Advancement of AEF0117 as a potential treatment for Cannabis Use Disorder: Preclinical toxicity and Clinical pharmacokinetic studies

AEF0117 作为大麻使用障碍潜在治疗方法的进展：临床前毒性和临床药代动力学研究

• 批准号: 10668477
• 负责人: Frances Rudnick Levin
• 金额: $ 125.4万
• 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/10668477
• 关键词: Adverse event; Agonist; Animals; Anxiety; Behavior; Behavioral; Binding; Biological Availability; CNR1 gene; Canis familiaris; Cannabis; Characteristics; Clinical; Clinical Research; Clinical Trials; Collaborations; Cyclic AMP; Data; Dedications; Development; Dose; Double-Blind Method; Drug Kinetics; Embryonic and Fetal Development; Evaluation; Fasting; Female; Food; Funding; GTP-Binding Proteins; Goals; Guidelines; Hour; Human; Human Volunteers; Laboratories; Laboratory Study; MAP Kinase Gene; Marketing; Maximum Tolerated Dose; Mediating; Mental Depression; Moods; National Institute of Drug Abuse; Oral; Oral Administration; Oryctolagus cuniculus; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phototoxicity; Physiological; Placebo Control; Public Health; Randomized; Rattus; Recommendation; Relapse; Research; Research Personnel; Rodent; Safety; Signal Pathway; Signal Transduction; Site; Sleep; Smoke; Testing; Text; Therapeutic Index; Toxic effect; Toxicology; United States; antagonist; cannabis administration; cannabis self-administration; design; drug candidate; drug development; drug production; efficacy evaluation; genotoxicity; healthy volunteer; immunotoxicity; in vivo; inhibitor; marijuana smoker; marijuana use; marijuana use disorder; novel; pharmacologic; phase I trial; phase III trial; pre-clinical; preclinical study; preclinical toxicity; pregnant; process optimization; public health priorities; reproductive toxicity; response; 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.

在此输入文本，它是应用程序的新摘要信息。此部分不得超过30行文本。 项目概要：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。该提案的目的是进行必要的补充开发和药代动力学研究，以支持AEF 0117的III期试验，AEF 0117是Aelis Farma开发的一种专门用于治疗CUD的新药。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，AEF 0117减少了每日吸食大麻者的大麻自我给药及其滥用相关影响（“良好的药效”），而不会产生身体不适或扰乱情绪或睡眠。AEF 0117良好的药代动力学和安全性特征以及临床前和人体实验室数据使该化合物成为治疗CUD的非常有前途的方法。在对CUD患者进行AEF 0117大规模临床试验之前，有必要在人类志愿者中进行非临床毒理学研究以及安全性和药代动力学研究：（1）非临床AEF 0117开发（遵循FDA和ICH指南）：毒性。我们将进行6个月啮齿类动物（大鼠）和9个月非啮齿类动物（犬）经口给药毒性研究，包括免疫毒性评价。该药物将以超过预期人体剂量的倍数的三个剂量给予动物。光毒性。大鼠将接受AEF 0117的三种剂量的每日三次给药。也将在无UVR暴露的情况下给予最高剂量。生殖毒性。在为期7天的最大耐受剂量研究期间，将在非妊娠雌性家兔中以三种剂量检测AEF 0117的毒性。随后的剂量范围探索研究将在妊娠大鼠和家兔中检测3种剂量的AEF 0117，并在另一组妊娠雌性大鼠和家兔中检测胚胎-胎仔发育。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AEF 0117的口服生物利用度的影响和2）吸食大麻和口服施用AEF 0117之间的潜在药代动力学相互作用。具体而言，将在10小时空腹（n=24）和非空腹（n = 24）条件下评估14天内AEF 0117（1 mg PO）的药代动力学。此外，将在3组大麻吸烟者（n=15/组）中比较14天内AEF 0117和/或大麻的药代动力学，这些大麻吸烟者将接受（a）AEF 0117（1 mg）单独给药，（B）AEF 0117（1 mg）和大麻（7.0%），（c）大麻（7.0%）单独给药。总之，该提案的一个重要优势是将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配对。通过这种合作关系，我们将进行FDA要求的研究，为AEF 0117的3期试验做好准备。该项目具有很大的影响力，产生了必要的结果，使AEF 0117更接近FDA批准作为治疗CUD的第一种药物。