Principal Investigator: Vasisht, Niraj ABSTRACT The opioid epidemic is ravaging the United States, as drug overdose deaths reported have risen almost four- fold from 2002 to 2015. In 2016, over 64,000 deaths from opioid overdose occurred in the US, which predominantly occur due to respiratory depression as a result of agonism of the µ-opioid receptor (MOR). Rescue of victims of opioid overdose is accomplished by treatment with antagonist drugs that can reverse the respiratory depression. The currently used rescue medication is naloxone that is available in generic injection (Narcan®), intranasal (IN Narcan®) and an auto-injector (Evzio®) forms. However, naloxone has serious liver toxicity, a short half-life, and its complete antagonism results in emesis due to a withdrawal effect. Nalmefene is a FDA approved opioid derivative that is an antagonist of the MOR and a weak agonist of the k-opioid receptors (KOR). An immediate release intravenous injectable formulation was approved by the US FDA in 1995 for opioid overdose, however, the requirement for intravenous administration has limited its clinical use. Since nalmefene has a longer elimination half-life than naloxone, the need for repeat dosing in the case of accidental overdose of long acting opioids is decreased. Furthermore, nalmefene has significantly less hepatotoxicity than compared to naloxone, thus providing a safer option for opioid users that have hepatic impairment. Avior aims to develop a fast-onset, rapidly-dissolving, mucoadhesive thin film formulation that carries a uniformly distributed nalmefene nanoparticles on the surface of the film. This film, produced using Avior’s proprietary Speedit™ transmucosal drug delivery technology, rapidly delivers nalmefene when the film is placed in contact with the lower lining of the inner lip. This innovative product is designed for simplicity for non-medical personnel to administer in case of emergency, thus offering an alternative option for the first responder in the treatment of accidental opioid overdose. During this Phase I SBIR, Avior will prepare nalmefene nanoparticle- based, mucoadhesive, transmucosal films and evaluate the pharmacokinetic profile of nalmefene formulations to determine the suitability for overdose rescue and/or use as prophylaxis by first-responders and emergency care personnel because of its safer drug profile as compared to Naloxone. Through this Phase I project, we will generate non-clinical data to support critical human clinical trials to determine if a transmucosal film can be developed with a rapid onset of action that is required for rescue of opioid overdose patients or taken prophylactically to prevent respiratory depression. Our goal is to assess the effective speed of delivery. If successful in demonstrating that a plasma concentration (Cp) equal to 3.7 ng/mL (the mean dose achieved by IV nalmefene that is effective in overdose reversal) is achieved by 5 minutes, we will move forward to conduct a human clinical trial using Phase II grant funds. 1

Principal Investigator: Vasisht, Niraj NARRATIVE Among 47,055 drug overdose deaths that occurred in 2014 in the United States, 28,647 (60.9%) involved an opioid. This problem is accelerating with over 64,000 deaths from opioid overdose in 2016. The majority of deaths is a result of respiratory depression caused by agonist binding to the µ-opioid receptor (MOR). Thus, rapid delivery of antagonists of the MOR provide the ability to rescue the overdosed patients. Avior aims to develop a fast-onset, rapidly-dissolving, mucoadhesive transmucosal thin film that carries a uniformly distributed nalmefene nanoparticles. This film, produced using Avior’s proprietary Speedit™ transmucosal drug delivery technology, rapidly delivers nalmefene when the film is placed in contact with the lower lining of the inner lip. Importantly, the product is simple so that non-medical personnel can administer the rescue medication in case of overdose. During this Phase I SBIR, Avior will evaluate the suitability of the nalmefene formulations to provide this life- saving medication in a rapid manner that is required for overdose rescue. Through this Phase I project, we will generate non-clinical data to support critical human clinical trials to determine if a transmucosal film can be developed with a rapid onset of action that is required for rescue of opioid overdose patients or taken prophylactically to prevent respiratory depression. Our goal is to assess the effective speed of onset. If successful in demonstrating equal to or superior absorption as compared to naloxone, our goal is to conduct a human clinical trial using Phase II grant funds. 2