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

项目总结 管理阿片类药物的复杂风险-收益概况是当今 医生。处方阿片类止痛药提供了极好的止痛效果，但同时也让患者 有严重不良反应的危险，最明显的是阿片类药物使用障碍(OUD)。美国目前的阿片类药物危机 美国反映了这些风险，超过240万美国人患有OUD，其中超过5万人患有OUD 每年都有病人死亡。目前的临床指南敦促医生将阿片类药物的剂量降至最低，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的能力，而不会失去疗效。因此， 对新技术的迫切需求尚未得到满足，这些新技术可以显著减少阿片类药物的剂量 有效缓解中度至重度疼痛。Amalgent Treateutics，LLC通过以下方式直接满足这一需求 开发AMGT-0220，一种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。我们的初选和动物和 人体数据显示，普拉克索显著增加了吗啡的镇痛特性，降低了 与单独使用阿片类药物相比，止痛所需的阿片类药物剂量。我们出版的作品也 证明普拉克索可减轻与吗啡相关的奖赏寻求行为并恢复 神经病理性疼痛模型中的阿片类镇痛。重要的是，FDA批准普拉克索用于治疗帕金森氏症 疾病和不宁腿综合症。在我们的第一次试验中，将两种批准的药物普拉克索和吗啡联合使用 Treatative允许使用505(B)2批准途径，并减轻批准的重大风险 与一种新的分子相比。我们的核心目标是创造一流的固定剂量联合治疗 用于治疗疼痛，以减少阿片类药物的剂量提供疼痛缓解，并可取代阿片类药物 单一疗法。这种疗法将显著减少处方阿片类药物的数量，降低风险 副作用，包括上瘾。在直接到第二阶段，我们建议量化以下因素的缓解效果 普拉克索对吗啡滥用责任的影响，并在恢复模型中测试其组合。这项工作将 作为一种阿片类药物节约组合推动开发，降低开发OUD的风险。我们还提供Ind 能够进行安全性研究，并开发准备供应临床材料的制造工艺。之后 完成这些目标后，我们将很好地提交IND，为我们的第一次临床试验做准备。

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.