Document text
Principal Investigator: Frances Rudnick Levin
Organization: PHOENIX PHARMALABS, INC.
Fiscal Year: 2024
Award: $3,623,079
Funding agency: National Institute on Drug Abuse
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.
Terms: <ADME Study><Absorption, Distribution, Metabolism, and Excretion Study><Affinity><Agonist><Alcohol Chemical Class><Alcohols><Analgesic Agents><Analgesic Drugs><Analgesic Preparation><Analgesics><Animals><Anodynes><Antinociceptive Agents><Antinociceptive Drugs><Attenuated><Behavior><Bioavailability><Biological><Biological Availability><Blood Pressure><Brain><Brain Nervous System><Buprenorphine><Businesses><Cardiac Chronotropism><Cardiovascular Physiology><Chemicals><Chronic><Clinical><Cocaine><Cocaine use disorder><Code><Coding System><Common Rat Strains><Constipation><Cross-Over Studies><Crossover Studies><Crystal Meth><Crystal methamphetamine><Data><Deoxyephedrine><Desoxyephedrine><Development><Disease><Disorder><Dose><Drug Interactions><Drug Kinetics><Drug Therapy><Drug abuse><Drug usage><Drugs><Early-Stage Clinical Trials><Effectiveness><Encephalon><Eye><Eyeball><Family><Female><Financial Support><Formulation><Freeze Drying><Freeze Dryings><Funding><Future><Genetic Toxicology><Goals><Heart Rate><Human><Human Volunteers><Husband><In Vitro><Laboratories><Licensing><Ligands><Lyophilization><M mulatta><M. mulatta><Macaca mulatta><Medication><Methamphetamine><Methamphetamine use disorder><Methylamphetamine><Modern Man><N-Methylamphetamine><NIDA><Nalorex><Naltrexone><Names><National Institute of Drug Abuse><National Institute on Drug Abuse><Nemexin><Nicotine><Opiate Receptors><Opiates><Opioid><Opioid Receptor><Pharmaceutical Preparations><Pharmacokinetics><Pharmacology><Pharmacotherapy><Phase 1 Clinical Trials><Phase I Clinical Trials><Physiologic Availability><Polymorph><Powder dose form><Powders><Pre IND FDA meeting><Pre-IND mtg><Privatization><Process><Public Health><Rat><Rats Mammals><Rattus><ReVia><Receptor Protein><Regulatory Affairs><Relapse><Research Priority><Respiration><Rewards><Rhesus Macaque><Rhesus Monkey><Rodent><Rodentia><Rodents Mammals><Running><Safety><Self Administered><Self Administration><Societies><Sodium Chloride><Specific qualifier value><Specified><System><Testing><Therapeutic><Toxic effect><Toxicities><Toxicogenetics><Toxicology><Toxicology Genetics><Treatment Efficacy><Universities><Vivitrol><Work><abuse of drugs><abused drug><abused drugs><abuses drugs><addiction><addictive disorder><alcohol abuse therapy><alcohol abuse treatment><alcohol treatment><antagonism><antagonist><attenuate><attenuates><biologic><cardiovascular function><cocaine seeking><cocaine self-administration><craving><design><designing><developmental><drug abused><drug discovery><drug of abuse><drug reward><drug treatment><drug use><drug/agent><drugs abused><drugs of abuse><effective therapy><effective treatment><efficacy study><experience><experiment><experimental research><experimental study><experiments><financial assistance><first in man><first-in-human><in vivo><inhibitor><intervention efficacy><lung function><male><manufacture><manufacturing process development><meth><meth abuse><meth use disorder><methamphetamine abuse><mu receptors><name><named><naming><non-human primate><nonhuman primate><novel><opiate consumption><opiate drug use><opiate intake><opiate use><opioid consumption><opioid drug use><opioid intake><opioid use><pain killer><pain medication><pain reliever><painkiller><phase I protocol><pre-IND consultation><pre-IND discussion><pre-IND enabling studies><pre-IND experiments><pre-IND meeting><pre-IND studies><pre-Investigational New Drug meeting><pre-clinical><pre-clinical development><pre-clinical study><preclinical><preclinical development><preclinical study><prevent><preventing><process optimization><product development><programs><psychostimulant><psychostimulant abuse><public-private partnership><pulmonary function><receptor><respiratory mechanism><safety study><salt><screening><screenings><self-administer cocaine><sex><side effect><stability testing><stimulant abuse><success><therapeutic agent development><therapeutic development><therapeutic efficacy><therapy efficacy><μ receptors>