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.

项目概要该申请题为“治疗尼古丁的 mGlu2 正变构调节剂的临床开发” 成瘾”是对 PAR-18-219“物质使用药物开发的巨大机遇”的回应疾病（U01 临床试验可选）”。该申请代表了我们当前工作的延续。 U01 DA041731于2017年9月1日至2020年5月31日期间资助，题为“开发的临床前研究” 选择性 mGlu2 正变构调节剂治疗药物滥用障碍”。主要归因于尼古丁的成瘾特性，是最大的可预防疾病原因之一代谢型谷氨酸受体亚型 2 (mGlu2) 受体正变构调节剂 (PAM) 代表了一种治疗尼古丁成瘾的创新策略，可激活 mGlu2 受体。可以通过双重机制有效：a）逆转尼古丁的急性作用，从而减少药物强化，b) 将谷氨酸功能恢复到正常水平，从而防止吸毒复发。主要候选药物 SBI-0069330 是一种有效的选择性 mGlu2 PAM，具有优异的药物样特性重要的是，SBI-0069330 会降低口服生物利用度、脑渗透性和代谢稳定性。大鼠的尼古丁自我给药和提示诱导尼古丁恢复，而不影响自然食物奖励。此外，在大鼠和小鼠中进行的 14 天毒理学研究表明，SBI-0069330 具有良好的耐受性和安全性。我们正在按计划完成数据包，以支持 SBI-0069330 作为临床候选药物。当前的 U01 DA041731 赠款将于 2020 年 5 月 31 日之前完成。该赠款申请的总体目标是推进 SBI- 0069330 进入临床并确定其在健康人体中的安全性、耐受性和药代动力学（PK）特征本提案的具体目标是：（1）完成新药临床试验（IND）申请。 SBI-0069330，提交食品药品监督管理局（FDA）审核，并获得人体测试许可； (2) 生产适合 1 期临床研究中人体剂量的制剂 (3)；在健康志愿者中完成 1 期临床研究，并确定该药物的安全性、耐受性和 PK 特征 SBI-0069330 在人类中的应用以及 (4) 完成 CMC 开发和毒理学测试以支持未来 12 周我们组建了一支具有深度的多学科研究人员团队进行 2A 期临床疗效试验。以及广泛的知识和经验来实现这些里程碑。与 NIDA 的 Jane Acri 和 David White 团队在当前 U01 DA041731 下卓有成效且有效地合作开展拟议工作所需的基础设施已完全建立并投入运行。还制造了足够的 SBI-0069330 活性药物成分（API），可以很容易地验收后立即配制为药品并用于一期临床研究的给药 IND 申请的完成将生产出可供临床使用的化合物。尼古丁成瘾的 2A 期概念验证功效研究。