Arylepoxamides: A new class of potent, safer analgesics

项目摘要： 这项补充资金申请旨在解决不可预见但可以解决的问题， 在SBS-1000的开发中出现，SBS-1000由母基金DA 048379 -01资助， ”《明史》：“一种新的、更有效的药物。母UG 3赠款提供资金， SBS-1000和UH 3基金第1阶段的CMC开发和IND启用毒理学研究 临床试验SBS-1000是一种通过新发现的靶点-AEAr发挥作用的新型镇痛剂。在 在临床前研究中，SBS-1000已证明对伤害性、神经性和 炎症性疼痛模型，并且没有表现出呼吸抑制，滥用倾向或身体 依赖 初步规模扩大的API合成、纯化和制剂开发证明具有挑战性， Patheon/Thermo Fisher，并导致未识别的工艺杂质和 需要强缓冲液和低pH。杂质、酸性制剂和 Charles River实验室的激进给药模式导致7天非GLP大鼠中的假结果 毒理学研究这些结果与MTD大鼠和犬研究不一致，7天非 GLP犬研究，以及从学术和行业申办的研究中积累的8年既往数据。 对API和制剂的重新检查表明，毒性是由溶剂引起的， 实验设计，而不是药物本身。本申请建议专门解决这些问题 开发新的纯化方法，优化配方，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，因为我们 已经在纯化方法方面取得了进展，已经产生了关于新配方的初步数据， 并已决定对大鼠毒性研究采用不同的给药模式。补充资金，我们 对于完成这项工作并解决不可预见的CMC和毒性问题至关重要。的 母基金中的剩余资金全部分配给GMP生产和GLP研究， 将需要满足UG 3里程碑和IND提交。除了概述的并发症 在本申请中，没有药物相关问题妨碍成功开发 SBS-1000来自探索性毒性工作、MTD研究、7天非GLP犬研究或任何 体外试验。 注：MP 1000 = SBS-1000 - MP 1000是在原始资助申请中使用的实验室名称。SBS-1000-Sparian Biosciences的新名称

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