Nalmefene Implant for the Long-Term Treatment of Opioid Use Disorder

项目摘要： 纳美芬埋植剂长期治疗阿片类药物使用障碍 美国目前面临着一个重大危机，因为阿片类药物过量导致的死亡人数不断增加， 美国人患有慢性疾病，称为阿片类药物使用障碍（OUD）。阿片类药物的危害 滥用和成瘾也会造成巨大的经济代价。阿片类激动剂药物治疗OUD， 或在用阿片样物质拮抗剂解毒后，是安全有效的，并且可以减少或消除 戒断症状，减弱或阻断非法阿片类药物的作用，并减少或消除渴望。但安 缓解期OUD受试者有很高的机会复发阿片类药物使用;这可能发生在任何时间-从少数 排毒后几天到几个月。阿片类拮抗剂的预防性治疗可以阻断 阿片类药物的使用，可以有效地预防戒毒后OUD复发， 过量死亡;然而，患者对维持脑阿片类药物所需的频繁给药依从性低 受体阻断阻止了广泛采用。对慢性治疗的迫切需求尚未得到满足 范例能够提供6个月或更长时间的增强依从性，以防止OUD复发， 脱毒受试者的再麻醉。泰坦专有的皮下植入物可以提供长期的，非- 在单次基于办公室的插入程序之后，药物的治疗水平持续波动。非 可生物降解的固体基质植入物制剂实际上消除了意外药物倾倒的风险， 相关的严重毒性，其皮下位置可确保患者对6个月治疗的依从性 持续时间盐酸纳美芬（纳美芬）是一种阿片受体拮抗剂， 以及阿片类药物过量的逆转，包括呼吸抑制。与其他阿片类拮抗剂相比， 包括更高的效力、更长的半衰期和无肝毒性。纳美芬植入物原型 在大鼠中皮下连续递送纳美芬数月而没有任何可观察到的安全性问题。的 数据表明，一个三植入物可能提供足够的药物，以提供高达90%的阻塞， 人脑阿片受体因为纳美芬是FDA批准的药物，而且泰坦的植入物 该技术已在用于OUD维持治疗的获批和上市产品中得到验证， 开发该产品的潜在监管风险相对较低。发展可能具有成本效益 并且该产品用于预防复发的成功商业化的可能性很高， 阿片类药物戒毒后的阿片类药物依赖。目标是开发一种6个月的植入式设备 以稳定的速度全天候提供纳美芬，以防止阿片类药物依赖复发， 阿片类药物解毒目标是生产纳美芬植入物，完成非临床安全性， 药理学研究，并在OUD受试者中进行临床研究，以支持新药申请。这 新产品可能会提高治疗的有效性，提高依从性，降低个体 这将大大有助于减轻这一流行病的致命后果。

Project Summary: Nalmefene Implant for the Long-Term Treatment of Opioid Use Disorder The U.S. currently faces a major crisis from the increasing number of deaths due to opioid overdose among Americans afflicted with the chronic medical condition called opioid use disorder (OUD). Harm from opioid misuse and addiction also comes at a huge economic cost. Pharmacotherapy for OUD with an opioid agonist, or following detoxification with an opioid antagonist, is safe and effective, and can reduce or eliminate withdrawal symptoms, blunt or block the effects of illicit opioids, and reduce or eliminate cravings. However, an OUD subject in remission has a high chance of relapse to opioid use; which can occur at any time - from a few days to months following detoxification. Prophylactic treatment with opioid antagonists can block the effect of opioid use and can be an effective treatment for preventing OUD relapse following detoxification and potential overdose death; however, low patient compliance to frequent dosing necessary to maintain brain opioid receptor blockade has prevented widespread adoption. There is an urgent unmet need for a chronic treatment paradigm capable of providing enhanced compliance for 6-months or longer to prevent OUD relapse and renarcotization in detoxified subjects. Titan's proprietary subdermal implants can provide long-term, non- fluctuating therapeutic levels of drug continuously following a single office-based insertion procedure. The non- biodegradable solid matrix implant formulation virtually eliminates the risk of accidental drug dumping and associated serious toxicity, and its subdermal location assures patient compliance for the 6-month treatment duration. Nalmefene hydrochloride (nalmefene) is an opioid receptor antagonist approved for the management and reversal of opioid overdose, including respiratory depression. Its advantage over other opioid antagonists includes higher potency, longer half-life, and no liver toxicity. Prototype nalmefene implants inserted subdermally in rats delivered nalmefene continuously for months without any observable safety concerns. The data suggests that one-three implants could potentially deliver sufficient drug to provide up to 90% blockage of human brain opioid receptors. Since nalmefene is an FDA approved drug, and because Titan's implant technology has been validated in an approved and marketed product for the maintenance treatment of OUD, the potential regulatory risk for developing this product is relatively low. Development could be cost-effective and the probability is high for successful commercialization of this product for the prevention of relapse to opioid dependence, following opioid detoxification. The objective is to develop a 6-month implantable device that delivers nalmefene around the clock at a steady rate to prevent relapse to opioid dependence following opioid detoxification. The goals are to manufacture nalmefene implants, complete nonclinical safety and pharmacology studies, and conduct clinical studies in OUD subjects to support a New Drug Application. This novel product could potentially improve effectiveness of the treatment, enhance compliance, lower individual and societal costs, and significantly contribute towards alleviating the deadly consequences of this epidemic.