To the Editor: Insomnia is a common disorder and public health burden. Frequently prescribed hypnotics enhance γ-aminobutyric acid or block orexin signaling. With few pharmacological modalities and limitations associated with traditional targets, there is high interest in new mechanisms involved in sleep/wake regulation. The utility of the nociceptin/orphanin FQ receptor (NOP) system as a treatment for insomnia in humans has not been described. We utilized a potent and selective partial agonist that originated from our laboratories, sunobinop (1), to study the role of NOP in sleep/wake in rats and human patients; this is the first manuscript, to our knowledge, that describes the pharmacology of sunobinop.

We characterized the in vitro, ex vivo, and in vivo pharmacology and pharmacokinetics of sunobinop in cells stably overexpressing human NOP, rat brain sections, and rats. We utilized EEG to characterize sleep/wake and behavioral assays to characterize learning and memory, reward, respiration, and intestinal transit. We determined safety, tolerability, and pharmacokinetics in a cohort of 18 healthy male human subjects and assessed sleep using polysomnography in 22 patients with insomnia disorder (for detailed description of procedures, see Supplemental Methods; supplemental material available online with this article; https://doi.org/10.1172/JCI171172DS1).

Sunobinop is a potent partial agonist at human NOP receptors with high affinity (K_i of 3.3 ± 0.4 nm; EC₅₀ of 4.03 ± 0.86 nm, E_max of 47.8% ± 1.31%) (Supplemental Figure 1A). Sunobinop competitively inhibited [³H]-NOP-1A binding in rat-brain sections (IC₅₀ of 7.7 nM) and achieved an in vivo NOP receptor occupancy in the hypothalamus of 74.7% ± 11.3% at 30 mg/kg (Supplemental Figure 1, B and C). Importantly, sunobinop does not activate human μ and κ receptors and is a low-affinity, weak partial agonist at human δ receptors (Supplemental Figure 1A). After oral administration to rats (0.3–30 mg/kg), plasma concentration reached a maximum at 2.50–4.50 h with C_max and AUC_inf values that increased dose proportionally and bioavailability that ranged from 31.2% to 42.1%. (Figure 1A). Administration of 30 and 300 mg/kg of sunobinop induced obvious EEG changes in rats; wakefulness was significantly decreased (P < 0.01). Conversely, non–rapid eye movement (non-REM) sleep was significantly increased (P < 0.01). A non–dose-dependent effect on REM sleep was noted (significant at 30 but not 300 mg/kg) (Figure 1B). To confirm these effects were mediated via activation of NOP, 300 mg/kg of sunobinop was administered to NOP-KO rats and the EEG changes observed in WT were near abolished (Figure 1B and Supplemental Figure 2B). Zolpidem induced a short-lived significant increase in non-REM sleep, indicating an intact functional GABAergic system in the knockouts (Supplemental Figure 2C). No statistically significant treatment-related changes were noted in rat assays of learning and memory, reward, respiration, and intestinal transit (Figure 1, C and D, and Supplemental Figure 1, D and E) at doses substantially above those required for a therapeutic effect.

Sunobinop pharmacokinetics in rat and human, lack of reward and lack of effect on learning and memory in rats, and effects on sleep parameters in rats and human patients. (A) Pharmacokinetic profile in rats after oral dosing. (B) Effect on sleep stages as measured by EEG in WT and NOP-KO rats. (C and D) Effect on learning and memory and reward in rats as measured by Morris water maze and conditioned place preference. (E) Pharmacokinetic profile in healthy male human subjects after oral dosing. (F–H) Polysomnography results in patients with insomnia disorder: (F) sleep parameters, subjective sleep quality (sSQ) (G), and sleep architecture (H). NAW, number of awakenings. Data are represented as means ± SEM (A–C and H), means ± SD (E), and median ± interquartile range (D, F, and G), with dotted lines (D) and error bars (F and G) showing 10th to 90th percentiles, outliers shown, and plus signs indicating the mean (F and G). Data points in H represent raw data. *P ≤ 0.05, ANOVA (D); t test (all others).

