Development of a Novel Calcium Channel Therapeutic for Opioid Use Disorder

Vivreon生物科学有限责任公司 圣卡罗尔峡谷路4940号110 加州圣地亚哥，邮编92121 邮箱：milton@vivreonbiosciences.com NIDA RFA-DA-23-021 项目摘要 阿片类药物使用障碍(OUD)是长期使用阿片类药物，导致临床上严重的痛苦或损害。 大多数住在创伤病房或重症监护病房(ICU)的住院患者接受阿片类药物治疗，通常为 部分止痛和镇静方案。反复接触阿片类药物会产生行为敏感化， 导致药物渴求、阿片类药物诱导的痛觉过敏(OIH)和戒断症状。阿片依赖 在接受了长时间阿片类药物剂量方案的住院患者中可能会出现这种情况，患者目前处于 在出院后继续使用阿片类药物的重大风险。住院时间通常延长至递减剂量。 患者戒断阿片类药物，但这些患者仍然面临阿片类药物依赖、戒断和 奥德。阿片类药物治疗、阿片类药物依赖、阿片类药物逐渐减少的循环，以及发展的潜力 出院是一种紧急的未得到满足的医疗需求，助长了阿片类药物的流行。一种小分子 预防阿片类药物依赖的治疗将减少住院时间，改善患者状况 结果，降低OUD的风险，并显著降低护理成本。Vivreon Biosciences打算 通过开发一种用于预防阿片类药物的非阿片类新化学实体(NCE)来满足这一未得到满足的需求 对战斗的依赖。 组织损伤性小胶质细胞，静止的中枢神经系统小胶质细胞在反应中向炎症行为转变 对阿片受体(OR)激活等特定信号的激活，被证明与OUD有关。 治疗性预防炎性小胶质细胞增多症是预防急性髓细胞白血病发生发展的创新途径 阿片类药物依赖。中枢神经系统小胶质细胞被ORs激活并支持炎症 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的 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 围绕我们的领先VV分子的开发计划来治疗OUD。在第一阶段，我们将发展出剂量反应 阿片类药物依赖小鼠模型的多读数和剂量范围发现研究中的指标 建立两种治疗性化合物的治疗窗口指数。这将允许选择最多的 具有开发前景的先导化合物。成功选择销售线索将证明输入完整销售线索的合理性 第二阶段的开发研究。这些研究将包括标准的小分子研究新 药物(IND)努力，包括ADME/PK、毒理学和制造研究，以降低铅的风险。成功 该项目的结束将产生一个吸引第三方投资者的有吸引力的一揽子计划，能够提供 将铅推进到临床验证所需的财政支持。

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.