, KS. Two studies were approved by IntegReview IRB (now Advarra) in Austin, TX, and conducted at PPD Phase 1 Clinic in Austin, TX. All participants provided written informed consent.

Study 1 was a single-center, randomized, double-blind, placebo-controlled study evaluating single-ascending dose (SAD) administration of sunobinop oral aqueous suspension in 0.5% methylcellulose 400 cP to sequential cohorts of healthy male participants in the morning (AM). Nonsmoking healthy male participants aged 18-45 years who exhibited no clinically significant medical history or disease were eligible. Participants were excluded if they had a recent or past history of obstructive uropathy and/or renal disease/dysfunction (creatinine clearance [CrCl] <60 mL/min) and any cardiovascular disorder. The total study duration was approximately 41 days.

Study 2 was a randomized, double-blind, placebo-controlled, multiple-ascending dose (MAD) study. Sunobinop oral aqueous suspension was administered nightly at bedtime (PM) to sequential groups of 12 participants (9 active and 3 placebo) for each of 3 cohorts. The total study duration was approximately 55 days.

Study 3 was a randomized, open-label, single-dose, 4-way crossover study (crossover) of oral and sublingual formulations of sunobinop (each administered in the AM and PM). The total study duration was approximately 49 days.

The MAD and crossover studies included male and non-childbearing-potential female participants aged 18-45 years who exhibited no clinically significant medical history or disease.

Each study included a prerandomization screening phase, a treatment phase, and a posttreatment phase that consisted of a follow-up phone call 7-10 days after the last sunobinop administration (Figure S1).

Screening and Baseline Parameters

In the prerandomization phase, all participants were screened within 28 days of baseline. Screening activities consisted of drug, alcohol, and cotinine screens; serum pregnancy test and serum follicle-stimulating hormone levels (female participants only); physical examination; 12-lead electrocardiogram (ECG); vital signs (systolic/diastolic blood pressure, pulse rate, respiration rate, and oral temperature); oxygen saturation (SpO₂); medical and medication history; and clinical laboratory testing. Inclusion/exclusion criteria were evaluated (including completion of the Columbia-Suicide Severity Rating Scale [C-SSRS] in the MAD study only). In addition, 24-hour outpatient digital ECG (Holter) monitoring data were collected.

At baseline, drug, alcohol, and cotinine screens; 12-lead ECG; vital signs; SpO₂; and clinical laboratory testing (including microscopic examination of urine for crystalluria) were performed. Serum and urine samples for CrCl estimation were collected, and 24-hour digital ECG (Holter) monitoring was initiated; C-SSRS assessment was performed (MAD study only); and blood and urine samples were collected. The C-SSRS, a validated instrument for assessing suicidal ideation and behavior,¹² was utilized because sunobinop is a novel, central nervous system (CNS)-active compound with a mechanism of action that has not been extensively characterized in humans to date.

In the double-blind treatment phase of Study 1 (SAD), the planned dose-escalation sequence for sunobinop was 3, 10, 30, 100, 300, 600, and 1000 mg administered orally as an aqueous suspension. However, the maximum dose administered was 30 mg, dosing occurred in 3 cohorts (3, 10, and 30 mg), and each cohort received a single dose of sunobinop. In Study 2 (MAD), sunobinop was administered as an oral aqueous suspension nightly at bedtime on day 1 and days 3-16. The nominal doses for cohorts 1, 2, and 3 were 0.6, 2, and 10 mg, respectively. In the open-label treatment phase of Study 3 (crossover), a sunobinop 0.6-mg tablet was administered orally or sublingually in the AM and PM to participants in the fasted state.

PK Analysis

In Study 1 (SAD), blood samples for determining sunobinop plasma concentrations were obtained predose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, 84, and 96 hour(s) postdose. Urine samples for determining concentrations of sunobinop were collected predose and at 0-2, 2-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours postdose.

In Study 2 (MAD), blood samples for determining sunobinop plasma concentrations were obtained from days 1-3 and 16-18 predose and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 18, 24, 30, 36, and 48 hour(s) after sunobinop administration; and predose on days 4, 5, 6, 14, and 15. Urine samples for determining concentrations of sunobinop were collected on days 1 and 16 at 0-8, 8-16, 16-24, 24-32, 32-40, and 40-48 hours after sunobinop administration.

