Development of PPL-138, a Novel Mixed NOP/Mu Partial Agonist for Treatment of CocaineUse Disorder

开发 PPL-138，一种用于治疗可卡因使用障碍的新型混合 NOP/Mu 部分激动剂

基本信息

批准号：
10707176
负责人：
Frances Rudnick Levin
金额：
$ 238.03万
依托单位：
PHOENIX PHARMALABS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10707176
关键词：
ADME Study Affinity Agonist Alcohols Analgesics Animals Attenuated Behavior Biological Biological Availability Blood Pressure Brain Buprenorphine Businesses Cardiovascular Physiology Chemicals Chronic Clinical Cocaine Cocaine use disorder Code Constipation Cross-Over Studies Data Development Disease Dose Drug Interactions Drug Kinetics Drug abuse Drug usage Effectiveness Eye Family Female Financial Support Formulation Freeze Drying Funding Future Goals Heart Rate Human Human Volunteers Husband In Vitro Laboratories Licensing Ligands Macaca mulatta Methamphetamine Methamphetamine use disorder Naltrexone Names National Institute of Drug Abuse Nicotine Opioid Opioid Receptor Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase I Clinical Trials Polymorph Powder dose form Privatization Process Public Health Rattus Regulatory Affairs Relapse Research Priority Respiration Rewards Rodent Running Safety Self Administration Societies Sodium Chloride Specific qualifier value System Testing Therapeutic Toxic effect Toxicogenetics Toxicology Treatment Efficacy Universities Work addiction alcohol abuse therapy antagonist cocaine seeking cocaine self-administration craving design drug discovery drug of abuse drug reward effective therapy efficacy study experience experimental study first-in-human forest in vivo inhibitor male manufacture manufacturing process development methamphetamine abuse mu receptors nonhuman primate novel opioid use pre-IND studies pre-Investigational New Drug meeting pre-clinical preclinical development preclinical study prevent process optimization product development programs psychostimulant public-private partnership pulmonary function receptor safety study screening sex side effect stability testing stimulant abuse success therapeutic development

项目摘要

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.

抽象的目前，临床上使用的药物滥用药物用于治疗阿片类药物、酒精和尼古丁成瘾，但不包括可卡因和甲基苯丙胺 (METH) 等精神兴奋剂。 PPL-138 是一种非选择性阿片类药物受体配体，对 NOP 和 mu 受体具有部分激动剂活性，对 kappa 和 delta 具有拮抗剂活性。该化合物最初由 Drs 合成。 Lawrence Toll 和 Stephen Husbands 在 NIDA 资助的努力下，现已获得 Phoenix PharmaLabs (PPL) 的许可，Toll 博士是该公司的创始人。该化合物已被被证明是可卡因和冰毒自我给药和大鼠恢复的有效抑制剂，并且不得在大鼠或 NHP 中自行给药。在啮齿类动物和动物中进行的其他药代动力学和安全性研究 NHP 已被证明对呼吸、便秘、心率或血压（最高可达高水平）几乎没有影响。剂量，从而表现出大的表观治疗窗。我们的假设是 NOP 的增加与丁丙诺啡相比，PPL-138 的受体亲和力和活性较低，但阻断效果更好药物奖励高于丁丙诺啡，丁丙诺啡是一种被证明可以减少对精神兴奋剂的渴望的化合物。在这个拟议项目中，PPL 将重点关注可卡因使用障碍 (CUD)，并着眼于继续冰毒使用障碍（MUD），在未来。为了开发 PPL-138，PPL 组建了一支经验丰富的团队，拥有以下专业知识：药理学、化学制造、支持 IND 的临床前研究、监管以及首次人体研究并计划让 PPL-138 完成每一步，最终进行 I 期临床试验。为了实现这些目标，实验旨在涵盖以下 5 个目标。 Wake 进行的具体目标 1 研究森林大学将进行最终功效研究，以确定 PPL-138 是否能有效减少与大鼠一样，NHP 中可卡因的自我给药和复发。具体目标2，将继续化学制造，涵盖制造工艺开发和优化、配方和 GMP 药品开发和制造。以药物发现和毒理学为指导的具体目标 3 顾问并主要在查尔斯河实验室进行，将包括一个完整的 IND-计划实现体外和体内 GLP 毒理学研究，并支持 ADME 研究。这些将建立在该化合物的先前被许可人已完成的研究以及 PPL 资助的当前研究。具体目标 4 将由 ICON 指导，致力于制定监管流程和提交 IND。最后，具体目标 5 将首先涵盖人类研究，由 Frances Levin 博士指导并由 ICON 运营，进行单剂量递增 (SAD) 和多次递增剂量 (MAD) 研究，然后进行单剂量人类志愿者的交叉研究。专家团队开发了一种非常安全的化合物，具有新颖的作用机制，我们希望确定 NOP/mu 部分激动剂是否可以安全地在人体中使用有效减少精神兴奋剂滥用。重要的是，PPL 致力于提供大量资金支持该项目，以按照提案中的规定本着公私伙伴关系的精神实现这一目标。