Abstract Prescription opioid abuse, addiction and overdose are major burdens to patients and society, resulting in significant costs, illnesses, and deaths. The intertwined issues of i) the ongoing abuse of prescription opioids, and ii) reluctance of prescribers to write prescriptions for opioid analgesics, have resulted in the under-treatment of patients with moderate-to-severe pain. Several abuse-deterrent opioid products (primarily formulations) are currently marketed, but they fall short of being resistant to abuse. Notably, currently marketed abuse deterrent technologies do not effectively deter one of the most common forms of opioid abuse – swallowing an increased number of tablets or capsules than are prescribed. In order to address this crisis Ensysce Biosciences has created two complementary, novel technologies that control the release of known opioids. The abuse resistant and overdose protection features of Ensysce Biosciences’ TAAP™ (Trypsin Activated Abuse Protection) with MPAR® (multi-pill-abuse-resistant) prodrugs are built into the chemical modification of the opioid and are not just formulation-based changes. PF614-MPAR is the first opioid being developed with overdose protection. PF614-MPAR is a combination product of the TAAP-oxycodone prodrug, PF614, and the trypsin inhibitor nafamostat. Because exposure to trypsin is required to activate PF614 for the release of oxycodone, it provides a number of features that deter abuse while addition of nafamostat adds the overdose protection. As a combination product, we have filed two INDs to evaluate both PF614 and the trypsin inhibitor separately for safety and PK, and have filed a third IND to evaluate the combination. The data from the Phase 1 study that evaluated the combination of PF614 and nafamostat, have provided the first proof of concept that we can deliver pain relieving levels of oxycodone from PF614-MPAR administration and still achieve overdose protection. The overdose protection of PF614-MPAR only is activated when more than a prescribed dose is taken at one time. The amount of nafamostat in a dose unit of PF614-MPAR is designed to be ineffective when taken at the prescribed dose. However, small increments over the prescribed dose or if taken in large excess, the increased amount of nafamostat will inhibit the trypsin conversion of PF614 to oxycodone reducing the opioid release. It is designed to put the brakes on the activation of PF614 if too much is taken at one time, averting an overdose. We have now examined the PF614-MPAR 25 mg dosage strength in a two-part Phase 1 study and found that the combination showed an equivalent safety profile to PF614 alone. A 25 mg PF614-MPAR dose unit was defined in Part 1 of the study and proof-of-concept was demonstrated successfully when overdose protection was provided when excess PF614-MPAR 25 mg was taken simultaneously in Part 2. PF614-MPAR was designed to allow an anticipated prescribed dose of 1 to 2 dose units twice daily to provide relief from severe pain. If more than a prescribed dose is consumed the increased amount of nafamostat ingested from the combination product is sufficient to inhibit the activity of trypsin, therefore allowing excess inactive PF614 prodrug to pass through the body unchanged and ultimately prevent an overdose. The objective of this proposal is to continue the clinical development of PF614-MPAR ensure all dosage strengths 25, 50 and 100 mg, have the same ability to provide pain relief at prescribed dose but overdose protection at greater than prescribed dose levels. A multi-ascending dose study will evaluate PF614-MPAR 25, 50 and 100 mg for safety and ensure that repeat dosing of the combination product does not result in attenuation of the oxycodone release from PF614 at anticipated prescribed doses of 2 pill equivalents delivered orally, twice daily. These studies will be carried out in parallel with non- clinical studies that are needed to support a New Drug Application.

Narrative Prescription opioid abuse and addiction are major burdens to patients and society, resulting in significant costs, illnesses, and deaths from overdose. Ensysce Biosciences has created two complementary, novel technologies that control the release of known opioids and limit their use to oral administration. The abuse resistant features of Ensysce Biosciences’ TAAP™ and MPAR are built into the chemical modification of each prodrug. Our TAAP (Trypsin Activated Abuse Protection) prodrugs are “activated” by our own body to release clinically effective opioid drugs when swallowed and exposed to a ‘food digesting’ enzyme call trypsin found only in the gastrointestinal track. MPAR (multi-pill abuse resistance) involves regulation of the opioid delivery through the use of an added trypsin inhibitor in combination with the TAAP prodrugs, providing oral overdose protection to our opioid products. We have combined our TAAP oxycodone prodrug, PF614 with the trypsin inhibitor, nafamostat to produce PF614-MPAR. This combination with overdose protection has been evaluated in a two-part Phase 1 study which defined the 25 mg dosage strength combination. PF614-MPAR has shown to have a good safety profile and all the similar features of PF614 alone, with added overdose protection. The objective of this proposal is to advance the clinical development of PF614-MPAR through a multi-ascending dose study to move this highly novel opioid with overdose protection to a NDA and FDA approval as quickly as possible.