In Study 3 (crossover), blood samples for determining sunobinop plasma concentrations were obtained predose, at 5 and 10 minutes, and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 18, 24, 36, and 48 hours after sunobinop administration. Urine samples for determining concentrations of sunobinop were collected at 0-8, 8-16, 16-24, 24-32, 32-40, and 40-48 hours after sunobinop administration.

For each blood sample, 4 mL of venous blood was drawn into tubes containing K₂EDTA solution. Samples were centrifuged (1500 g, 4°C, 15 minutes) within 30 minutes of collection, and clear plasma was collected and frozen at −20°C until analysis.

Bioanalysis of PK Samples

The concentrations of sunobinop in plasma and urine samples were analyzed using validated liquid chromatography (LC)-tandem mass spectrometry (LC-MS/MS) methods.

A protein precipitation extraction method was used to extract sunobinop from 100-µL plasma samples and from 50-µL urine/acetonitrile composite samples containing sunobinop-d4 (V117957-d4) as an internal standard. The extracted samples were analyzed by LC-MS/MS using a Waters Atlantis dC18, 5 µm, 2.1 × 50 mm, reversed-phase high-performance LC column. The LC mobile phase used for plasma samples was 100:0.1 (v/v) water:formic acid ratio (mobile phase A) and 100:0.1 (v/v) acetonitrile:formic acid ratio (mobile phase B). The LC mobile phase used for urine/acetonitrile composite samples was 100:0.1 (v/v) water:acetic acid (mobile phase A) and 100:0.1 (v/v) acetonitrile:acetic acid (mobile phase B). The mass spectrometer was operated in the multiple reaction monitoring mode with positive ion detection. The mass transitions for multiple reaction monitoring were m/z 436.3 → 246.2 for sunobinop (V117957) and m/z 440.3 → 246.2 for the internal standard (V117957-d4). The method's performance during validation for both intra- and interday precision and accuracy was deemed acceptable.

The lower limit of quantitation for sunobinop in plasma was 1 ng/mL (Study 1) and 5 pg/mL (Study 2 and 3), and urine was 100 ng/mL.

Safety Variables

Safety was assessed in all participants using recorded adverse events (AEs), clinical laboratory tests (chemistry, hematology, and urinalysis, including microscopic evaluation of urine for crystalluria), vital signs, SpO₂, physical examination, telemetry, ECGs (12-lead and Holter recordings), and the C-SSRS (MAD study only).

Statistical Methods

For each study, the full analysis population included all participants who were randomly assigned, received sunobinop, and had ≥1 valid PK metric for that treatment. Plasma concentrations of sunobinop versus time data were analyzed by noncompartmental methods to determine the following PK metrics: peak plasma concentration (C_max), time to C_max (T_max), area under the plasma concentration–time curve from time 0 to the time of last quantifiable concentration (AUC_0-t), area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC_inf), and terminal phase t_1/2.

The safety population consisted of participants who were randomly assigned and received ≥1 dose of sunobinop. All safety data (AEs, clinical laboratory results, vital signs, SpO₂, and ECGs) were listed for participants. AEs were categorized into preferred terms and associated system organ class (SOC) using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent AEs (TEAEs) were defined as AEs that started or increased in severity after the first dose of sunobinop. TEAEs were summarized by presenting the incidence of AEs for each treatment group by the MedDRA preferred term, nested within SOC for the randomized safety population.

Laboratory evaluations, ECGs, vital signs, and SpO₂ were summarized by time point for the randomized safety population.

