Background

The delta opioid receptor (DOR) has been identified as a therapeutic target for migraine, with DOR agonists exhibiting low abuse potential compared with conventional µ-opioid agonists. TRV250 is a novel small molecule agonist of the DOR that is preferentially selective for G-protein signaling, with relatively little activation of the β-arrestin2 post-receptor signaling pathway. This selectivity provides reduced susceptibility to proconvulsant activity seen with non-selective DOR agonists. TRV250 significantly reduced nitroglycerin-evoked hyperalgesia in rodents, indicating a potential utility in acute migraine without the risk of seizure activity or abuse potential.

Objective

This trial evaluated the safety, tolerability, and pharmacokinetics of ascending dose levels of TRV250 administered subcutaneously (SC) and the relative bioavailability of TRV250 administered orally compared with SC administration.

Methods

This was a two-part, single ascending dose study. Part A included four cohorts of healthy adults (N = 38). Each cohort was dosed on three occasions (placebo and two different dose levels of TRV250, allocated in randomized order and administered by SC route). In Part B, a single cohort of nine subjects received an oral dose of either TRV250 (n = 7) or placebo (n = 2) in a fed or fasted state. Serial blood samples were obtained for pharmacokinetic determination across a 24-h post-dose period. Safety assessments included clinical laboratory measures, vital signs, 12-lead electrocardiogram (ECG), and electroencephalogram (EEG) pre- and post-dosing.

Results

TRV250 was well tolerated. There were no serious adverse events (SAEs), and all AEs were mild in severity. Injection-site reactions and headache were the most common AEs. One subject was withdrawn from the study due to a TRV250-related AE of postural orthostatic tachycardia. There were no clinically relevant changes in physical examination, hematology, clinical chemistry, urinalysis, suicidal ideation, or vital signs, with the exception of orthostatic changes in some subjects. No subject experienced abnormalities in EEGs or experienced a change from baseline in heart-rate-corrected QT interval (QTcF) > 60 ms, or an absolute QTcF interval > 480 ms at any post-dosing observation. Peak and total plasma exposure to TRV250 increased in a dose-proportional manner following 0.1–30 mg SC doses, with the mean half-life ranging from 2.39 to 3.76 h. Oral bioavailability of TRV250 ranged from 14% (fasting) to 19% (fed) relative to SC dosing, while administration with food increased the AUC but decreased the rate of absorption as reflected by a modest delay in median time to maximum concentration and a slight reduction in maximum concentration.

Conclusion

The findings from the first-in-human study support further evaluation of TRV250, a G-protein selective DOR agonist, in the treatment of acute migraine.

中文翻译：

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在健康受试者中对皮下和口服 TRV250（一种 G 蛋白选择性 Delta 受体激动剂）的安全性、耐受性和药代动力学进行的 I 期随机、单盲、安慰剂对照、单剂量递增研究。

背景

δ 阿片受体 (DOR) 已被确定为偏头痛的治疗靶点，与传统的 µ-阿片受体激动剂相比，DOR 激动剂的滥用可能性较低。TRV250 是一种新型 DOR 小分子激动剂，对 G 蛋白信号传导具有优先选择性，β-arrestin2 受体后信号传导途径的激活相对较少。这种选择性降低了对非选择性 DOR 激动剂所见的促惊厥活性的敏感性。TRV250 显着降低了啮齿动物中硝酸甘油诱发的痛觉过敏，表明其在急性偏头痛中具有潜在效用，而没有癫痫发作或滥用的风险。

目标

该试验评估了皮下 (SC) 给药的 TRV250 递增剂量水平的安全性、耐受性和药代动力学，以及与 SC 给药相比，口服给药的 TRV250 的相对生物利用度。

方法

这是一项由两部分组成的单次递增剂量研究。A 部分包括四组健康成人（N  = 38）。每个队列在三个场合给药（安慰剂和两个不同剂量水平的 TRV250，按随机顺序分配并通过 SC 途径给药）。在 B 部分，一组 9 名受试者 在进食或禁食状态下接受口服剂量的 TRV250（n  = 7）或安慰剂（n = 2）。获得连续血样用于整个给药后 24 小时期间的药代动力学测定。安全性评估包括给药前后的临床实验室测量、生命体征、12 导联心电图 (ECG) 和脑电图 (EEG)。

结果

TRV250 耐受性良好。没有严重的不良事件 (SAE)，所有 AE 的严重程度都是轻微的。注射部位反应和头痛是最常见的 AE。由于姿势性直立性心动过速的 TRV250 相关 AE，一名受试者退出研究。除了一些受试者的直立性变化外，体格检查、血液学、临床化学、尿液分析、自杀意念或生命体征没有临床相关的变化。在任何给药后观察中，没有受试者出现 EEG 异常或心率校正 QT 间期 (QTcF) > 60 ms 或绝对 QTcF 间期 > 480 ms 从基线变化。在 0.1–30 mg SC 剂量后，TRV250 的峰值和总血浆暴露以剂量成比例的方式增加，平均半衰期为 2.39 到 3.76 小时。

结论

首次人体研究的结果支持对 TRV250（一种 G 蛋白选择性 DOR 激动剂）治疗急性偏头痛的进一步评估。