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.

在此处输入文本，该文本是您的应用程序的新摘要信息。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首要任务。该提案的目标是进行必要的补充开发和药代动力学研究，以支持 AEF0117 的 3 期试验，AEF0117 是 Aelis Farma 专门为治疗 CUD 开发的一种新型药物。除了高度积极的临床前和一期安全数据外，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”），而不会产生身体不适或扰乱情绪或睡眠。 AEF0117 良好的药代动力学和安全性与临床前和人体实验室数据相结合，使该化合物成为治疗 CUD 的一种非常有前景的方法。在 CUD 患者中测试 AEF0117 的大规模临床试验之前，有必要在人类志愿者中进行与安全性和药代动力学研究并行的非临床毒理学研究：（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体剂量数倍的三剂剂量施用于动物。光毒性。大鼠每天将接受 3 次 AEF0117 的三剂量给药。最高剂量也将在没有紫外线照射的情况下施用。生殖毒性。 AEF0117 的毒性将在为期 7 天的最大耐受剂量研究中在非怀孕雌性兔子中以三种剂量进行测试。随后的剂量范围探索研究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：将进行两部分的单剂量平行组药代动力学研究，以研究 a) 食物对 AEF0117 口服生物利用度的影响和 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 小时禁食 (n=24) 和非禁食条件 (n=24) 的情况下在 14 天内评估 AEF0117（1 mg PO）的药代动力学。此外，将在 14 天内比较 3 组大麻吸烟者（n=15/组）的 AEF0117 和/或大麻的药代动力学，这些大麻吸烟者将接受（a）单独的 AEF0117（1 毫克），（b）AEF0117（1 毫克）和大麻（7.0％），（c）单独的大麻（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 CUD 治疗领域的领先学术研究人员结合起来。通过此次合作，我们将进行 FDA 要求的研究，为 AEF0117 的 3 期试验做好准备。该项目具有产生巨大影响的潜力，产生必要的结果，使 AEF0117 更接近 FDA 批准作为第一种治疗 CUD 的药物。