In healthy male human subjects, sunobinop exhibited rapid absorption after oral administration across a wide dose range (3–30 mg) and a half-life of 2.1–3.2 h, suggesting suitability for once-daily dosing at nighttime with low concentrations present the following morning. Beyond 10 mg, systemic exposure increased less than dose proportionally (Figure 1E), with a lower percentage of unchanged drug recovered in urine (70% at 10 mg; 28% at 30 mg; 89% at 3 mg) and no detectable levels of metabolites identified in plasma or urine, suggesting dose-limiting absorption and a predominantly renal route of excretion of absorbed drug.

In patients with insomnia disorder, sleep efficiency (SE), the primary end point, was significantly higher after dosing with sunobinop (10 mg) than after placebo (91.4% versus 79.8%, respectively). The drug-effect difference between sunobinop and placebo was 11.8% (P < 0.0001). Sunobinop also produced a reduction in latency to persistent sleep (LPS) (P = 0.0136), less wake after sleep onset (WASO) (P < 0.0003), and fewer nighttime awakenings (P < 0.0001). Sleep-stage analysis revealed little-to-no change in the placebo-treated subjects, while sunobinop-treated subjects had less stage N1 sleep, more stage N2 sleep, a reduced REM period, and no significant change in stage N3 sleep or REM latency (Figure 1, F and H). Sunobinop also increased perceived sleep quality (P = 0.002) (Figure 1G).

Sunobinop was generally well tolerated in healthy subjects and patients (Supplemental Table 1, A and B). There were no deaths, serious adverse events (SAEs), or discontinuations due to adverse events (AEs). The most commonly reported treatment-emergent events were fatigue/somnolence (following 10 and 30 mg, 1 of 4 subjects experienced somnolence sufficient to interfere with activities of daily living), euphoria, and dizziness in healthy subjects and somnolence/sedation in patients. Sunobinop did not produce clinically relevant changes in hematology, chemistry, and urinalysis results, and no meaningful changes from baseline were observed in ECGs and SpO₂.

We conclude that a 10 mg oral dose of sunobinop has a large positive effect on sleep/wake function in subjects with insomnia, thus providing a more consolidated, quality sleep. However, observations of next-day residual effects, as supported by the frequency of reported somnolence AEs, indicate that dose-ranging studies are needed to define the optimal effective dose (for additional details on findings, see Supplemental Results). Our translational research demonstrates that activation of NOP represents an additional mechanism and an attractive treatment approach for insomnia disorder in humans. Sunobinop’s profile is suitable for continued clinical development, and several additional clinical studies have been initiated, including a phase 2 trial in patients suffering from insomnia during recovery from alcohol use disorder (ClinicalTrials.gov NCT04035200) (2).

Supplemental material

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Footnotes

Authorship note: SKW is deceased.

Conflict of interest: GTW, AC, EH, MSS, and SCH are employees of Imbrium Therapeutics. KF, YM, MU, SH, and NT are employees of Shionogi & Co Ltd. Sunobinop is under development by Imbrium Therapeutics. GTW, DJK, RPK, and SCH are coinventors on related patents (US-11576913-B2, 2023-02-14; US-10974081-B2, 2021-04-13; US-20200345726-A1, 2020-11-05; US-20190282836-A1, 2019-09-19).

Copyright: © 2024, Wang et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Submitted: April 4, 2023; Accepted: October 23, 2023; Published: January 2, 2024.

Reference information: J Clin Invest. 2024;134(1):e171172.

References

1. National Center for Biotechnology Information. PubChem Compound Summary for CID 155801560, Sunobinop. https://pubchem.ncbi.nlm.nih.gov/compound/Unii-I1X86U5474 Accessed November 8, 2023.
2. Sessler N, et al. Results From a Phase 2, Randomized, Double-Blind, Multi-Center, Placebo-Controlled, Parallel-Group Study of Sunobinop in Subjects who are Experiencing Insomnia During Recovery From Alcohol Use Disorder. Paper presented at: the 85th Annual Scientific Meeting for The College on Problems of Drug Dependence; June 17–21, 2023; Denver, Colorado, USA. Accessed December 11, 2023. View this article via: PubMedGoogle Scholar

