Arylepoxamides: A new class of potent, safer analgesics

项目总结： 这项补充资金申请建议解决无法预见但可解决的问题， 出现在SBS-1000的开发中，该项目由名为DA048379-01的母公司资助 芳泊沙胺：一种新的强效、更安全的止痛药。母公司UG3赠款提供资金用于 SBS-1000和UH3基金第一阶段的CMC开发和启用IND的毒理学研究 临床试验。SBS-1000是一种通过新发现的靶点--AAR发挥作用的新型止痛药。在……里面 临床前研究表明，SBS-1000对伤害性、神经病理性和 炎症性疼痛模型，没有表现出呼吸抑制、滥用倾向或身体 依赖。 最初的放大原料药合成、纯化和配方开发被证明是具有挑战性的 Patheon/Thermo Fisher，并导致无法识别的工艺杂质和配方 需要很强的缓冲液和低pH值。杂质、酸性配方和AN的组合 Charles River实验室的积极剂量模式导致7日龄非GLP大鼠出现虚假结果 毒理学研究。这些结果与MTD大鼠和狗的研究不一致，7天的非 GLP狗研究，以及8年前从学术和行业赞助的研究中积累的数据。 对原料药和配方的重新检查表明，毒性是由于车辆和 实验设计而不是药物本身。此应用程序建议专门解决这些问题 意外事件，开发新的提纯方法，优化配方，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，因为我们已经 已经在提纯方法方面取得了进展，已经产生了关于新配方的初步数据， 并决定为老鼠毒性研究选择不同的剂量范例。我们的补充资金 对完成这项工作和解决不可预见的CMC和毒性问题至关重要。这个 家长资助金中的剩余资金全部分配给GMP制造和GLP研究，这些研究 将被要求达到UG3里程碑和IND提交。超越概述的复杂情况 在这项应用中，没有与药物有关的问题阻碍了成功的开发 SBS-1000来自探索性毒性工作、MTD研究、为期7天的非GLP犬研究或以下任何一项 体外检测。 注：MP1000=SBS-1000 -MP1000是最初拨款申请中使用的实验室名称。斯帕里安生物科学公司的新名称--SBS-1000

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