The CB1 Signaling-Specific Inhibitor, AEF0117, for Cannabis Use Disorder: A Multi-Site Treatment Trial

CB1 信号传导特异性抑制剂 AEF0117，用于治疗大麻使用障碍：多部位治疗试验

• 批准号: 10249716
• 负责人: Frances Rudnick Levin
• 金额: $ 159.44万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10249716
• 关键词: Adverse event; Agonist; Animals; Anxiety; Behavior; Behavioral; Binding; Biological Availability; CNR1 gene; Canis familiaris; Cannabinoids; Cannabis; Characteristics; Clinical Research; Clinical Trials; Collaborations; Cyclic AMP; Data; Development; Dose; Double-Blind Method; Drug Kinetics; Evaluation; Fasting; Female; Food; Funding; GTP-Binding Proteins; Goals; Guidelines; Hour; Human; Human Volunteers; Laboratories; Laboratory Study; MAP Kinase Gene; Maximum Tolerated Dose; Mediating; Mental Depression; Moods; National Institute of Drug Abuse; Oral; Oral Administration; Oryctolagus cuniculus; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Phototoxicity; Physiological; Placebos; Public Health; Randomized; Rattus; Relapse; Research; Research Personnel; Rodent; Safety; Self Administration; Signal Pathway; Signal Transduction; Sleep; Smoke; Testing; Text; Therapeutic Index; Toxic effect; United States; base; design; drug candidate; drug development; drug production; efficacy evaluation; genotoxicity; healthy volunteer; immunotoxicity; in vivo; inhibitor/antagonist; marijuana smoker; marijuana use; marijuana use disorder; novel; phase I trial; phase III trial; pre-clinical; preclinical study; pregnant; process optimization; public health priorities; reproductive toxicity; response; treatment site; treatment trial; volunteer

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Project Summary: Cannabis use disorder (CUD) is a significant and escalating problem in the United States, and the development of an efficacious medication is a public health priority. The goal of this proposal is to conduct the complementary development and pharmacokinetic studies necessary to support Phase 3 trials of AEF0117, a novel medication developed by Aelis Farma specifically for the treatment of CUD. In addition to highly positive preclinical and Phase 1 safety data, a recent human laboratory study showed that AEF0117 decreased cannabis self-administration and its abuse-related effects (‘good drug effect’) in daily cannabis smokers without producing physical discomfort or disrupting mood or sleep. AEF0117’s favorable pharmacokinetic and safety profile combined with the preclinical and human laboratory data make this compound a highly promising approach for the treatment of CUD. Prior to large-scale clinical trials to test AEF0117 in patients with CUD, it is necessary to conduct non-clinical toxicology studies in parallel with safety and pharmacokinetic studies in human volunteers: (1) Non-Clinical AEF0117 Development (following FDA and ICH guidelines): Toxicity. We will conduct a 6-month rodent (rats) and 9-month non-rodent (dogs) oral toxicity studies including immunotoxicity evaluation. The drug will be administered to animals at three doses that are multiples in excess of the anticipated human dose. Phototoxicity. Rats will receive three daily administrations of AEF0117 at three doses. The highest dose will also be administered without UVR exposure. Reproductive toxicity. The toxicity of AEF0117 will be tested at three doses in non-pregnant female rabbits during a 7-day maximum-tolerated dose study. A subsequent dose range-finding study will test three doses of AEF0117 in pregnant rats and rabbits, and embryo-fetal development will be tested in an additional set of pregnant females rats and rabbits. Clinical Studies: A single dose parallel group pharmacokinetic study in two parts will be conducted to investigate a) the effect of food on oral bioavailability of AEF0117 and 2) a potential pharmacokinetic interaction between smoked cannabis and oral administration of AEF0117. Specifically, the pharmacokinetics of AEF0117 (1 mg PO) will be assessed over 14 days under 10-hour fasting (n=24) and non-fasting conditions (n= 24). In addition, the pharmacokinetics of AEF0117 and/or cannabis will be compared over 14 days across 3 groups of cannabis smokers (n=15/group) who will receive either (a) AEF0117 (1 mg) alone, (b) AEF0117 (1 mg) and cannabis (7.0%), (c) cannabis (7.0%) alone. To conclude, a substantial strength of this proposal is in pairing Aelis Farma, a company dedicated to the development of a treatment for CUD, with leading academic investigators in the field of CUD treatment. With this partnership, we will conduct FDA-required studies to ready AEF0117 for Phase 3 trials. This project has the potential for high impact, yielding the necessary results to advance AEF0117 closer to FDA approval as the first medication to treat CUD.

在此输入您的申请的新摘要信息的文本。此部分的文本长度不得超过 30 行。 项目摘要：大麻使用障碍 (CUD) 在美国是一个严重且不断升级的问题，开发有效的药物是公共卫生的优先事项。该提案的目标是进行支持所需的补充开发和药代动力学研究。 AEF0117 是 Aelis Farma 开发的一种专门用于治疗 CUD 的新型药物，其 3 期试验除了高度积极的临床前和 1 期安全性数据外，最近的一项人体实验室研究表明： AEF0117 减少了日常吸食大麻者的大麻自我给药及其滥用相关效应（“良好的药物效应”），且不会产生身体不适或扰乱情绪或睡眠。在 CUD 患者中测试 AEF0117 的大规模临床试验之前，有必要同时进行非临床毒理学研究。在人类志愿者中的安全性和药代动力学研究： (1) 非临床 AEF0117 开发（遵循 FDA 和 ICH 指南）：毒性 我们将进行为期 6 个月的啮齿动物（大鼠）和 9 个月的非啮齿动物（狗）口服毒性研究。包括免疫毒性评估。该药物将以超过预期人类剂量的三倍剂量给予动物，大鼠将接受每日三剂 AEF0117 给药。最高剂量也将在没有 UVR 暴露的情况下进行，在随后的剂量范围探索研究中，将在非怀孕雌性兔子中测试三种剂量的 AEF0117 的毒性。将在怀孕大鼠和兔子中测试三种剂量的 AEF0117，并将在另一组怀孕雌性大鼠和兔子中测试胚胎-胎儿发育。 临床研究：将分两部分进行单剂量平行组药代动力学研究。进行研究 a) 食物对 AEF0117 口服生物利用度的影响，以及 2) 吸食大麻和 AEF0117 口服给药之间潜在的药代动力学相互作用 具体而言，将在 10 天内评估 AEF0117（1 mg PO）的药代动力学。空腹 (n=24) 小时和非空腹条件 (n=24) 此外，AEF0117 和/或的药代动力学。将在 14 天内对 3 组大麻吸烟者（n=15/组）进行比较，这些吸烟者将接受 (a) 仅 AEF0117（1 毫克），(b) AEF0117（1 毫克）和大麻（7.0%），（ c) 仅大麻（7.0%） 总而言之，该提案的一大优势在于将 Aelis Farma（一家致力于开发 CUD 治疗方法的公司）与该领域的领先学术研究人员结合起来。通过此次合作，我们将开展 FDA 要求的研究，为 AEF0117 进行 3 期试验做好准备。该项目具有巨大影响力，能够产生必要的结果，使 AEF0117 更接近 FDA 批准为治疗 CUD 的药物。