Results

PK Results

In Study 1 (SAD), each of 3 cohorts included 6 participants randomly assigned 2:1 to sunobinop versus placebo. The PK metrics of mean plasma and urine sunobinop concentration versus time are presented in Table 1 and Figure 2A.¹⁰ Systemic exposure of sunobinop (C_max, AUC_0-t, and AUC_inf) increased less than proportionally across the dose range studied (3, 10, and 30 mg). Median T_max was 1.5 hours and independent of dose. The mean t_1/2 was independent of dose. The amount of unchanged sunobinop excreted in urine over a 96-hour period increased less than dose proportionally. The absolute bioavailability (based on absence of significant metabolism and assumed total urinary recovery of absorbed sunobinop) of sunobinop was 88.7%, 69.5%, and 28.0% at 3, 10, and 30 mg, respectively. Total renal clearance was unchanged across the 10-fold dose range over 96 hours (Table 2).¹⁰

Table 1. Summary Statistics for Plasma Sunobinop Pharmacokinetics¹⁰

	Study 1 (SAD)			Study 2 (MAD)			Study 3 (crossover)
Study treatment	Sunobinop AQS 3 mg	Sunobinop AQS 10 mg	Sunobinop AQS 30 mg	Sunobinop AQS 0.6 mg	Sunobinop AQS 2 mg	Sunobinop AQS 10 mg	Sunobinop oral tablet 0.6 mg, AM	Sunobinop oral tablet 0.6 mg, PM	Sunobinop sublingual tablet 0.6 mg, AM	Sunobinop sublingual tablet 0.6 mg, PM
Metrics
Cmax (ng/mL)
Mean	30.3	76.9	82.9	4.9	21.3	56.6	8.3	7.6	8.3	7.4
SD	5.19	17.15	17.40	1.08	2.29	8.27	1.33	1.39	0.95	1.39
Tmax (hour)
Median	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5	2.0	2.0
Minimum, maximum	1.5, 2.0	1.0, 2.0	1.0, 3.0	1.0, 1.5	1.5, 2.0	1.0, 3.0	0.50, 3.0	1.0, 3.0	1.5, 3.0	1.0, 4.0
AUC0-t (h*ng/mL)
Mean	153	430	496	27.4	105	408	35.0	34.3	34.3	34.4
SD	14.11	103.40	136.10	4.52	15.10	72.01	5.34	5.45	5.86	5.38
AUCinf (h*ng/mL)
Mean	159	440	503	27.4	105	408	35.1	34.4	34.6	34.4
SD	13.30	97.83	135.20	4.520	15.12	71.98	5.35	5.46	6.00	5.38
t1/2 (hour)
Mean	2.4	2.7	2.7	3.19	4.0	4.0	2.7	3.0	2.8	3.1
SD	0.37	0.15	0.38	0.43	0.70	0.35	0.44	0.52	0.60	0.55

• Reproduced from Whiteside et al.¹⁰ AM, morning; AQS, aqueous suspension; AUC_inf, area under the plasma concentration-time curve from time 0 extrapolated to infinity; AUC_0-t, area under the plasma concentration-time curve from time 0 to the time of last quantifiable concentration; C_max, maximum plasma concentration; PM, evening; SD, standard deviation; t_1/2, terminal phase half-life; T_max, time to maximum plasma concentration at steady state.

Figure 2

(A) Study 1 (SAD) mean plasma concentration versus time on a linear scale (inset, semilog scale). Reproduced from Whiteside et al.¹⁰ (B) Study 2 (MAD) mean plasma concentration versus time on a linear scale following single dose administration (inset, semilog scale). (C) Study 2 (MAD) mean plasma concentration versus time on a linear scale (inset, semilog scale). MAD, multiple-ascending dose; SAD, single-ascending dose.

Table 2. Renal Clearance and % Renal Excretion, Full Analysis Population (Study 1 [SAD])¹⁰

Cohort (n = 4 each)	Dose (mg)	Mean total renal clearance (mL/min)	Mean total amount excreted unchanged (mg)	Mean % of dose excreted unchanged over 96 hours
1	3	278	2.66	88.7
2	10	270	6.95	69.5
3	30	274	8.36	28.0

• Reproduced from Whitesdie et al.¹⁰ SAD, single-ascending dose.

