Development of a Novel Calcium Channel Therapeutic for Opioid Use Disorder

Vivreon Biosciences，LLC 4940卡罗尔峡谷路，Ste. 110 San Diego，CA milton@vivreonbiosciences.com NIDA RFA-DA-23-021 项目摘要 阿片类药物使用障碍（OUD）是阿片类药物的长期使用，导致临床显着的痛苦或损害。 大多数进入创伤病房或重症监护病房（ICU）的住院患者接受阿片类药物，通常作为 镇痛和镇静的一部分。反复暴露于阿片类药物会产生行为敏感， 导致药物渴求、阿片样物质诱导的痛觉过敏（OIH）和戒断症状。阿片类药物依赖 在接受长期阿片类药物给药方案的住院患者中， 出院后继续使用阿片类药物的重大风险。住院时间通常延长到逐渐减少剂量 并使患者戒断阿片类药物，但这些患者仍然存在阿片类药物依赖，戒断和 OUD。阿片类药物治疗、阿片类药物依赖、阿片类药物逐渐减少以及在治疗后发生OUD的可能性的循环 出院是一种未得到满足的紧急医疗需求，助长了类阿片大流行。小分子 预防阿片类药物依赖的治疗方法将减少住院时间，改善患者 结果，降低OUD的风险，并显着降低护理成本。Vivreon Biosciences打算 通过开发用于预防阿片类药物的非阿片类药物新化学实体（NCE）来解决这一未满足的需求 依赖于对抗OUD。 组织损伤性小胶质细胞增生，静止的CNS小胶质细胞向炎症行为的转变 阿片受体（OR）激活等特定信号与OUD相关。 炎性小胶质细胞增生症的治疗性预防是预防炎性小胶质细胞增生症发展的创新方法。 阿片类药物依赖中枢神经系统小胶质细胞被OR激活并支持炎症反应 小胶质细胞极化。我们已经证明，我们的候选治疗钝化了多个维度， 吗啡诱导的行为适应在这个快速通道SBIR项目中，Vivreon将建立一个完整的临床前 围绕我们的Lead VV分子开发计划，以治疗OUD。在第一阶段，我们将开发剂量反应 在阿片类药物依赖小鼠模型中使用多个读数和剂量范围探索研究， 建立两种治疗化合物的治疗窗指数。这将允许选择最 有前途的先导化合物。成功的Lead选择将证明进入完整的 第二阶段的发展研究。这些研究将包括标准的小分子研究性新 药物（IND）工作，包括ADME/PK、毒理学和生产研究，以降低电极导线的风险。成功 该项目的结束将产生一个有吸引力的一揽子计划，吸引第三方投资者能够提供 将电极导线推进临床确认所需的财务支持。

Vivreon Biosciences, LLC 4940 Carroll Canyon Rd., Ste. 110 San Diego, CA 92121 milton@vivreonbiosciences.com NIDA RFA-DA-23-021 Project Summary Opioid use disorder (OUD) is the chronic use of opioids that causes clinically significant distress or impairment. Most hospitalized patients admitted to the trauma unit or intensive care unit (ICU) receive opioids, commonly as part of analgesia and sedation regimens. Repeated opioid exposure produces behavioral sensitization that contributes to drug craving, opioid-induced hyperalgesia (OIH), and withdrawal symptoms. Opioid dependence can be expected in hospitalized patients who have received lengthy opioid dose regimens, and patients are at significant risk of continuing opioid use following discharge. Inpatient stays are often extended to taper dosages and wean patients off opioids, yet these patients remain at increased risk of opioid dependence, withdrawal, and OUD. This cycle of opioid treatment, opioid dependence, opioid tapering, and potential for developing OUD upon discharge represents an urgent unmet medical need that contributes to the opioid pandemic. A small molecule therapeutic that prevents opioid dependence would reduce the length of hospital stays, improve patient outcomes, reduce the risk of OUD, and significantly reduce the cost of care. Vivreon Biosciences intends to address this unmet need by developing a non-opioid new chemical entity (NCE) for prevention of opioid dependence to combat OUD. Tissue damaging microgliosis, the shift of quiescent CNS microglia towards inflammatory behaviors in response to specific signals such as opioid receptor (OR) activation, is documented to be associated with OUD. Therapeutic prevention of inflammatory microgliosis is an innovative approach to preventing the development of opioid dependence. Central nervous system microglial cells are activated by ORs and support inflammatory microglial polarization. We have demonstrated that our candidate therapeutic blunts multiple dimensions of morphine-induced behavioral adaptations. In this Fast Track SBIR project Vivreon will build a full preclinical development program around our Lead VV molecule to treat OUD. In Phase I we will develop dose-response metrics in a mouse model of opioid dependence with multiple readouts and dose-range finding studies to establish therapeutic window indices for two therapeutic compounds. This will allow selection of the most promising Lead compound for further development. Successful Lead selection will justify entering full development studies in Phase II. These studies will encompass standard small molecule Investigational New Drug (IND) efforts including ADME/PK, toxicology and manufacturing studies to de-risk the Lead. Successful conclusion of the project will yield an attractive package that is enticing to third party investors able to provide the financial support required for advancement of the Lead into clinical validation.