Safety/Toxicology, ADME and CMC Activities to Support the Assessment of the mGlu2 PAM SBP-9330 in a Phase 2 Clinical Study in Smokers

项目总结 这份重新提交的申请，“安全/毒理学，ADME和CMC活动，以支持评估 MGlu2 PAM SBP-9330在吸烟者中的第二阶段临床研究“，是对PAR-22-202的回应，代表了 继续我们目前的工作，直到2023年7月31日由U01 DA051077资助的mGlu2的临床开发 治疗尼古丁成瘾的正变构调节剂“。吸烟仍然是导致癌症的主要原因之一。 世界范围内的死亡和疾病。只有三种戒烟药物被批准 美国食品和药物管理局(FDA)(安非他酮、伐伦克林和尼古丁替代品 治疗)，所有这些都有较差的疗效和耐受性。正变构调节剂(PAM) 代谢型谷氨酸受体亚型2(MGlu2)减少尼古丁自身给药和线索诱导 在动物模型中恢复尼古丁寻求，为mGlu2作为有效治疗靶点提供支持 尼古丁成瘾。我们的研究药物，小分子mGlu2 PAM SBP-9330(在 之前的授权U01 DA041731)，最近在健康的非吸烟者和服用安慰剂的吸烟者中进行了评估。 对照、随机、双盲的1期临床研究(NCT04948827)。到目前为止，健康人的数据 对不吸烟的人进行了非盲目和分析，结果显示SBP-9330耐受性良好，没有严重的 不良事件或安全问题。人体药代动力学数据显示，血浆暴露几乎是 剂量成比例，在14天的剂量内累积约2倍，并足以 潜在的疗效。这些有希望的数据支持SBP-9330临床开发的继续。 这项拨款申请中提出的研究是FDA要求的，然后我们才能给SBP-9330服用更长时间的药物 第二阶段及以后研究中吸烟者的持续时间。为此，我们的具体目标是：(1)履行 支持第二阶段所需的临床前吸收、分布、代谢和排泄(ADME)研究 SBP-9330在吸烟者中的临床开发；(2)进行临床前毒理学研究，以支持 SBP-9330在吸烟者中的第二阶段临床开发；以及(3)执行化学、制造和 支持吸烟者第二阶段临床发展所需的对照(CMC)活动。要实现这些具体目标 ，我们保留了同样的经验丰富和合格的多学科调查团队， 在上一次拨款(U01 DA041731)和当前有效的拨款(U01)期间进行了富有成效的协作 DA051077)。我们还编制了一套广泛的数据包，以支持进一步的临床开发 SBP-9330。实现本提案中的里程碑将提供额外的数据和药物物质 需要将SBP-9330推进到吸烟者的第二阶段概念验证临床研究中。我们的团队有深度 以及广泛的专业知识和经验来执行拟议的研究计划，如完整的 并在过去六年中及时实现了U01 DA041731和U01 DA051077的里程碑。

PROJECT SUMMARY This resubmission application, “Safety/toxicology, ADME and CMC activities to support the assessment of the mGlu2 PAM SBP-9330 in a Phase 2 clinical study in smokers”, is in response to PAR-22-202 and represents the continuation of our current work funded through 07/31/2023 by U01 DA051077 “Clinical development of an mGlu2 positive allosteric modulator to treat nicotine addiction”. Cigarette smoking remains one of the leading causes of death and disease worldwide. Only three types of medications for smoking cessation have been approved by the United States Food and Drug Administration (FDA) (bupropion, varenicline, and nicotine replacement therapy), all of which have poor efficacy and tolerability. Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor subtype 2 (mGlu2) decrease nicotine self-administration and cue-induced reinstatement of nicotine seeking in animal models, providing support for mGlu2 as a valid target for the treatment of nicotine addiction. Our investigational drug, the small molecule mGlu2 PAM SBP-9330 (characterized during prior grant U01 DA041731), has recently been evaluated in healthy nonsmokers and smokers in a placebo- controlled, randomized, and double-blind Phase 1 clinical study (NCT04948827). To date, the data for the healthy nonsmokers have been unblinded and analyzed, revealing that SBP-9330 was well tolerated, with no serious adverse events or safety concerns. Human pharmacokinetic data revealed that plasma exposures were nearly dose-proportional, accumulated approximately 2-fold over 14 days of dosing, and were sufficiently high for potential efficacy. These promising data support continuation of the clinical development of SBP-9330.The studies proposed in this grant application are required by the FDA before we can dose SBP-9330 for longer duration in tobacco smokers in a Phase 2 study and beyond. To this end, our Specific Aims are: (1) Perform the preclinical absorption, distribution, metabolism, and excretion (ADME) studies needed to support the Phase 2 clinical development of SBP-9330 in smokers; (2) Perform the preclinical toxicology studies needed to support Phase 2 clinical development of SBP-9330 in smokers; and (3) Perform the Chemistry, Manufacturing, and Controls (CMC) activities needed to support Phase 2 clinical development in smokers. To achieve these Specific Aims, we have retained the same highly experienced and qualified multidisciplinary team of investigators that has collaborated productively during the previous grant (U01 DA041731) and the currently active grant (U01 DA051077). We have also compiled an extensive data package to support the further clinical development of SBP-9330. Achievement of the milestones in this proposal will provide the additional data and drug substance needed to advance SBP-9330 into a Phase 2 proof-of-concept clinical study in smokers. Our team has the depth and breadth of expertise and experience to execute the proposed research plan, as evidenced by the complete and timely achievement of the milestones for both U01 DA041731 and U01 DA051077 in the past six years.