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

NMDA 调节剂 NYX-783 用于 OUD 的临床前和临床评价

基本信息

批准号：
9905187
负责人：
RALPH J DILEONE
金额：
$ 218.21万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9905187
关键词：
Abstinence Address Affect Amendment Analgesics Animal Model Animals Award Behavior Buprenorphine Cessation of life Clinical Clinical Trials Cues Data Development Disease Dose Drug Interactions Drug Kinetics Drug Prescriptions Drug abuse Fentanyl Glutamates Human Inpatients Intake Learning Maintenance Medical Methadone Modeling Moods Morphine N-Methyl-D-Aspartate Receptors N-Methylaspartate Naltrexone National Institute of Drug Abuse Neurotransmitters Opiate Addiction Opioid Oral Outcome Outpatients Overdose Oxycodone Pathway interactions Patients Pharmaceutical Preparations Phase Phase II Clinical Trials Placebos Post-Traumatic Stress Disorders Preclinical Testing Prevention strategy Public Health Quality of life Recurrence Refractory Relapse Research Personnel Rodent Model Role Safety Sleep Stress Synaptic plasticity Testing Therapeutic Agents Universities Ventilatory Depression Withdrawal Work addiction analog animal data cognitive control craving cue reactivity disorder later incidence prevention drug candidate drug of abuse efficacy study experimental study heroin use human data human subject memory process novel novel therapeutic intervention novel therapeutics opioid epidemic opioid mortality opioid use opioid use disorder opioid withdrawal overdose death phase 1 study pre-clinical preclinical evaluation prescription opioid public-private partnership research clinical testing safety study safety testing small molecule stress reactivity therapeutic target treatment strategy

项目摘要

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.

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流行病的新型治疗剂。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。