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

项目摘要 本申请题为“治疗尼古丁的mGlu 2阳性变构调节剂的临床开发 成瘾”是对PAR-18-219“药物开发的重大机遇”的回应 疾病（U 01临床试验可选）"。该应用程序代表了我们目前工作的继续， U 01 DA 041731资助时间为2017年9月1日至2020年5月31日，题为“开发 选择性mGlu 2阳性别构调节剂治疗物质滥用障碍”。抽烟， 主要归因于尼古丁的成瘾特性，是最大的可预防的疾病原因之一 死亡在美国。代谢型谷氨酸受体亚型2（mGlu 2）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mGlu 2受体的药物 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 加强，和B）将神经元能功能恢复到正常水平，从而防止药物使用的复发。我们 先导候选药物SBI-0069330是一种有效和选择性mGlu 2 PAM，具有优异的药物样性质 包括口服生物利用度、脑渗透性和代谢稳定性。重要的是，SBI-0069330减少了 尼古丁自我给药和提示诱导的尼古丁恢复，而不影响天然食物奖励。 此外，SBI-0069330在大鼠14天毒理学研究中显示耐受性良好且安全， 狗我们正在按计划完成数据包，以支持SBI-0069330作为 当前U 01 DA 041731补助金到2020年5月31日。这项赠款申请的总体目标是推动履行机构- 0069330进入临床，并确定其在健康人中的安全性、耐受性和药代动力学（PK）特征 科目本提案的具体目的是：（1）完成以下研究性新药（IND）申请： SBI-0069330，提交食品药品监督管理局（FDA）审查，并获得人体试验许可; (2)生产具有适合于1期临床研究中人体给药的制剂的制剂;（3） 在健康志愿者中完成I期临床研究，并确定 SBI-0069330在人体中的应用和（4）完成CMC开发和毒理学试验，以支持未来12周的 2A期临床疗效试验。我们已经组建了一个多学科的调查小组， 以及知识和经验的广度来实现这些里程碑。这个团队一直在合作 根据当前的U 01 DA 041731，与NIDA的Jane阿克里和大卫白色团队一起， 格兰特.开展拟议工作所需的基础设施已完全建立并投入运作。我们有 还生产了足够的SBI-0069330活性药物成分（API）， 配制成制剂，并在接受后立即用于I期临床研究给药 IND申请。实现指定的里程碑将产生一种临床化合物， 尼古丁成瘾的2A期概念验证疗效研究。

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.