致编辑：失眠是一种常见疾病和公共卫生负担。经常开的安眠药会增强 γ-氨基丁酸或阻断食欲素信号传导。由于与传统靶标相关的药理学方式和局限性很少，因此人们对涉及睡眠/觉醒调节的新机制非常感兴趣。伤害感受肽/孤啡肽 FQ 受体 (NOP) 系统作为治疗人类失眠的用途尚未被描述。我们利用源自我们实验室的强效选择性部分激动剂 sunobinop ( 1 ) 来研究 NOP 在大鼠和人类患者睡眠/觉醒中的作用；据我们所知，这是第一份描述 Sunobinop 药理学的手稿。

我们在稳定过表达人 NOP 的细胞、大鼠脑切片和大鼠中表征了 sunobinop 的体外、离体和体内药理学和药代动力学。我们利用脑电图来表征睡眠/觉醒和行为分析来表征学习和记忆、奖励、呼吸和肠道转运。我们确定了 18 名健康男性受试者的安全性、耐受性和药代动力学，并使用多导睡眠图评估了 22 名失眠症患者的睡眠（有关程序的详细说明，请参阅补充方法；补充材料可与本文一起在线获取；https：/ /doi.org/10.1172/JCI171172DS1）。

Sunobinop 是人类 NOP 受体的有效部分激动剂，具有高亲和力（K _i为 3.3 ± 0.4 nm；EC ₅₀为 4.03 ± 0.86 nm，E _max为 47.8% ± 1.31%）（补充图 1A）。Sunobinop 竞争性抑制大鼠脑切片中的[ ^{3 H]-NOP-1A 结合（IC} ₅₀为 7.7 nM），并在 30 mg/kg 剂量下实现下丘脑体内 NOP 受体占有率 74.7% ± 11.3%（补充图 1） 、B 和 C)。重要的是，sunobinop 不会激活人类 μ 和 κ 受体，并且是人类 δ 受体的低亲和力、弱部分激动剂（补充图 1A）。大鼠口服给药（0.3-30 mg/kg）后，血浆浓度在 2.50-4.50 h 达到最大值，C _max和 AUC _inf值随剂量成比例增加，生物利用度范围为 31.2% 至 42.1%。（图1A）。给予30和300 mg/kg的sunobinop可引起大鼠明显的脑电图变化；觉醒度显着降低（P <0.01）。相反，非快速眼动 (non-REM) 睡眠显着增加 ( P < 0.01)。注意到对快速眼动睡眠的非剂量依赖性影响（30 mg/kg 时显着，但 300 mg/kg 时不显着）（图 1B）。为了确认这些效应是通过 NOP 激活介导的，对 NOP-KO 大鼠施用 300 mg/kg Sunobinop，并且在 WT 中观察到的脑电图变化几乎消失（图 1B 和补充图 2B）。唑吡坦诱导非快速眼动睡眠的短暂显着增加，表明基因敲除中具有完整的功能性 GABA 能系统（补充图 2C）。在大大高于治疗所需剂量的大鼠学习和记忆、奖赏、呼吸和肠道转运测定中，未发现统计学上显着的治疗相关变化（图 1、C 和 D，以及补充图 1、D 和 E）影响。

Sunobinop 在大鼠和人类中的药代动力学、奖励缺乏和对大鼠学习和记忆缺乏影响，以及对大鼠和人类患者睡眠参数的影响。( A ) 口服给药后大鼠的药代动力学特征。( B ) 通过脑电图测量 WT 和 NOP-KO 大鼠对睡眠阶段的影响。（C和D）通过莫里斯水迷宫和条件位置偏好测量对大鼠学习、记忆和奖励的影响。( E ) 健康男性受试者口服给药后的药代动力学特征。( F – H ) 失眠障碍患者的多导睡眠图结果：( F ) 睡眠参数、主观睡眠质量 (sSQ) ( G ) 和睡眠结构 ( H )。NAW，觉醒次数。数据表示为平均值±SEM（A – C和H）、平均值±SD（E）和中位数±四分位数范围（D、F和G），并带有虚线（D）和误差线（F和G）显示第 10 到 90 个百分位数、显示异常值以及表示平均值的加号（F和G）。H中的数据点代表原始数据。* P ≤ 0.05，方差分析（D）；t检验（所有其他）。

