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员和经济损失令人震惊。阿片类药物使用障碍(OUD)被认可 作为一种慢性疾病，药物辅助治疗(MAT)现在被认为是一线的和必要的 长期治疗的组成部分。FDA批准的治疗OUD的药物，包括纳曲酮，是有效的和 拯救生命。长期服药与改善结果有关。以下是一些 美国国家科学院最近一份共识报告的结论。2017年超过1100万人 滥用阿片类药物，200多万人报告服用过。吸毒过量是导致 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人的预期寿命 好几年了。2017年，阿片类药物危机的年度成本估计为1150亿美元。垫子是主要的 联邦政府应对美国阿片类药物流行的支柱。纳曲酮是三种药物之一 通常用于治疗OUD，可作为每日一次的药片或每月一次的注射剂。现有 配方持续时间短，PK曲线差，导致药物依从性差，有滞留 4个月后低至10%。OUD患者缺乏长效预防药物选择 在维持治疗期间是一种未得到满足的医疗需求。德尔福在做出贡献方面处于独特的地位，而且速度很快。 建议的产品是一种钛植入物，含有纳曲酮和自然生成的 羧酸。该装置通过定制的植入器工具植入腹部皮下，局部 在简单的10分钟的办公室程序中使用麻醉剂。这项技术基于一种独特的配方， 使储水池内的pH值保持在较低水平，这样做可以促进纳曲酮的被动扩散。好处是 该产品的优点包括：a)一次服药后完全坚持服药1年；b)减少复发 C)平滑的PK轮廓确保完全预防，而不存在亚治疗性血浆槽，d)完全可逆性 以防需要疼痛治疗(意外、手术)，以及e)以较少的药物暴露获得相同的疗效。 该技术已在另一种药物(利培酮)进行了临床验证，并在临床前进行了测试 纳曲酮。已经选择了首选的纳曲酮配方；初步动物数据显示为零级 药物释放没有下降，我们预测在2-3岁的受试者中可以实现1年的系统 设备。本申请的UG3阶段包括最终确定化学制造和控制， 生产IND用品，进行IND启用安全研究，并提交IND。UG3过渡 里程碑是对IND的接受。UH3阶段将完成以下所需的开发计划 一份保密协议文件。该计划将遵循505(B)(2)监管路径，提供快速审查，并利用 德尔波领先项目的研究已经完成。开发方案技术风险低，最大限度地发挥 获得批准的可能性。拟议的项目将导致提交为期1年的纳曲酮的保密协议 在5年内植入，预计将减少复发，提高治疗成功率，并降低医疗成本。

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.