PF614 MPAR Abuse Deterrent opioid prodrug with overdose protection: Pre-Clinical Development and Phase 1 Clinical Trial

摘要 处方阿片类药物的滥用和成瘾是患者和社会的主要负担，导致巨大的成本、疾病和死亡。一)处方阿片类药物普遍和日益严重的滥用，以及二)处方医生不愿开阿片类止痛药处方，这些相互交织的问题导致中度至重度疼痛的患者得不到足够的治疗。目前有几种具有抗滥用威慑作用的阿片类药物(主要是制剂)在市场上销售或在临床开发中，但它们不能抵抗滥用。与这些以配方为基础的战略不同，Ensysce生物科学公司创造了两种互补的新技术，控制已知阿片类药物的释放。从分子水平上介绍了Ensysce Bio-MD™与MPAR™前药的抗滥用特性。 我们的Bio-MD™[生物激活的分子递送]系统是生物激活的，可以释放临床上有效的阿片类药物 仅当暴露在正确的生理条件下(即，摄入并暴露在小肠中的胰酶)。我们的 前药提供了一些重要的特征来阻止滥用。这些包括：i)µ-阿片受体活性低，ii) 静脉注射后向阿片类药物的最小全身转换，III)对普通家庭的抗药性 篡改/提取方法，以及四)阿片类药物释放的PK曲线是前药固有的，而不是基于配方。 一种同时抵抗口服和肠外滥用的阿片类药物对社会的潜在好处是相当大的。我们已经在人体临床试验中评估了Bio-MD™阿片产品，并成功地展示了具有延缓释放特征的活性阿片类药物的口服给药。 MPAR™(多药滥用抵抗)涉及我们的Bio-MD™系统对阿片类药物输送的原位生物调节， 实现对口服多剂量药代动力学(PK)曲线的控制。MPAR™口服过量保护是通过与Bio-MD™系统共同配方的胰酶抑制剂的作用而实现的。随着多剂量的共同摄入，胰酶的“生物激活”被逐渐抑制，导致治疗有效剂量的阿片类药物，而不存在口服过量的风险。我们的羟考酮前体药物PF614的MPARTM保护作用已在大鼠和狗身上成功证明。 这项建议的目标是推进MPARTM技术，并最终将我们的老鼠/狗MPARTM 结果进入人体，并消除阿片类生物MDTM产品的口服过量潜力。

Abstract Prescription opioid abuse and addiction are major burdens to patients and society, resulting in significant costs, illnesses, and deaths. The intertwined issues of i) the widespread and increasing 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 or in clinical development, but they fall short of being resistant to abuse. In contrast to these formulation-based strategies, Ensysce Biosciences has created two complementary, novel technologies that control the release of known opioids. The abuse resistant features of Ensysce Biosciences' BIO-MD™ with MPAR™ prodrugs are imparted at the molecular level. Our Bio-MD™ [Bio-Activated Molecular Delivery] systems are “bio-activated” to release clinically effective opioid drugs only when exposed to the correct physiologic conditions (i.e., ingested and exposed to trypsin in the small bowel). Our prodrugs provide a number of important features to deter abuse. These include: i) low activity at the µ-opioid receptor, ii) minimal systemic conversion to opioid following IV administration, iii) resistant to common household tampering/extraction methods, and iv) the PK profile of opioid release is inherent to the prodrug, not based on a formulation. The potential benefits to society of an opioid that resists both oral and parenteral abuse are considerable. We have evaluated Bio-MD™ opioid products in human clinical trials and demonstrated successfully the oral delivery of active opioids with extended release profiles. MPAR™ (multi-pill abuse resistance) involves in situ bio-regulation of opioid delivery from our Bio-MD™ systems, enabling control over oral multi-dose pharmacokinetic (PK) profiles. MPAR™ oral overdose protection is conferred by the action of a trypsin inhibitor that is co-formulated with the Bio-MD™ system. As multiple doses are co-ingested, the trypsin “bio-activation” is progressively inhibited, resulting in a therapeutically effective dose of opioid without the risk of oral overdose. MPARTM protection of our oxycodone prodrug PF614 has been successfully demonstrated in both rat and dog species. The objective of this proposal is to advance the MPARTM technology and ultimately to translate our rat/dog MPARTM results into humans, and to eliminate the oral overdose potential of opioid BIO-MDTM products.