Abstract Prescription opioid abuse and addiction are major burdens to patients and society, resulting in significant costs, illnesses, and deaths. Approximately 3 million persons in the United States and almost 16 million worldwide have a current or past opioid-use disorder (OUD). Because opioid-withdrawal syndromes are caused by rapidly decreasing drug levels after repeated exposure, symptoms can be reduced by administering other opioids to diminish symptoms and then weaning the patient off the new drug. Methadone is useful in the treatment of opioid dependence. As the use of methadone has increased over the past decade, there has also been an increase in the amount of diversion and abuse of the drug. It is much easier to overdose on methadone than other opioid drugs. Furthermore, there has been an alarming increase in methadone related fatalities in patients that have been prescribed the drug The intertwined issues of i) the widespread and increasing abuse of prescription opioids, and ii) the diversion and abuse of methadone and iii) deaths due to the interindividual variation of response to methadone have led us to focus on a producing safer methadone product to reduce overdose in patients suffering from OUD. Ensysce Biosciences has created two complementary, novel technologies that it is applying to methadone. The abuse resistant features of Ensysce Biosciences’ TAAP™ with MPAR™ prodrugs are imparted at the molecular level. Our TAAP™ [Trypsin Activated Abuse Protection] prodrugs are “enzyme-activated” to release clinically effective opioid drugs only when taken orally and exposed to the correct physiologic conditions (i.e., ingested and exposed to trypsin in the small bowel). We have evaluated TAAP™ opioid products in human clinical trials and demonstrated successfully the oral delivery of active opioids with extended release profiles. MPAR™ [multi-pill abuse resistance] involves in situ bio-regulation of opioid delivery from our TAAP™ systems, enabling control over oral multi-dose pharmacokinetic (PK) profiles. MPAR™ oral overdose protection is conferred by the action of a trypsin inhibitor, nafamostat, that is co-formulated with the TAAP™ system. As multiple doses are co-ingested, the trypsin “bio-activation” is progressively inhibited, resulting in a therapeutically effective dose of opioid without the risk of oral overdose. MPARTM protection of our opioid prodrugs has been successfully demonstrated in both rat and dog species, and evaluated in a human Phase 1 trial. The potential benefits to society of a product that resists both oral and parenteral abuse are considerable Methadone, an oral mu-opioid agonist, has a high potential for abuse that can be quite lethal due to its long half-life in an overdose situation usually as a result of respiratory depression. The R-methadone drug product is not available in the US, but it has been reported to have reduced QT-interval prolongation as compared to the S enantiomer. It is envisaged that a R-methadone-TAAP prodrug would demonstrate similar reduced abuse potential as we have shown with other opioid-TAAP products, have reduced cardiac toxicity, and combined with nafamostat, a R-methadone/TAAP/MPAR product could reduce methadone overdose that often results in death. The objective of this proposal is to develop an R-methadone/TAAP/MPARTM drug through Phase 1 clinical studies, to translate our TAAP/MPARTM results into humans, to ultimately reduce the abuse and oral overdose potential of methadone.

Narrative Prescription opioid abuse and addiction are major burdens to patients and society, resulting in significant costs, illnesses, and deaths. Approximately 3 million persons in the United States and almost 16 million worldwide have a current or past opioid-use disorder (OUD). Methadone is useful in the treatment of opioid dependence. As the use of methadone has increased over the past decade, there has also been an increase in the amount of diversion and abuse of the drug. It is much easier to overdose on methadone than other opioid drugs. Ensysce Biosciences has created two complementary, novel technologies that control the release of prescription drugs, limit their use to oral administration, and provide abuse resistant and overdose protection features. The platforms, TAAP™ with MPAR™, impart protection by limiting release of the active agent to oral administration, and overcome potential overdose by preventing release when too many pills are consumed. Methadone is widely used for OUD but also has a high potential for abuse and can be quite lethal due to its long half-life in the body. The R-methadone drug product is not available in the US, but it has been reported to have reduced cardiac side effects. Ensysce is developing an R-methadone-TAAP prodrug with reduced abuse potential as we have shown with other opioid-TAAP products, and reduced cardiac toxicity. This R-methadone-TAAP will be ultimately be combined into a R- methadone/TAAP/MPAR combination product to reduce methadone overdose that often results in death.