In Study 2 (MAD), 36 participants were included in the randomized safety population and 27 participants were included in the full-analysis population. Plasma PK metrics for sunobinop at dose strengths of 0.6, 2, and 10 mg for days 1-3 are presented in Table 1 and Figure 2B,C. After a single dose, oral administration of sunobinop, mean peak (C_max), and total exposure (AUC_0-t and AUC_inf) increased with increasing dose over the 0.6-, 2-, and 10-mg dose range for day 1. The median T_max was 1.5 hours and the t_1/2 ranged from 3.2 to 4.0 hours over the 0.6- to 10-mg dose range. Clearance of the drug from plasma (CL/F) was comparable across all 3 dose strengths (0.6, 2, and 10 mg). Following multiple-dose administration (days 3 through 15), the trough concentrations measured on days 4-6 and 14-16 showed that sunobinop was near steady state before the second multiple dose. Plasma PK metrics for sunobinop for days 16-18 are presented in Table 3. Following 14 consecutive once-daily oral doses (days 3-16) of sunobinop, mean peak and total exposure increased with increasing dose over the 3-dose range for day 16. The median T_max at steady state was 1.5 hours and the t_1/2 at steady state (t_1/2ss) ranged from 3.2 to 4.5 hours over the 0.6- to 10-mg dose range. CL/F at steady state was comparable across all 3 dose strengths. Following 14 consecutive days of once-daily sunobinop dosing, the accumulation ratio was ≤1.21 for all dose levels, suggesting minimal accumulation. Sunobinop peak and total exposures appeared to be linear as the dose increased across the range studied. At the 0.6- to 2-mg dose range, the systemic exposure was dose proportional at steady state (day 16). The majority of the fraction of dose recovered in urine was unchanged sunobinop, suggesting renal clearance as the major route of elimination. Urinary recovery of unchanged sunobinop was nearly complete by 48 hours and was similar across the dose range. The mean total renal clearance of sunobinop was similar across all dose levels, ranging from 16.4 to 21.2 L/h, following dosing on days 1 and 16.

Table 3. Summary of Plasma Sunobinop Pharmacokinetics Days 16-18 (Study 2 [MAD])

Study treatment	Sunobinop AQS 0.6 mg	Sunobinop AQS 2 mg	Sunobinop AQS 10 mg
Metrics
Css,max (ng/mL)
Mean	6.7	22.5	80.2
SD	1.31	3.94	18.58
Tss,max (hour)
Median	1.5	1.5	1.5
Minimum, maximum	1.00, 2.00	1.00, 2.00	1.5, 2.0
Css,min (ng/mL)
Mean	0.03	0.08	0.42
SD	0.01	0.03	0.30
AUCss,tau (h∙ng/mL)
Mean	32.7	113.8	473.0
SD	3.90	16.70	96.92
t1/2ss (hour)
Mean	3.2	4.4	4.5
SD	0.49	0.86	0.36
AR
Mean	1.2	1.1	1.2
SD	0.17	0.10	0.18

• AQS, aqueous suspension; AR, accumulation ratio; AUC_ss,tau, area under the plasma concentration-time curve during a dosing interval at steady state; C_ss,max, maximum plasma concentration at steady state; SD, standard deviation; t_1/2ss, terminal phase half-life at steady state; T_ss,max, time to maximum plasma concentration at steady state.

In Study 3 (crossover), 16 participants were included in the randomized safety population and full-analysis population. Plasma PK metrics after oral or sublingual administration of sunobinop 0.6-mg tablets are presented in Table 1 and Figure 3. Mean peak exposures (C_max) were similar and comparable across all 4 treatments. Likewise, mean total exposures (AUC_0-t and AUC_inf) were similar and comparable across all 4 treatments. Median T_max was 1.5 hours for both oral treatments and 2.0 hours for both sublingual treatments. Mean t_1/2 was similar and comparable across all 4 treatments. Mean time to the first measurable plasma concentration value (T_lag) for oral tablets was slightly less (0.03 hours for AM and 0.02 hours for PM) than for sublingual treatments (0.10 hours for AM and 0.09 hours for PM). The relative bioavailability (estimated with C_max and AUC_inf) of oral sunobinop was comparable in the AM administration and PM administration, with the 90% confidence interval (CI) within the range of 80%-125%. Comparable results in the relative bioavailability of sublingual sunobinop were also seen with the AM administration and the PM administration (90% CI, 80%-125%). The statistical analysis of the plasma PK metrics of sunobinop is presented in Table 4. Most of the unchanged sunobinop was excreted in urine during the first 0-8 hours across all 4 treatments. The fraction of the dose excreted unchanged in urine (Fe24 and Fe48) was similar across all 4 treatments, ranging from 124% to 132% (fractional recovery estimates greater than 100% may be due to variability/limit of detection effects compounded over collection epochs spanning a long time period and with a compound with a relatively short half-life).

