Title: Development of an Affordable, Novel OTC Naloxone Product to Reverse Opioid Overdoses Program Summary (Abstract) Every day, 180 Americans die from opioid overdoses. Starting with the misuse of prescription opioids, then increased use of heroin, and now with the emergence of synthetic and powerful opioids such as fentanyl, the number of overdose deaths will continue to remain high. Naloxone, first approved by the FDA nearly 50 years ago, is a safe and effective opioid antagonist used to treat and reverse opioid overdoses. The auto-injector product EVZIO was approved in 2014 (now discontinued) was priced at $2,000 retail for one dose. The intranasal spray product, Narcan Nasal Spray was approved in 2015 and is priced at $140 retail for two doses. Generic intranasal sprays are currently blocked from entering the market due to patent litigation by the owners of Narcan. Additionally, even though many states do not require a prescription for purchase, these products continue to be kept behind-the-pharmacy counter. Apart from the price, stigma and its associated embarrassment and fear prevents speaking to a pharmacist to purchase a naloxone product. Therefore, the FDA has made an unprecedented call for an over-the-counter (OTC) naloxone products in January 2019 and tested and published a consumer- friendly model drug facts label (DFL) to support urgent development of such products. There are currently no OTC naloxone products approved by the FDA. To address this unmet need, Pocket Naloxone Corp. (PNC) has developed a novel intranasal delivery method for naloxone intended to be affordable and used in OTC settings ($10 per dose). There are precedent clinical pathways for new naloxone products that have been approved by the FDA (although only available with a prescription) including appropriate approaches on study designs to evaluate bioequivalence for PNC’s intranasal naloxone compared to reference naloxone product. A first-in-human pilot clinical study has been completed and the second part of the pilot program will refine dosing and administration. This is expected to begin in second half of 2021 followed by a final pivotal comparative bioequivalence study. The specific aims of this U01 grant are to: (1) Utilize data obtained from pilot first-in-human pharmacokinetic study and initiate new pilot studies to refine administration method and target doses and conduct final pivotal comparative bioequivalence study to naloxone nasal spray; (2) Establish user Instruction for Use for the target general public (lay persons) and consumer drug-fact label through (a) FDA required Human Factors study testing and (b) FDA established label comprehension study; (3) Submit an NDA to the FDA and apply for Priority Review status for the OTC naloxone nasal swab.

Title: Development of an Affordable, Novel OTC Naloxone Product to Reverse Opioid Overdose Public Health Relevance Statement (Narrative): Opioid overdoses were responsible for 50,000 deaths in 2017, and though provisional CDC data for 2018 indicate a slight decrease the numbers have increased to record levels with the pandemic. Naloxone is a safe and effective opioid antagonist, but currently available products have barriers including high price and stigma that limit widespread access to the general public. The proposed project is to develop an affordable novel intranasal naloxone product to be available in OTC settings, thereby meeting the need for widespread access to an easy-to-use naloxone product for reversal of opioid overdose by non-medical individuals.