Development of an Opioid Sparing Therapeutic to Minimize Opioid Use Disorderand Tolerance in the Treatment of Pain

开发阿片类药物节约疗法，以最大限度地减少阿片类药物使用障碍和疼痛治疗耐受性

• 批准号: 10760487
• 负责人: MALCOLM A MEYN
• 金额: $ 257.99万
• 依托单位: AMALGENT THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10760487
• 关键词: Address; Adjuvant; Adverse effects; Agonist; American; Analgesics; Animal Model; Animals; Behavior; Benefits and Risks; Clinic; Clinical; Clinical Research; Clinical Trials; Complex; Constipation; Development; Dose; Drug abuse; FDA approved; Face; Formulation; Goals; Guidelines; Human; Lethargies; Marketing; Modeling; Morphine; Morphine Abuse; Nausea; Opioid; Opioid Analgesics; Oral; Pain; Pain management; Parkinson Disease; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Physicians; Positioning Attribute; Preparation; Property; Psyche structure; Publishing; Restless Legs Syndrome; Rewards; Risk; Risk Reduction; Self Administration; Small Business Innovation Research Grant; Tablets; Testing; Therapeutic; Therapeutic Index; Time; Toxicology; United States; Ventilatory Depression; Withdrawal Symptom; Work; abuse liability; addiction; adverse event risk; animal data; clinical material; dopamine D3 receptor; dosage; drug development; human data; innovation; manufacturing process; new technology; novel; novel drug combination; novel therapeutics; opiate tolerance; opioid epidemic; opioid sparing; opioid therapy; opioid use; opioid use disorder; pain model; pain patient; pain reduction; pain relief; painful neuropathy; pramipexol; prescription opioid; prevent; research and development; research clinical testing; safety study; safety testing; side effect; therapeutic opioid; willingness

PROJECT SUMMARY Managing the complex risk-benefit profile of opioid therapeutics is a significant challenge for today’s physicians. Prescription opioid analgesics provide excellent pain relief but, at the same time, put patients in danger of severe adverse effects, most notably opioid use disorder (OUD). The current opioid crisis in the United States reflects these risks, as over 2.4 million Americans suffer from OUD, and over 50,000 of these patients die each year. Current clinical guidelines urge physicians to minimize opioid doses, but a narrow therapeutic window limits their ability to accomplish this goal in a meaningful way without losing efficacy. Thus, there is a critical unmet need for new technologies that significantly minimize the opioid doses needed for effective relief from moderate to severe pain. Amalgent Therapeutics, LLC is directly addressing this need by developing AMGT-0220, a fixed-dose combination therapeutic for the treatment of pain that utilizes the dopamine D3 receptor agonist pramipexole as a novel adjuvant to morphine. Our preliminary and animal and human data show that pramipexole significantly increases the analgesic properties of morphine, decreasing the opioid dose needed for pain relief compared to the opioid administered alone. Our published work also demonstrates that pramipexole mitigates the reward seeking behavior associated with morphine and restores opioid analgesia in a neuropathic pain model. Importantly, pramipexole is FDA approved to treat Parkinson’s Disease and Restless Legs Syndrome. Combining two approved drugs, pramipexole and morphine, in our first therapeutic allows the use of the 505(b)2 approval pathway and mitigates significant risks to approval compared to a new molecule. Our core objective is to create a first-in-class fixed-dose combination therapeutic for the treatment of pain that provides pain relief at decreased opioid doses and can replace opioid monotherapy. This therapeutic will significantly minimize the quantity of prescribed opioids, reducing the risk of side effects, including addiction. In Direct to Phase 2, we propose to quantify the mitigating effect of pramipexole on morphine abuse liability and to test the combination in a reinstatement model. This work will drive the development as an opioid sparing combination with decreased risk for developing OUD. We also IND enabling safety studies and develop a manufacturing process ready to supply clinical material. After completing these Aims, we will be well-positioned to submit an IND in preparation for our first clinical trial.

项目概要 管理阿片类药物治疗的复杂风险收益状况是当今的一项重大挑战 处方阿片类镇痛药可以很好地缓解疼痛，但同时也会让患者陷入困境。 严重不良反应的危险，最值得注意的是阿片类药物使用障碍（OUD）当前的阿片类药物危机。 美国反映了这些风险，因为超过 240 万美国人患有 OUD，其中超过 50,000 人患有 OUD 每年都有患者死亡。目前的临床指南敦促尽量减少阿片类药物的剂量，但范围很窄。 治疗窗口限制了他们以有意义的方式实现这一目标而不失去疗效的能力。 对于能够显着减少阿片类药物剂量的新技术的迫切需求尚未得到满足 Amalgent Therapeutics, LLC 正在通过以下方式直接满足这一需求：有效缓解中度至重度疼痛。 开发 AMGT-0220，一种用于治疗疼痛的固定剂量组合疗法，利用 多巴胺D3受体激动剂普拉克索作为吗啡的新型佐剂我们初步和动物实验。 人体数据显示普拉克索显着增加吗啡的镇痛作用，降低吗啡的镇痛作用 与单独服用阿片类药物相比，缓解疼痛所需的阿片类药物剂量。 表明普拉克索可以减轻与吗啡相关的奖励寻求行为并恢复 重要的是，普拉克索已被 FDA 批准用于治疗帕金森病。 疾病和不宁腿综合症，在我们的第一个药物中结合了两种批准的药物：普拉克索和吗啡。 治疗允许使用 505(b)2 批准途径并降低批准的重大风险 与新分子相比，我们的核心目标是创造一流的固定剂量组合疗法。 用于治疗疼痛，减少阿片类药物剂量即可缓解疼痛，并且可以替代阿片类药物 这种疗法将显着减少处方阿片类药物的数量，从而降低风险。 在直接进入第二阶段时，我们建议量化副作用的缓解效果。 普拉克索对吗啡滥用的影响，并在恢复模型中测试该组合。 我们还推动阿片类药物节约组合的开发，并降低开发 OUD 的风险。 进行安全研究并开发准备供应临床材料的制造工艺。 完成这些目标后，我们将能够提交 IND ，为我们的首次临床试验做准备。