Non-Metabolized Pregnenolone Derivatives:New Treatment for Cannabis Use Disorder

非代谢孕烯醇酮衍生物：大麻使用障碍的新治疗方法

• 批准号: 9337422
• 负责人: MARGARET HANEY
• 金额: $ 142.79万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9337422
• 关键词: Abstinence; Acute; Advanced Development; Adverse effects; Agonist; Alcohol or Other Drugs use; Attenuated; Award; Behavior; Behavioral; Behavioral Model; Binding; Biological Availability; Biotechnology; CNR1 gene; Cannabis; Cardiovascular system; Clinical; Clinical Research; Collaborations; Development; Diagnosis; Dose; Drug Industry; Drug Kinetics; Eating; Endocannabinoids; FDA approved; Female; Funding; Funding Mechanisms; Goals; Half-Life; Hormones; Human; Investments; MAPK3 gene; Medical Marijuana; Memory impairment; Moods; Neurobiology; Oral; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Preclinical Testing; Pregnenolone; Program Development; Public Health; Randomized; Research; Research Personnel; Resources; Rodent; Safety; Self Administration; Series; Signal Transduction; Site; Sleep; Smoker; Steroids; Task Performances; Testing; Tetrahydrocannabinol; Translating; Withdrawal; base; cannabinoid receptor; cognitive task; drug development; experience; healthy volunteer; improved; inhibitor/antagonist; innovation; male; marijuana legalization; marijuana use; marijuana use disorder; novel; phase I trial; phase II trial; pre-clinical; preclinical development; preclinical study; programs; public health priorities; public health relevance; receptor; research clinical testing; screening; steroid hormone; success; volunteer

 DESCRIPTION (provided by applicant): Efficacious treatments for cannabis use disorder (CUD) are critically needed yet there are currently no advanced development programs in the pharmaceutical industry focusing on cannabis treatment. This Strategic Alliance aims to develop a first-in-class medication ready for Phase II clinical testing for CUD, based on our recent discovery that pregnenolone (PREG) is an allosteric, signaling-specific, inhibitor of the type-1 cannabinoid receptor (CB1). CB1 agonists like Δ9-tetrahydrocannabinol (THC) bind to the CB1 receptor activating a series of intracellular cascades. PREG, by binding to a distinct site on the CB1 receptor, selectively attenuates one of these intracellular effects (ERK1/2 activation), and in doing so, markedly reduces the somatic and behavioral effects of THC, including its self-administration. However, PREG is a poor medication (short half-life, poor bioavailability and conversion to downstream active steroids). We have developed a non-metabolized PREG derivative, AEF0117, that has a long half-life, is orally available, not converted into downstream active steroids, and that potently attenuates all of THC's effects in preclinical behavioral models (self-administration, food intake, memory impairment, tetrad effects). Importantly, AEF0117 produced none of the problems associated with orthosteric antagonists: precipitated withdrawal and mood-related side effects. The preclinical development of AEF0117 is almost complete and the IND for Phase I trials will be obtained shortly. Our objective is to leverage the significant financial investment of Aelis Farma to date to establish AEF0117 as a first-in-class treatment for CUD. The proposal has three components: A. Phase la trial: Tolerability and pharmacokinetics of escalating single and multiple oral doses of AEF0117 in healthy volunteers. B. Phase lb trial: Safety of AEF0117 (4 doses) in daily cannabis smokers, including assessment of precipitated withdrawal and effects on cannabis' positive subjective effects, food intake, sleep, cardiovascular effects, and cognitive task performance. C. Preclinical testing prior to Phase II: Complementary ADMET characterization of AEF0117 to ready the compound for a Phase II randomized clinical study. AEF0117 has been exceedingly safe in all preclinical studies, so we are confident that it will be successfully translated to human use. Yet there are clear entry and exit points along the development pathway, including contingencies if AEF0117 fails in Phase I testing. Given that the PI (Haney) has led the field in developing paradigms to screen candidate medications for CUD, her collaboration with a highly innovative preclinical investigator with experience in drug development (Piazza, INSERM), a biotech company (Aelis Farma, co-founded by Piazza) with substantial investment in AEF0117 development, as well as well-regarded regulatory consultants (Ready Clinical) has a high likelihood of success. We predict that this Strategic Alliance will allow us to rapidly advance and improve treatment for what will only be escalating rates of CUD, and will therefore have a high potential for immediate and far-reaching public health impact.

 描述（由申请人提供）：大麻使用障碍（CUD）的有效治疗是迫切需要的，但目前制药行业还没有专注于大麻治疗的先进开发计划。该战略联盟旨在开发一种一流的药物，为CUD的II期临床试验做好准备，基于我们最近的发现，即双烯醇酮（PREG）是1型大麻素受体（CB 1）的变构，信号特异性抑制剂。CB 1激动剂如Δ9-四氢大麻酚（THC）与CB 1受体结合，激活一系列细胞内级联反应。PREG通过与CB 1受体上的不同位点结合，选择性地减弱这些细胞内效应之一（ERK 1/2激活），并且在这样做时，显著降低THC的躯体和行为效应，包括其自身给药。然而，PREG是一种差的药物（半衰期短，生物利用度差，转化为下游活性类固醇）。我们已经开发了一种非代谢的PREG衍生物，AEF 0117，具有长半衰期，可口服，不转化为下游活性类固醇，并且在临床前行为模型中有效减弱THC的所有影响 （自我给药、食物摄入、记忆障碍、四分体效应）。重要的是，AEF 0117没有产生与正构拮抗剂相关的问题：沉淀戒断和情绪相关的副作用。AEF 0117的临床前开发已接近完成，I期临床试验的IND将很快获得。我们的目标是利用Aelis Farma迄今为止的重大财务投资，将AEF 0117确立为CUD的一流治疗药物。该提案有三个组成部分：A。la期试验：健康志愿者单次和多次口服剂量递增的AEF 0117的耐受性和药代动力学。B。Ib期试验：AEF 0117（4次剂量）在每日大麻吸烟者中的安全性，包括评估突然戒断和对大麻积极主观效应、食物摄入、睡眠、心血管效应和认知任务表现的影响。C. II期之前的临床前试验：AEF 0117的补充ADMET表征，为II期随机临床研究准备化合物。AEF 0117在所有临床前研究中都非常安全，因此我们相信它将成功地转化为人类使用。然而，在开发过程中有明确的入口和出口点，包括如果AEF 0117在第一阶段测试中失败的意外情况。鉴于PI（Haney）在开发用于筛选CUD候选药物的范例方面处于领先地位，她与具有药物开发经验的高度创新的临床前研究者（Piazza，CIMM），一家在AEF 0117开发方面有大量投资的生物技术公司（Aelis Farma，由Piazza共同创立）以及备受尊敬的监管顾问（Ready Clinical）合作成功的可能性很高。我们预计，这一战略联盟将使我们能够迅速推进和改善治疗，因为CUD的发病率只会不断上升，因此将对公共卫生产生直接和深远的影响。