Clinical development of an mGlu2 positive allosteric modulator to treat nicotine addiction

治疗尼古丁成瘾的 mGlu2 正变构调节剂的临床开发

基本信息

批准号：
10231218
负责人：
ROBERT M ANTHENELLI
金额：
$ 415.49万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10231218
关键词：
Abstinence Achievement Acute Adult Affect Animal Model Applications Grants Biological Availability Brain Bupropion Canis familiaris Categories Cessation of life Chemistry Clinic Clinical Clinical Protocols Clinical Research Clinical Trials Clinical Trials Design Cues Data Development Disease Dose Double-Blind Method Drug Kinetics Drug usage Electrocardiogram Food Formulation Funding Future Generations Glutamates Grant Human Infrastructure Investigational Drugs Investigational New Drug Application Knowledge Laboratories Lead Mental Health Metabolic Metabotropic Glutamate Receptors Morbidity - disease rate National Institute of Drug Abuse Nicotine Nicotine Dependence Oral Oral Administration Penetration Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Physical Examination Placebos Prevalence Property Public Health Randomized Rattus Relapse Research Personnel Rewards Running Safety Self Administration Smoking Societies Substance Use Disorder Substance abuse problem Testing Time Toxicology United States United States Food and Drug Administration Work adverse event monitoring arm base cigarette smoking clinical candidate clinical development cohort combat design drug candidate drug reinforcement efficacy clinical trial efficacy study environmental tobacco smoke exposure experience falls first-in-human healthy volunteer human subject in vivo innovation mortality multidisciplinary nicotine replacement nicotine user novel drug class pandemic disease phase 1 study positive allosteric modulator preclinical study prevent receptor research clinical testing response safety study smoking cessation success symposium tablet formulation therapeutically effective tobacco user varenicline

项目摘要

PROJECT SUMMARY This application entitled “Clinical development of an mGlu2 positive allosteric modulator to treat nicotine addiction” is in response to PAR-18-219 “Grand Opportunity in Medications Development for Substance-Use Disorders (U01 Clinical Trial Optional)”. This application represents the continuation of our current work under the U01 DA041731 funded from 9/1/2017 through 5/31/2020 entitled “Preclinical Studies for the Development of Selective mGlu2 Positive Allosteric Modulators to Treat Substance Abuse Disorders”. Cigarette smoking, attributable primarily to the addictive properties of nicotine, is one of the largest preventable causes of disease and death in the US. Metabotropic glutamate receptor subtype 2 (mGlu2) receptor positive allosteric modulators (PAMs) represent an innovative strategy to treat nicotine addiction. Medications that activate mGlu2 receptors can be effective via a dual mechanism by a) reversing the acute effects of nicotine, thus decreasing drug reinforcement, and b) restoring glutamatergic function to normal levels, thus preventing relapse to drug use. Our lead drug candidate, SBI-0069330, is a potent and selective mGlu2 PAM with excellent drug-like properties including oral bioavailability, brain penetration, and metabolic stability. Importantly, SBI-0069330 reduces nicotine self-administration and cue-induced nicotine reinstatement in rats without affecting natural food reward. In addition, SBI-0069330 has been shown to be well-tolerated and safe in 14-day toxicology studies in rats and dogs. We are on track to complete the data package to support SBI-0069330 as a clinical candidate under the current U01 DA041731 grant by May 31, 2020. The overall objective of this grant application is to advance SBI- 0069330 into the clinic and determine its safety, tolerability and pharmacokinetic (PK) profile in healthy human subjects. The specific aims of this proposal are: (1) Complete the investigational new drug (IND) application for SBI-0069330, submit for Food and Drug Administration (FDA) review, and obtain allowance for human testing; (2) Manufacture drug product with a formulation suitable for human dosing in Phase 1 clinical studies; (3) Complete Phase 1 clinical studies in healthy volunteers and determine the safety, tolerability, and PK profile of SBI-0069330 in humans and (4) Complete CMC development and toxicology testing to support a future 12-week Phase 2A clinical efficacy trial. We have assembled a multidisciplinary team of investigators who have the depth and breadth of knowledge and experience to achieve these milestones. This team has been collaborating fruitfully and effectively with the team of Jane Acri and David White at NIDA under the current U01 DA041731 grant. The infrastructure required to undertake the proposed work is fully established and operational. We have also manufactured sufficient active pharmaceutical ingredient (API) of SBI-0069330 that can be readily formulated into drug product and used for dosing in the Phase 1 clinical studies without delay after acceptance of the IND application. Achievement of the indicated milestones will produce a clinical compound ready for a Phase 2A proof-of-concept efficacy study for nicotine addiction.

项目摘要该应用名为“ MGLU2阳性变构调节剂的临床开发以治疗尼古丁成瘾”是对Par-18-219的回应，“药物开发的巨大机会 - 物质使用疾病（U01临床试验可选）”。此应用代表我们当前工作的继续 U01 DA041731从2017年9月1日至5/31/2020资助，标题为“开发的临床前研究选择性MGLU2阳性变构调节剂以治疗药物滥用障碍”。吸烟，可归因于尼古丁的添加特性，是最大的可预防原因之一和在美国的死亡。代谢性谷氨酸受体亚型2（MGLU2）受体阳性变构调节剂（PAM）代表了治疗尼古丁成瘾的创新策略。激活MGLU2受体的药物通过双重机制可以通过a）逆转尼古丁的急性作用来有效，从而减少了药物加强和b）将谷氨酸能功能恢复到正常水平，从而防止了药物使用的缓解。我们的铅药物候选人SBI-0069330是具有出色类似药物的特性的潜在和选择性的MGLU2 PAM 包括口服生物利用度，大脑渗透和代谢稳定性。重要的是，SBI-0069330减少了尼古丁自我给药和提示引起的大鼠恢复尼古丁的恢复，而不会影响天然食物的奖励。此外，在大鼠和狗。我们有望完成数据包，以支持SBI-0069330作为临床候选人当前的U01 DA041731赠款到2020年5月31日。该赠款申请的总体目标是促进SBI- 0069330进入诊所，并确定健康人类的安全性，耐受性和药代动力学（PK）特征主题。该提案的具体目的是：（1）完成研究性新药（IND）申请 SBI-0069330，提交食品和药物管理局（FDA）审查，并获得人类测试的津贴；（2）制造具有适用于人类剂量的公式在第1阶段临床研究中的药品；（3）在健康志愿者中完成1阶段的临床研究，并确定人类的SBI-0069330和（4）完整的CMC开发和毒理学测试，以支持未来的12周第2A阶段临床效率试验。我们已经组建了一个具有深度的调查员团队以及实现这些里程碑的知识和经验的广度。这个团队一直在合作在当前的U01 DA041731下，与NIDA的Jane Acri和David White团队有效地有效地有效授予。进行拟议的工作所需的基础设施已完全确立和运营。我们有还制造了足够的SBI-0069330的活性药物成分（API）在1期临床研究中制成药物，用于服用剂量 IND应用程序。实现指示的里程碑将产生临床化合物准备 2A阶段的概念验证效果研究尼古丁成瘾。