Figure 3

Study 3 (crossover) mean plasma concentration versus time and rate of rise.

Table 4. Statistical Analysis of Sunobinop Pharmacokinetics (Study 3 [Crossover])

Study treatment	Treatment	N	Geometric LS means	Treatment comparison	Ratio of geometric LS means (test/reference)	90% CI of the ratio
Metrics
AUC0–t (h∙ng/mL)	O (AM)	16	34.6	O (AM)/O (PM)	101.46	97.46, 105.62
	O (PM)	15	34.1
	S (AM)	16	33.8	S (AM)/S (PM)	99.09	95.19, 103.16
	S (PM)	15	34.1
AUCinf (h∙ng/mL)	O (AM)	16	34.6	O (AM)/O (PM)	101.50	97.46, 105.70
	O (PM)	15	34.1
	S (AM)	15	33.9	S (AM)/S (PM)	99.27	95.24, 103.47
	S (PM)	15	34.1
Cmax (ng/mL)	O (AM)	16	8.2	O (AM)/O (PM)	109.69	101.09, 119.03
	O (PM)	15	7.5
	S (AM)	16	8.3	S (AM)/S (PM)	114.37	105.41, 124.11
	S (PM)	15	7.3

• AM, morning; AUC_inf, area under the plasma concentration-time curve from time 0 extrapolated to infinity; AUC_0-t, area under the plasma concentration-time curve from time 0 to the time of last quantifiable concentration; CI, confidence interval; C_max, maximum plasma concentration; LS, least squares; PM, evening.

Safety

TEAEs by MedDRA SOC, preferred term, and maximum severity reported for ≥2 participants in any treatment group are presented in Table S1. TEAEs related specifically to the CNS are reported in Table 5.

Table 5. Summary of CNS-Related TEAEs

	Study 1 (SAD)								Study 2 (MAD)								Study 3 (Crossover)
Study treatment	Placebo		Sunobinop						Placebo		Sunobinop						Sunobinop oral tablet 0.6 mg				Sunobinop sublingual tablet 0.6 mg
			AQS 3 mg		AQS 10 mg		AQS 30 mg				AQS 0.6 mg		AQS 2 mg		AQS 10 mg		AM		PM		AM		PM
	N = 6		N = 4		N = 4		N = 4		N = 9		N = 9		N = 9		N = 9		N = 16		N = 15		N = 16		N = 15
MedDRA System Organ Class
Preferred term	n	%	n	%	n	%	n	%	n	%	n	%	n	%	n	%	n	%	n	%	n	%	n	%
General disorders and administration site conditions
Fatigue	–	–	3	75	4	100	2	50	–	–	–	–	–	–	–	–	1	6	–	–	–	–	–	–
Nervous system disorders
Disturbance in attention	–	–	–	–	–	–	1	25	–	–	–	–	–	–	–	–	–	–	–	–	–	–	–	–
Dizziness	–	–	2	50	1	25	2	50	–	–	–	–	–	–	–	–	–	–	–	–	–	–	–	–
Headache	1	17	2	50	–	–	1	25	–	–	1	11	–	–	–	–	–	–	–	–	–	–	–	–
Somnolence	–	–	–	–	–	0	3	75	–	–	–	–	–	–	2	22	1	6	–	–	–	–	–	–
Presyncope	–	–	–	–	–	–	–	–	–	–	–	–	–	–	–	–	–	–	–	–	1	6	–	–
Psychiatric disorders
Insomnia	–	–	–	–	–	–	–	–	–	–	–	–	–	–	5	56	–	–	–	–	–	–	–	–
Euphoric mood	–	–	1	25	–	–	2	50	–	–	–	–	–	–	–	–	–	–	–	–	–	–	–	–

• AM, morning; AQS, aqueous suspension; CNS, central nervous system; MAD, multiple-ascending dose; MedDRA, Medical Dictionary for Regulatory Activities; PM, evening; SAD, single-ascending dose; TEAE, treatment-emergent adverse event.

