Arylepoxamides: A new class of potent, safer analgesics

芳基环酰胺：一类新型强效、更安全的镇痛药

基本信息

批准号：
10291187
负责人：
YING-XIAN PAN
金额：
$ 32.95万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-15 至 2021-07-31
项目状态：
已结题

项目摘要

Project Summary: This supplemental funding application proposes to address unforeseen, yet solvable issues which arose in the development of SBS-1000 which is being funded by the parent grant DA048379-01 entitled “Arylepoxamides: A new class of potent, safer analgesics.” The parent UG3 grant provides funding for CMC development and IND-enabling toxicology studies for SBS-1000 and the UH3 funds phase 1 clinical trials. SBS-1000 is a novel analgesic acting through a newly discovered target – the AEAr. In preclinical studies, SBS-1000 has demonstrated potent analgesia across nociceptive, neuropathic, and inflammatory pain models and has not demonstrated respiratory depression, abuse liability, or physical dependence. The initial scale up API synthesis, purification and formulation development proved challenging for Patheon/Thermo Fisher and resulted in unrecognized process impurities and a formulation that required a strong buffer and low pH. The combination of the impurities, acidic formulation, and an aggressive dosing paradigm at Charles River Labs lead to spurious results in the 7-day non-GLP rat toxicology study. These results were inconsistent with the MTD rat and dog studies, the 7-day non- GLP dog study, and 8 years of prior data accumulated from academic and industry sponsored research. Re-examination of the API and formulation indicate that the toxicity was a result of the vehicle and experimental design rather than the drug itself. This application proposes to specifically address these unforeseen events and develop a new purification method, optimize the formulation, and repeat the 7- day non-GLP rat toxicology study. We are confident that these aims are achievable given that we have already made progress in a purification method, have generated preliminary data on a new formulation, and have decided on a different dosing paradigm for the rat tox study. The supplemental funding we are requesting is critical to complete this work and address the unforeseen CMC and tox issues. The remaining funding in the parent grant is all allocated for the GMP manufacturing and GLP studies which will be required to meet the UG3 milestone and for IND submission. Beyond the complications outlined in this application there have been no drug-related issues to preclude the successful development of SBS-1000 from either the exploratory tox work, MTD studies, the 7-day non- GLP dog study, or any of the in vitro assays. NOTE: MP1000 = SBS-1000 - MP1000 was laboratory name used in original grant application. SBS-1000 the new name from Sparian Biosciences

项目摘要：这项补充资金申请建议解决了无法预见但可解决的问题，这出现在SBS-1000的开发中，由父母赠款DA048379-01资助 “ Arylepoxamides：一种新的潜力，更安全的镇痛药。”父母UG3赠款为 CMC开发和SBS-1000和UH3基金1阶段的毒理学研究临床试验。 SBS-1000是一种新颖的镇痛药，它通过新发现的目标 - AEAR。在临床前研究，SBS-1000在伤害性，神经性和炎症性疼痛模型，尚未表现出呼吸抑郁症，虐待责任或身体依赖。初始规模提高API合成，纯化和配方开发为挑战提供了挑战 Patheon/Thermo Fisher，导致未识别的过程杂质和一个公式需要强大的缓冲液和低pH值。杂质，酸性配方和A的组合查尔斯河实验室的积极给药范式导致7天非GLP大鼠的虚假结果毒理学研究。这些结果与MTD大鼠和狗研究不一致，这是7天的非 - GLP Dog研究以及从学术和行业赞助的研究中积累了8年的先前数据。重新检查API和制定指标，表明毒性是车辆的结果实验设计而不是药物本身。本申请提案专门解决这些不可预见的事件并开发了一种新的纯化方法，优化公式并重复7-- 日非GLP大鼠毒理学研究。我们相信这些目标是可以实现的已经在纯化方法中取得了进展，已经在新公式上生成了初步数据，并为大鼠TOX研究决定了不同的剂量范例。我们的补充资金要求完成这项工作至关重要，并解决不可预见的CMC和TOX问题。父母赠款中的剩余资金全部分配给GMP制造和GLP研究将要求达到UG3里程碑并提交IND。超越概述的并发症在此应用中，没有与毒品有关的问题来排除成功发展探索性毒品工作，MTD研究，7天的非GLP狗研究或任何一项的SBS-1000 体外测定。注意：MP1000 = SBS-1000 -MP1000是原始赠款应用程序中使用的实验室名称。 SBS-1000 Sparian Biosciences的新名称