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

支持在吸烟者 2 期临床研究中评估 mGlu2 PAM SBP-9330 的安全性/毒理学、ADME 和 CMC 活动

• 批准号: 10829189
• 负责人: ROBERT M ANTHENELLI
• 金额: $ 306.4万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10829189
• 关键词: ADME Study; Abstinence; Achievement; Acute; Adult; Adverse event; Animal Model; Applications Grants; Autoradiography; Biological Availability; Brain; Bupropion; Canis familiaris; Categories; Cause of Death; Cessation of life; Chemistry; Clinical Research; Clinical Trials; Collaborations; Cues; Cytochrome P450; Data; Development; Disease; Dose; Double-Blind Method; Drug Kinetics; Drug or chemical Tissue Distribution; Drug usage; Evaluation; Excretory function; Funding; Gastrointestinal Diseases; Glutamates; Good Manufacturing Process; Grant; Hepatic; Human; Investigation; Investigational Drugs; Kidney; Label; Measures; Metabolic; Metabolism; Metabotropic Glutamate Receptors; Morbidity - disease rate; Nicotine; Nicotine Dependence; Nicotinic Agents; Oral; Penetration; Pharmaceutical Preparations; Phase; Placebo Control; Plasma; Prevalence; Productivity; Property; Qualifying; Randomized; Rattus; Research; Research Personnel; Safety; Series; Serious Adverse Event; Severities; Smoker; Smoking; Substance Use Disorder; Testing; Therapeutic Agents; Time; Toxic effect; Toxicology; United States; United States Food and Drug Administration; Work; absorption; body system; cigarette smoking; clinical development; cohort; design; drug reinforcement; environmental tobacco smoke exposure; experience; good laboratory practice; in vitro Assay; manufacture; metabolic abnormality assessment; mortality; multidisciplinary; nervous system disorder; neurotransmission; nicotine cessation; nicotine replacement; nicotine seeking behavior; nicotine self-administration; nicotine treatment; non-smoker; novel drug class; novel therapeutics; phase 1 study; phase 2 study; positive allosteric modulator; pre-clinical; receptor; relapse prevention; response; small molecule; smoking cessation; statistics; success; therapeutically effective; tobacco smokers; tobacco user; varenicline

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.

项目概要 此重新提交申请“支持评估的安全/毒理学、ADME 和 CMC 活动” mGlu2 PAM SBP-9330 在吸烟者的 2 期临床研究中”，是对 PAR-22-202 的回应，代表了 继续我们目前的工作，直至 2023 年 7 月 31 日为止，由 U01 DA051077“mGlu2 的临床开发”资助 治疗尼古丁成瘾的正变构调节剂”。吸烟仍然是导致尼古丁成瘾的主要原因之一。 全球仅批准了三种戒烟药物。 美国食品和药物管理局 (FDA)（安非他酮、伐尼克兰和尼古丁替代品） 疗法），所有这些都具有较差的疗效和耐受性。 代谢型谷氨酸受体亚型 2 (mGlu2) 减少尼古丁自我施用和提示诱导 在动物模型中恢复尼古丁寻找，为 mGlu2 作为有效治疗靶点提供支持 我们的研究药物，小分子 mGlu2 PAM SBP-9330（在 先前授予 U01 DA041731），最近已在健康非吸烟者和吸烟者中使用安慰剂进行了评估 对照、随机、双盲 1 期临床研究 (NCT04948827) 迄今为止，健康数据。 对非吸烟者进行了非吸烟者的非盲分析，结果表明 SBP-9330 具有良好的耐受性，没有出现严重的不良反应。 人体药代动力学数据显示，血浆暴露量接近不良事件或安全问题。 剂量成比例，在给药 14 天期间累积大约 2 倍，并且足够高 这些有希望的数据支持 SBP-9330 的临床开发的继续。 FDA 要求进行本拨款申请中提出的研究，然后我们才能更长时间地服用 SBP-9330 在第二阶段及以后的研究中，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) 进行支持所需的临床前毒理学研究； SBP-9330 在吸烟者中的 2 期临床开发；以及 (3) 进行化学、制造和 支持吸烟者第二阶段临床开发所需的控制（CMC）活动，以实现这些具体目标。 目标，我们保留了同样经验丰富、合格的多学科研究人员团队 在之前的赠款 (U01 DA041731) 和当前有效的赠款 (U01 DA051077）。我们还编制了广泛的数据包以支持进一步的临床开发。 SBP-9330。该提案中里程碑的实现将提供额外的数据和原料药。 将 SBP-9330 推进到吸烟者的 2 期概念验证临床研究所需，我们的团队拥有足够的深度。 以及执行拟议研究计划的专业知识和经验的广度，完整的证据证明了这一点 并及时实现了U01 DA041731和U01 DA051077在过去六年中的里程碑。