In Study 1 (SAD), 13 participants (72.2%) reported ≥1 TEAE and all AEs resolved by the end of the study. The incidence of TEAEs was higher following sunobinop treatment compared with placebo. The most common TEAEs were fatigue, dizziness, headache, somnolence, and euphoric mood. Most of the TEAEs were of mild to moderate intensity. There was 1 severe sunobinop-related TEAE for somnolence, which occurred after administration of sunobinop 30 mg. There were no discontinuations due to AEs. Overall, 9 (50.0%) participants reported 18 AEs assessed as definitely related to treatment with sunobinop.

In Study 2 (MAD), 54 TEAEs were reported overall and 32 of 36 (89%) participants had ≥1 TEAE. All TEAEs resolved by the end of the study. With the exception of 1 moderate TEAE of presyncope, all reported TEAEs were mild in severity. Insomnia was the most frequent drug-related TEAE, reported by 5 of 36 (14%) participants overall; it was only reported after administration of sunobinop 10-mg aqueous suspension (5 of 9 [56%] participants). In total, 2 participants discontinued from the study: 1 participant discontinued due to a mild TEAE of ventricular tachycardia considered not related to sunobinop by the investigator and 1 participant discontinued due to administrative reasons.

In Study 3 (crossover), 11 TEAEs were reported overall and 4 of 16 (25%) participants had ≥1 TEAE. All TEAEs resolved by the end of the study. With the exception of 2 TEAEs of moderate severity (abdominal pain and hematochezia) reported for 1 (6%) participant, all reported TEAEs were mild in severity. In all, 1 participant discontinued from the study due to a moderate TEAE of hematochezia considered not related to sunobinop.

Although not reported as AEs, clinically notable findings were observed in 4 (22.2%) participants for vital signs measurements in Study 1 (SAD). One participant who received sunobinop 10 mg experienced a clinically notable systolic blood pressure decrease that was reported as a sunobinop-related hypotension. Clinically notable findings were observed in 9 (50.0%) participants for clinical laboratory results; none were reported as TEAEs. One participant had a >30 to ≤60 milliseconds increase in QTcF relative to mean at baseline, 1 participant had a PR-interval change from baseline that was >25% increased when PR was >200 milliseconds, and 1 participant had inverted T waves postdose. No significant changes were observed in clinical laboratory values, vital signs, SpO₂, or 12-lead ECG results. In Studies 2 (MAD) and 3 (crossover), no clinically significant changes were observed in clinical laboratory values, vital signs, or SpO₂ measurements. In Study 3 (crossover), 1 participant experienced ventricular tachycardia considered not related to sunobinop. There was no clinically significant change in C-SSRS. There was no evidence of drug-related crystalluria, hematuria, or other findings suggestive of clinically significant renal effects in any study. Overall, the administration of oral doses of sunobinop 0.6, 2, and 10 mg, and AM and PM doses of oral and sublingual sunobinop 0.6 mg were safe and well-tolerated in healthy participants. No deaths or serious AEs occurred in any study.

Discussion

These studies assessed the first-in-human safety, tolerability, and PK of sunobinop, a potent partial agonist at recombinant human NOP receptors that displays high selectivity for NOP versus mu, kappa, and delta receptors.¹⁰

