Development of a Novel Calcium Channel Therapeutic for Opioid Use Disorder

开发一种治疗阿片类药物使用障碍的新型钙通道疗法

• 批准号: 10684558
• 负责人: Milton L Greenberg
• 金额: $ 32万
• 依托单位: VIVREON BIOSCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10684558
• 关键词: Absence of pain sensation; Address; Affect; Affective; Attenuated; Behavior; Behavioral; Biological Availability; Biological Sciences; Brain; Calcium Channel; Cell membrane; Central Nervous System; Chronic; Clinical; Data; Development; Diagnostic; Dimensions; Disease; Disease model; Distress; Dose; Financial Support; Funding; Gliosis; Grant; Hospitalization; Hyperalgesia; Immunomodulators; Impairment; Inflammatory; Inpatients; Intensive Care Units; Investigational Drugs; Lead; Length of Stay; Marketing; Medical; Microglia; Mission; Modeling; Molecular; Morphine; Mus; National Institute of Drug Abuse; Neurons; Opiate Addiction; Opioid; Opioid Receptor; Oral; Pain management; Patient Admission; Patient-Focused Outcomes; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Prevention; Program Development; Reactive Oxygen Species; Receptor Activation; Regimen; Risk; Risk Reduction; Sedation procedure; Signal Transduction; Small Business Innovation Research Grant; Synapses; Therapeutic; Tissues; Toxicology; Validation; Weaning; Withdrawal; Withdrawal Symptom; behavioral sensitization; care costs; clinically significant; combat; commercialization; cytokine; dosage; drug candidate; drug craving; good laboratory practice; hospital care; improved; indexing; innovation; manufacture; mouse model; neuroinflammation; neuroprotection; neurotoxic; new chemical entity; new therapeutic target; non-opioid analgesic; novel; opioid exposure; opioid tapering; opioid therapy; opioid use; opioid use disorder; pain behavior; pandemic disease; pre-clinical; preclinical development; prescription opioid; prevent; response; small molecule; small molecule therapeutics; stimulant use disorder; targeted treatment; therapeutic candidate; therapeutic opioid; trauma units; trend; withdrawal-induced anxiety

Vivreon Biosciences, LLC 4940 Carroll Canyon Rd., Ste. 110 San Diego, CA 92121 [e-mail] 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.

Vivreon Biosciences，LLC 4940 Carroll Canyon Rd。，Ste。 110 圣地亚哥，加利福尼亚州92121 [e-mail] NIDA RFA-DA-23-021 项目摘要 阿片类药物使用障碍（OUD）是对阿片类药物的长期使用，导致临床上的痛苦或损害。 大多数住院的患者进入创伤部门或重症监护病房（ICU）的患者通常会接受阿片类药物，通常为 镇痛和镇静方案的一部分。重复的阿片类药物暴露会产生行为敏感性 有助于渴望药物，阿片类药物诱发的痛觉过敏（OIH）和戒断症状。阿片类药物依赖性 在接受长期接受阿片类剂量方案的住院患者中，可以预期 出院后继续使用阿片类药物的重大风险。住院住宿通常扩展到锥度剂量 和断裂患者的阿片类药物，但这些患者仍然有阿片类药物依赖，戒断和的风险增加 Oud。阿片类药物治疗，阿片类药物依赖性，阿片类药物逐渐减少以及开发Oud的潜力的周期 排放代表了有助于阿片类大流行的紧急未满足的医疗需求。一个小分子 防止阿片类药物依赖性的治疗性会减少住院时间，改善患者 结果，降低OUD风险，并大大降低护理成本。 Vivreon Biosciences打算 通过开发非阿片类化学实体（NCE）来预防阿片类药物，以解决这种未满足的需求 依赖对抗Oud。 组织破坏小胶质细胞增多，静止中枢神经系统小胶质细胞向炎症行为转移 对于特定的信号，例如阿片受体（OR）激活，记录在与OUD相关联。 预防炎症性小胶质细胞症的治疗性是一种创新的方法来防止发展 阿片类药物依赖性。中枢神经系统小胶质细胞被ORS激活并支持炎症 小胶质极化。我们已经证明，我们的候选治疗性钝器具有多个维度 吗啡诱导的行为适应。在这个快速轨道中，SBIR项目Vivreon将建立​​一个完整的临床前 围绕我们的铅VV分子进行的开发计划，以治疗OUD。在第一阶段，我们将发展剂量反应 阿片类药物依赖性小鼠模型中的指标，具有多个读数和剂量范围的研究研究 为两种治疗化合物建立治疗窗口指数。这将允许最多选择 有希望的铅化合物用于进一步发展。成功的铅选择将证明进入完整 第二阶段的发展研究。这些研究将涵盖标准的小分子研究新的 药物（IND）的努力，包括ADME/PK，毒理学和制造研究，以降低铅的危险。成功的 该项目的结论将产生一个有吸引力的方案，该计划诱使能够提供的第三方投资者 将铅提高到临床验证所需的财政支持。