Preclinical and clinical evaluation of the NMDA modulator NYX-783 for OUD

阿片类药物使用障碍（OUD）和过量使用率的急剧增加需要进行测试 以及开发针对阿片类药物流行的新型治疗药物。本申请 提出了NMDA调节剂的分阶段临床前（UG 3）和临床（UH 3）评估 NYX-783用于治疗阿片类药物寻求和OUD复发。NYX-783，一种新颖的小 Aptinyx正在开发的分子，已在I期试验中显示出安全性/耐受性证据 目前正在进行创伤后应激障碍的第二阶段试验。动物数据 模型表明，在减少阿片寻求行为和拟议的UG 3 实验将在多个模型和剂量范围内更严格地评估这一点， 测试NYX-783与羟考酮联合使用的安全性。UH 3部分的进展情况 （人体试验）取决于安全性和有效性里程碑的成功完成 在UG 3部分，包括提交新的IND和/或修正案 Aptinyx现有IND用于OUD患者的UH 3试验。UH 3组件中的实验 将测试NYX-718在吗啡维持下的安全性、耐受性和药代动力学（PK）。 住院病人这将单独或与羟考酮联合完成 以确认不存在潜在的不良药物相互作用。这将是一个 合并住院（安全性/耐受性/PK）/门诊（初步疗效）研究检测 NYX-783对阿片类药物使用和复发，压力/线索反应，渴望和生活质量的影响 OUD受试者维持标准延长释放纳洛酮（NTX-XR，Vivitrol）超过100 mg。 10-周期间。UG 3和UH 3目标的成功完成将为 FDA最终要求的OUD疗效的更大规模II/III期研究 批准NYX-783用于治疗OUD的药物寻求和复发。

Dramatic increases in rates of opioid use disorder (OUD) and overdoses necessitate the testing and development of novel therapeutic agents to target the opioid epidemic. This application proposes phased preclinical (UG3) and clinical (UH3) assessments of the NMDA modulator NYX-783 for treatment of opioid drug-seeking and relapse to OUD. NYX-783, a novel small molecule being developed by Aptinyx, has shown evidence of safety/tolerability in Phase 1 studies and is currently in Phase 2 trials for Post-traumatic Stress Disorder. Data from animal models suggests efficacy in reducing opiate seeking behavior and the proposed UG3 experiments will evaluate this more rigorously over multiple models and dose-ranges while also testing the safety of NYX-783 in combination with oxycodone. Progress to the UH3 component (human testing) is contingent upon the successful completion of safety and efficacy milestones in the UG3 component, including either submission of a new IND and/or amendment of Aptinyx’s existing IND for UH3 testing in humans with OUD. Experiments in the UH3 component will test the safety, tolerability and pharmacokinetics (PK) of NYX-718 in morphine-maintained inpatient human subjects. This will be completed both alone and in combination with oxycodone to confirm the absence of potentially adverse drug-drug interactions. This will be followed by a combined inpatient (safety/tolerability/PK) / outpatient (preliminary efficacy) study testing NYX-783’s effects on opioid use and relapse, stress/cue reactivity, craving and quality of life in OUD subjects maintained on standard extended release naltrexone (NTX-XR, Vivitrol) over a 10-week period. Successful completion of the UG3 and UH3 aims will thus set the stage for larger scale Phase 2/3 studies of efficacy in OUD that will ultimately be required for FDA approval of NYX-783 for the treatment of drug-seeking and relapse in OUD.