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

项目总结 本申请题为《治疗尼古丁的mGlu2阳性变构调节剂的临床开发》 成瘾是对PAR-18-219的回应物质使用药物开发的重大机遇 障碍(U01临床试验可选)“。这个应用程序代表了我们当前工作在 U01 DA041731于2017年9月1日至2020年5月31日期间获得资助，名称为 选择性mGlu2阳性变构调节剂用于治疗药物滥用障碍“。吸烟， 主要归因于尼古丁的成瘾特性，是可预防疾病的最大原因之一 以及美国的死亡。代谢型谷氨酸受体亚型2(MGlu2)受体阳性变构调节剂 (PAMS)代表了一种治疗尼古丁成瘾的创新策略。激活mGlu2受体的药物 可通过双重机制有效，a)逆转尼古丁的急性影响，从而减少药物 强化，以及b)将谷氨酸功能恢复到正常水平，从而防止再次吸毒。我们的 先导候选药物SBI-0069330是一种高效、选择性强的mGlu2PAM，具有良好的类药物性能 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降低了 在不影响自然食物奖励的情况下，尼古丁自我给药和线索诱导的大鼠尼古丁恢复。 此外，在大鼠和小鼠身上进行的14天毒理学研究表明，SBI-0069330具有良好的耐受性和安全性 狗。我们正在按部就班地完成数据包，以支持SBI-0069330作为 目前的U01 DA041731在2020年5月31日之前授予。这项赠款申请的总体目标是推动履行机构-- 0069330进入临床并测定其安全性、耐受性和在健康人体内的药代动力学(PK) 研究对象。这项建议的具体目标是：(1)完成新药(IND)申请 SBI-0069330，提交食品和药物管理局审查，并获得人体试验补贴； (二)在一期临床试验中生产适合人体给药的制剂的； 在健康志愿者中完成1期临床研究，并确定其安全性、耐受性和PK曲线 (4)完成CMC开发和毒理学测试，以支持未来12周 A期临床疗效试验。我们已经组建了一支多学科的调查团队，他们有足够的深度 和广度的知识和经验，以实现这些里程碑。这个团队一直在合作 与简·阿克里和大卫·怀特在NIDA的团队在当前的U01 DA041731下卓有成效地合作 格兰特。开展拟议工作所需的基础设施已完全建立并开始运作。我们有 还生产了足够量的SBI-0069330活性药物成分，可以很容易地 经验收后立即配制成药品，用于一期临床研究的给药 IND应用程序的。达到指定的里程碑将产生一种临床化合物，准备用于 尼古丁成瘾的第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.