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.

Project Narrative: Nalmefene Implant for the Long-Term Treatment of Opioid Use Disorder The goal is to develop an implantable 6-month product that safely provides enhanced compliance towards preventing relapse following detoxification in opioid use disorder (OUD) patients and potential overdose death; about 2.1 million patients in the U.S. and around 64,000 drug overdose deaths in 2016. OUD patients in remission have a high rate of relapse to opioid use, and treatment with opioid antagonists like nalmefene can be an effective treatment for preventing relapse; however, low patient compliance to the frequent daily dosing necessary has prevented widespread adoption. Clinical grade subdermal implants that provide long-term continuous delivery of nalmefene will be manufactured and studied in OUD patients to generate data in support of a New Drug Application for this novel product, which has the potential to improve treatment effectiveness and enhance compliance, lower societal costs, and significantly contribute towards alleviating the deadly consequences of this epidemic.