Abstract Currently, clinically used drug abuse medications exist for treatment of addiction to opiates, alcohol, and nicotine, but not psychostimulants such as cocaine and methamphetamine (METH). PPL-138 is a non-selective opioid receptor ligand with partial agonist activity at NOP and mu receptors, and antagonist activity at kappa and delta. This compound, initially synthesized by Drs. Lawrence Toll and Stephen Husbands in a NIDA funded effort, has now been licensed by Phoenix PharmaLabs (PPL), where Dr. Toll is a founder. This compound has been demonstrated to be a potent inhibitor of both cocaine and METH self-administration and reinstatement in rats, and to be not self-administered in rats or NHPs. Additional pharmacokinetic and safety studies in rodents and NHPs have demonstrated little to no effect on respiration, constipation, heart rate or blood pressure, up to high doses, thereby demonstrating a large apparent therapeutic window. It is our hypothesis that the increase in NOP receptor affinity and activity, compared to buprenorphine, renders PPL-138 less rewarding and better at blocking drug reward than buprenorphine, a compound demonstrated to reduce craving for psychostimulants. In this proposed project, PPL will focus on cocaine use disorder (CUD) with an eye on continuing to METH use disorder (MUD), in the future. To develop PPL-138, PPL has put together an experienced team with expertise in pharmacology, chemical manufacturing, IND-enabling preclinical studies, regulatory, and first in human studies and plan to take PPL-138 through each step, culminating in Phase I clinical trials. To accomplish these goals, experiments have been designed to encompass the following 5 aims. Specific Aim 1 studies performed at Wake Forest University will conduct final efficacy studies to determine whether PPL-138 is as effective in reducing cocaine self-administration and relapse in NHPs as it is in rats. Specific Aim 2, will be continue chemical manufacturing and encompass manufacturing process development and optimization, formulation, and GMP drug product development and manufacturing. Specific Aim 3 directed by drug discovery and toxicology consultants and performed primarily at Charles River Laboratories, will include a complete program of IND- enabling in vitro and in vivo GLP toxicology studies, as well as supporting ADME studies. These will build upon studies already completed by the previous licensee of this compound and current studies funded by PPL. Specific Aim 4 will be directed by ICON and devoted to development of regulatory processes and filing an IND. Finally, Specific Aim 5 will encompass first in human studies, directed by Dr. Frances Levin and run by ICON, with Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) studies followed by a Single Dose Crossover study in human volunteers. With the team of experts developing a very safe compound with a novel mechanism of action, we expect to determine in humans whether a NOP/mu partial agonist can safely and effectively reduce psychostimulant abuse. Importantly, PPL is committed to providing considerable financial support for this project to make this in the spirit of a Public/Private Partnership, as specified in the proposal.

Narrative There are currently no approved medications for psychostimulant abuse. Phoenix PharmaLabs has put together a program to develop a novel, non-selective opioid compound (PPL-138) that blocks cocaine and methamphetamine self-administration in rats but is not self-administered in rats or non-human primates. This program will encompass chemical manufacturing, required safety toxicology and all pre-IND studies, filing an IND, and Phase I clinical trials to determine safety in humans. The ultimate goal is to develop PPL-138 as a medication to treat cocaine and methamphetamine use disorder.