1-Year Sustained Release Naltrexone Implant for the prevention of relapse to opioid dependence

阿片类药物流行造成的人类和经济损失是惊人的。阿片类药物使用障碍（OUD） 作为一种慢性疾病，药物辅助治疗（MAT）现在被认为是一线和必不可少的 长期治疗的一部分。FDA批准的治疗OUD的药物，包括纳洛酮，是有效的， 拯救生命长期保持药物治疗与改善结果相关。这些都是一些 美国国家科学院最近的一份共识报告的结论。2017年超过1100万人 滥用阿片类药物，超过200万人报告患有OUD。药物过量是导致 在过去的3年里，美国的意外死亡和阿片类药物过量死亡降低了美国的预期寿命。 年2017年，阿片类药物危机的年度成本估计为1150亿美元。MAT是一个主要的 联邦应对美国阿片类药物流行的支柱。纳洛酮是三种药物之一 通常用于治疗OUD，可作为每日一次的药丸或每月一次的注射剂。现有 制剂持续时间短，PK特征差，导致药物依从性差， 4个月后低至10%。缺乏OUD患者的长效预防性药理学选择 在维持治疗期间是未满足的医疗需求。Delpor处于一个独特的位置，可以迅速做出贡献。 申报产品是一种钛植入物，装载有纳洛酮制剂和天然存在的 羧酸·dmso该装置通过定制的植入工具皮下植入腹部，局部 在一个简单的10分钟的办公室程序中进行麻醉。该技术基于一种独特的配方， 保持储库内的pH较低，并且在这样做时，促进纳洛酮的被动扩散。的好处 包括：a）一次给药后1年内完全坚持用药B）复发率更低 c）平稳的PK曲线，确保完全预防而没有亚治疗血浆谷， 在需要疼痛治疗的情况下（事故、手术），和e）相同的功效，较少的药物暴露。 该技术已在另一种药物（利培酮）的临床上得到验证，并在临床前进行了测试， 纳洛酮。已经选择了优选的纳洛酮制剂;初步动物数据表明为零级 药物释放没有下降，我们预测，1年的系统是可以实现的人类受试者2-3 装置.本申请的UG 3阶段包括完成化学生产和控制， 生产IND供应品，进行IND启用安全性研究，并提交IND。 一个里程碑是接受IND。UH 3阶段将完成所需的开发计划， NDA提交。该计划将遵循505（B）（2）监管路径，提供快速审查，并利用 Delpor领先项目的研究已经完成。开发方案技术风险低， 批准的可能性。拟议的项目将导致1年纳洛酮的NDA提交 在5年内植入，预计将减少复发，增加治疗成功率，并降低医疗费用。

The human and economic toll of the opioid epidemic is staggering. Opioid Use Disorder (OUD) is recognized as a chronic condition and Medication Assisted Treatment (MAT) is now considered first-line and an essential component of long-term treatment. FDA-approved drugs to treat OUD, including naltrexone, are effective and save lives. Long-term retention on medications is associated with improved outcomes. These are some of the conclusions of a recent National Academy of Sciences consensus report. In 2017 over 11 million people misused opioids, and over 2 million people reported having OUD. Drug overdose is the leading cause of accidental death in the US, and opioid overdose deaths drove down the US life expectancy over the last 3 years. The annual cost of the opioid crisis was estimated at $115 billion in 2017. MAT is one of the major pillars of the federal response to the opioid epidemic in the US. Naltrexone is one of the 3 medications commonly used to treat OUD, available as a once daily pill, or as a once-monthly injectable. Existing formulations have a short duration and a poor PK profile, resulting in poor medication adherence, with retention as low as 10% after 4 months. The lack of longer acting prophylactic pharmacologic options for OUD patients during maintenance therapy is an unmet medical need. Delpor is in a unique position to contribute, and quickly. The proposed product is a titanium implant loaded with a formulation of naltrexone and a naturally occurring carboxylic acid. The device is implanted subcutaneously in the abdomen via a custom implanter tool, with local anesthetic during a simple 10-minute in-office procedure. The technology is based on a unique formulation that keeps the pH within the reservoir low, and in doing so, promotes passive diffusion of naltrexone. The benefits of the product include: a) complete medication adherence for 1 year after one administration b) fewer relapses c) smooth PK profile ensuring complete prophylaxis without sub-therapeutic plasma troughs, d) full reversibility in case pain treatment is needed (accident, surgery), and e) same efficacy with less drug exposure. The technology has been validated clinically with another drug (risperidone), and tested preclinically with naltrexone. A preferred naltrexone formulation has been selected; preliminary animal data indicate zero order drug release without decline, and we predict that a 1-year system is achievable in human subjects with 2-3 devices. The UG3 phase of this application includes finalizing the Chemistry Manufacturing and Controls, producing IND supplies, conducting an IND enabling safety study, and submitting the IND. The UG3 transition milestone is the acceptance of the IND. The UH3 phase will complete the development program required for an NDA submission. The program will follow the 505(b)(2) regulatory path offering expedited review, and utilize studies already completed for Delpor’s lead program. The development plan has low technical risk, maximizing the probability of approval. The proposed project will result in an NDA submission for a 1-year naltrexone implant within 5 years, expected to reduce relapses, increase treatment success, and reduce healthcare costs.