在健康男性受试者中，Sunobinop 在较宽的剂量范围（3-30 mg）内口服后表现出快速吸收，半衰期为 2.1-3.2 小时，表明适合在夜间每日一次低浓度给药，如下所示早晨。超过 10 mg 时，全身暴露量按比例增加小于剂量（图 1E），尿中回收的原形药物百分比较低（10 mg 时为 70%；30 mg 时为 28%；3 mg 时为 89%），并且未检测到在血浆或尿液中鉴定出代谢物，表明剂量限制性吸收和吸收药物主要通过肾脏排泄途径。

在失眠症患者中，服用 sunobinop (10 mg) 后的主要终点睡眠效率 (SE) 显着高于安慰剂组（分别为 91.4% 和 79.8%）。Sunobinop 和安慰剂之间的药效差异为 11.8% ( P < 0.0001)。Sunobinop 还可以减少持续睡眠潜伏期 (LPS) ( P = 0.0136)、减少入睡后觉醒 (WASO) ( P < 0.0003) 和减少夜间觉醒 ( P < 0.0001)。睡眠阶段分析显示，接受安慰剂治疗的受试者几乎没有变化，而接受 Sunobinop 治疗的受试者的 N1 阶段睡眠较少，N2 阶段睡眠较多，REM 期缩短，N3 阶段睡眠或 REM 潜伏期没有显着变化（图 1，F 和 H）。Sunobinop 还提高了感知睡眠质量（P = 0.002）（图 1G）。

Sunobinop 在健康受试者和患者中通常具有良好的耐受性（补充表 1、A 和 B）。没有死亡、严重不良事件 (SAE) 或因不良事件 (AE) 导致的停药。最常见的治疗突发事件是疲劳/嗜睡（服用 10 和 30 mg 后，4 名受试者中的 1 名出现足以干扰日常生活活动的嗜睡）、健康受试者的欣快感和头晕以及患者的嗜睡/镇静。Sunobinop 没有在血液学、化学和尿液分析结果中产生临床相关的变化，并且在心电图和 SpO ₂中没有观察到相对于基线的有意义的变化。

我们得出的结论是，口服 10 毫克 Sunobinop 剂量对失眠受试者的睡眠/觉醒功能具有很大的积极影响，从而提供更巩固、更优质的睡眠。然而，对第二天残留效应的观察，以及报告的嗜睡 AE 频率的支持，表明需要进行剂量范围研究来确定最佳有效剂量（有关研究结果的更多详细信息，请参阅补充结果）。我们的转化研究表明，NOP 的激活代表了人类失眠症的一种额外机制和一种有吸引力的治疗方法。Sunobinop 的概况适合持续的临床开发，并且已经启动了几项额外的临床研究，包括一项针对酒精使用障碍恢复期间失眠患者的 2 期试验 (ClinicalTrials.gov NCT04035200) ( 2 )。

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脚注

作者注： SKW 已去世。

利益冲突： GTW、AC、EH、MSS 和 SCH 是 Imbrium Therapeutics 的员工。KF、YM、MU、SH 和 NT 是 Shionogi & Co Ltd 的员工。Sunobinop 正在由 Imbrium Therapeutics 开发。GTW、DJK、RPK 和 SCH 是相关专利的共同发明人 (US-11576913-B2, 2023-02-14; US-10974081-B2, 2021-04-13; US-20200345726-A1, 2020-11-05; US-20200345726-A1, 2020-11-05; US-20190282836-A1，2019-09-19）。

版权所有： © 2024，王等人。这是一篇根据 Creative Commons Attribution 4.0 International License 条款发布的开放获取文章。

提交时间： 2023 年 4 月 4 日；接受时间： 2023年10月23日；发布日期： 2024 年 1 月 2 日。

参考信息：J Clin Invest。2024；134(1)：e171172。

参考

1. 国家生物技术信息中心。PubChem 化合物摘要，CID 155801560，Sunobinop。https://pubchem.ncbi.nlm.nih.gov/compound/Unii-I1X86U5474 访问日期：2023 年 11 月 8 日。
2. 塞斯勒 N 等人。Sunobinop 的 2 期、随机、双盲、多中心、安慰剂对照、平行组研究结果，受试者为酒精使用障碍恢复期间出现失眠的受试者。论文发表于：第 85 届学院药物依赖问题科学年会；2023 年 6 月 17 日至 21 日；美国科罗拉多州丹佛市。访问日期：2023 年 12 月 11 日。通过以下方式查看本文：PubMedGoogle Scholar