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

项目摘要 该重新提交申请，“安全性/毒理学、ADME和CMC活动，以支持 mGlu 2 PAM SBP-9330在吸烟者中的2期临床研究”，是对PAR-22-202的响应，代表了 继续我们目前的工作，直到2023年7月31日由U 01 DA 051077“mGlu 2的临床开发”资助 治疗尼古丁成瘾的正变构调节剂”。吸烟仍然是导致肥胖的主要原因之一。 世界范围内的死亡和疾病。只有三种类型的戒烟药物被批准， 美国食品药品监督管理局（FDA）（安非他酮、伐尼克兰和尼古丁替代品 治疗），所有这些都具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（mGlu 2）减少尼古丁自我给药和线索诱导的 在动物模型中恢复尼古丁寻求，为mGlu 2作为治疗的有效靶点提供支持 尼古丁成瘾我们的研究药物，小分子mGlu 2 PAM SBP-9330（在研究期间表征） 先前授权U 01 DA 041731），最近在健康的非吸烟者和吸烟者中进行了评估， 对照、随机、双盲、I期临床研究（NCT 04948827）。到目前为止，健康人的数据 对非吸烟者进行揭盲和分析，结果显示SBP-9330耐受性良好， 不良事件或安全性问题。人体药代动力学数据显示， 与剂量成比例，在给药14天内累积约2倍，并且足够高 潜在功效这些有希望的数据支持SBP-9330的临床开发的继续。 FDA要求在我们能够更长时间地给予SBP-9330之前， 在2期及以后研究中，吸烟者的持续时间。为此，我们的具体目标是：（1）执行 支持II期研究所需的临床前吸收、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II期临床开发;和（3）进行化学、生产和 支持吸烟者II期临床开发所需的对照（CMC）活动。为了实现这些具体 目的是，我们保留了相同的经验丰富和合格的多学科研究人员团队， 在上一次资助（U 01 DA 041731）和当前有效资助（U 01）期间进行了富有成效的合作 DA051077）。我们还编制了一个广泛的数据包，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原料药 需要将SBP-9330推进到吸烟者的2期概念验证临床研究中。我们的团队有能力 以及执行拟议研究计划的专业知识和经验的广度，如完整的 并在过去六年中及时实现了U 01 DA 041731和U 01 DA 051077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.