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

摘要 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 对NOP和μ受体具有部分激动剂活性，对κ和δ具有拮抗剂活性的受体配体。 这种化合物最初由Lawrence Toll博士和Stephen Husbands博士在NIDA资助的努力中合成， 现在已获得Phoenix PharmaLabs（PPL）的许可，Toll博士是该公司的创始人。此化合物 在大鼠中证明是可卡因和METH自我给药和恢复的有效抑制剂， 并且在大鼠或NHP中不自我给药。啮齿类动物中的其他药代动力学和安全性研究， NHP已被证明对呼吸、便秘、心率或血压几乎没有影响， 剂量，从而证明大的表观治疗窗。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使PPL-138的奖励更少，阻断效果更好 药物奖励比丁丙诺啡，一种化合物被证明可以减少对精神兴奋剂的渴望。在这 一个拟议的项目，PPL将侧重于可卡因使用障碍（CUD），着眼于继续甲基使用障碍 (MUD)，在未来。为了开发PPL-138，PPL组建了一支经验丰富的团队， 药理学、化学品生产、IND使能临床前研究、监管和首次人体研究 并计划将PPL-138贯穿每一步，最终进入I期临床试验。为了实现这些目标， 实验的设计包括以下5个目标。在Wake进行的特定目标1研究 森林大学将进行最终的疗效研究，以确定PPL-138是否有效地减少 可卡因自我管理和复发的NHP，因为它是在大鼠。具体目标2，将继续化学 包括生产工艺开发和优化、配方和GMP 药品开发和生产。具体目标3由药物发现和毒理学指导 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， 能够进行体外和体内GLP毒理学研究，以及支持ADME研究。这些将建立在 该化合物的前许可证持有人已经完成的研究和PPL资助的当前研究。 具体目标4将由ICON指导，并致力于制定监管流程和提交IND。 最后，具体目标5将包括第一次在人类研究，由博士弗朗西斯莱文和图标运行， 单次给药剂量递增（SAD）和多次给药剂量递增（MAD）研究，随后进行单次给药 人类志愿者的交叉研究。与专家团队开发一种非常安全的化合物， 作用机制，我们期望确定在人类中NOP/mu部分激动剂是否可以安全地 有效减少精神兴奋剂滥用。重要的是，PPL致力于提供大量的财政支持， 支持这个项目，使其在公共/私营伙伴关系的精神，在建议书中具体说明。

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.