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

摘要 处方阿片类药物滥用和成瘾是患者和社会的主要负担，导致重大费用，疾病和死亡。i）处方阿片类药物滥用的广泛和日益增加，以及ii）处方者不愿开具阿片类镇痛药处方的交织问题导致中度至重度疼痛患者治疗不足。目前有几种滥用威慑类阿片产品（主要是制剂）已上市或正在临床开发中，但它们不能抵抗滥用。与这些基于配方的策略相比，Ensysce Biosciences创造了两种互补的新技术，可以控制已知阿片类药物的释放。Ensysce Biosciences的BIO-MD™与MPAR™前药的抗滥用特征是在分子水平上赋予的。 我们的Bio-MD™ [生物活化分子递送]系统是“生物活化”的，可释放临床有效的阿片类药物 仅当暴露于正确的生理条件（即，摄入并暴露于小肠中的胰蛋白酶）。我们 前药提供了许多阻止滥用的重要特征。这些包括：i）μ-阿片受体活性低，ii） IV给药后向阿片类药物的全身转化最小，iii）对常见的家庭用药耐药， 干预/提取方法，和iv）阿片样物质释放的PK曲线是前药固有的，而不是基于制剂。 阿片类药物抵抗口服和胃肠外滥用对社会的潜在益处是相当大的。我们已经在人体临床试验中评估了Bio-MD™阿片类药物产品，并成功证明了具有缓释特性的活性阿片类药物的口服给药。 MPAR™（抗多药丸滥用）涉及从我们的Bio-MD™系统中原位生物调节阿片类药物的递送， 能够控制口服多剂量药代动力学（PK）曲线。MPAR™口服过量保护是通过与Bio-MD™系统共同配制的胰蛋白酶抑制剂的作用来实现的。由于同时摄入多个剂量，胰蛋白酶的“生物活化”逐渐受到抑制，从而产生治疗有效剂量的阿片类药物，而没有口服过量的风险。我们的羟考酮前药PF 614的MPAR ™保护作用已在大鼠和犬种中成功证实。 本提案的目的是推进MPAR TM技术，并最终将我们的大鼠/犬MPAR TM 因此，我们的目标是将阿片类BIO-MDTM产品用于人体，并消除阿片类BIO-MDTM产品口服过量的可能性。

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.