A total of 70 randomly assigned participants were included in the 3 phase 1 studies. In Studies 2 (MAD) and 3 (crossover), systemic exposure (C_max, AUC_0-t, and AUC_inf) of sunobinop was dose proportional in the range of 0.6-2 mg. In Study 1 (SAD), less-than-proportional increases in systemic exposure following administration of sunobinop aqueous suspension occurred across the dose range studied (3, 10, and 30 mg). The quantity of unchanged parent sunobinop recovered from the urine suggests near complete gastrointestinal absorption of sunobinop following oral doses up to 3 mg. The nonlinearity in the PK of sunobinop at doses above 3 mg is likely due to exposure-limiting gastrointestinal absorption. It is hypothesized that sunobinop is absorbed primarily in the proximal gastrointestinal tract and that absorption in this region is saturated at doses of 10 mg and above. Dose linearity is evident up to 3 mg and target engagement is evident at 3 mg (presence of fatigue/somnolence), suggesting that the maximum practical dose of sunobinop is 10 mg. This nonlinearity may limit unintended high plasma exposures in the event of accidental or intentional oral overdose. The total renal clearance of sunobinop ranged from 270 to 278 mL/min over the oral dose range of 3-30 mg. These values exceeded typical CrCl values of approximately 58-120 mL/min/1.73 m² in healthy adults,¹³ suggesting the presence of active tubular secretion of sunobinop in addition to glomerular filtration.

Based on the results of Study 3 (crossover), the PK of sunobinop was comparable when the AM administration was compared with the PM administration for the oral and sublingual formulations.

Following single and multiple doses, maximum plasma concentrations (C_max and C_ss,max) were attained (T_max and T_ss,max) at a median of 1.5 hours after dosing for each dose level.

Plasma concentrations declined across all doses, with mean sunobinop half-lives (t_1/2 and t_1/2ss) ranging from 2.4 to 2.7 hours following a single dose of sunobinop in Study 1 (SAD) and 3.2-4.5 hours in Study 2 (MAD).

Consistent with observations from nonclinical studies showing minimal to no metabolism, the high bioavailability and recovery of unchanged sunobinop in the urine samples over 96 hours support the finding that sunobinop is minimally metabolized in humans.

Overall, results of the clinical studies showed a safety profile for sunobinop suitable for continued development. Most TEAEs were mild in severity, 1 was a severe TEAE, and all TEAEs resolved by the end of the studies. The most prominent AE noted during the AM and PM dosing studies was dose-dependent sedation/somnolence, which was more common at doses greater than 10 mg. Sunobinop was not associated with any significant changes in laboratory parameters, vital signs, SpO₂, or ECG results at any of the dose levels in the studies.

Limitations of the SAD, MAD, and crossover studies include the use of healthy participants and the small number of participants, which limit the generalizability of the study results.

NOP is involved in a number of biologic functions, making it an interesting pharmacological target with broad potential for therapeutic utility, including disorders of the genitourinary and nervous systems. Sunobinop, based on its clinical tolerability and safety profile, PK characteristics, and exclusive renal clearance, is being explored for multiple indications, including substance use disorders, IC/BPS, and OAB. Finally, evidence for reduced wakefulness and increased nonrapid eye movement sleep in animal models¹⁰ and the occurrence of somnolence reported in the current studies has led to the subsequent exploration of sunobinop for the treatment of sleep disorders.

Conclusions

The results of the PK analysis demonstrated that T_max for sunobinop is independent of dose. Systemic exposure was characterized by dose proportionality in the dose range of 0.6-2 mg and increased less than proportionally across the dose range of 3-30 mg. The majority of absorbed sunobinop was excreted unchanged in the urine within 8 hours of dosing, showing rapid elimination with no appreciable accumulation following 14 consecutive days of once-daily dosing and suggesting exclusive renal elimination without hepatic metabolism. Sunobinop was generally well-tolerated and safe across the range of doses tested in healthy participants. Overall, sunobinop presents a clinical profile suitable for continued clinical development.

Acknowledgments

Technical, editorial, and medical writing assistance were provided under the direction of the authors by Amplity Health.

Conflicts of Interest

R.K., M.Z., M.S., G.W., A.C., and S.H. were all employees of Imbrium Therapeutics at the time of the study.

Funding

Funding for this research was provided by Purdue Pharma L.P. and Shionogi & Co. Ltd. Funding for manuscript preparation was provided by Imbrium Therapeutics L.P., a subsidiary of Purdue Pharma L.P.