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

项目概要：该补充资金申请旨在解决不可预见但可解决的问题出现在 SBS-1000 的开发中，该项目由母基金 DA048379-01 资助，题为 “芳基环酰胺：一种新型强效、更安全的镇痛药。”母公司 UG3 拨款为以下项目提供资金： SBS-1000 的 CMC 开发和 IND 毒理学研究以及 UH3 基金第一阶段 SBS-1000 是一种通过新发现的靶点——AEAr In 发挥作用的新型镇痛药。临床前研究表明，SBS-1000 对伤害性、神经性和神经性疼痛具有有效的镇痛作用。炎性疼痛模型，尚未表现出呼吸抑制、滥用倾向或身体不适依赖性。事实证明，最初扩大 API 合成、纯化和配方开发的规模具有挑战性 Patheon/Thermo Fisher 产生了无法识别的工艺杂质和配方需要强缓冲剂和低 pH 值，结合了杂质、酸性配方和 Charles River 实验室的激进剂量模式导致 7 天非 GLP 大鼠出现虚假结果这些结果与 MTD 大鼠和狗研究（7 天非-MTD）不一致。 GLP 狗研究，以及从学术和行业资助的研究中积累的 8 年先前数据。对 API 和配方的重新检查表明毒性是由载体和实验设计而不是药物本身。本申请旨在专门解决这些问题。意外事件并开发新的纯化方法，优化配方，并重复7- 鉴于我们已经完成了一天的非 GLP 大鼠毒理学研究，我们相信这些目标是可以实现的。已经在纯化方法方面取得了进展，已经生成了新配方的初步数据，并决定为大鼠毒性研究采用不同的剂量模式我们的补充资金。要求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。母公司拨款中的剩余资金全部分配给 GMP 生产和 GLP 研究，需要满足 UG3 里程碑并提交 IND 超出概述的复杂性。在本申请中，不存在妨碍成功开发的药物相关问题 SBS-1000 来自探索性毒物工作、MTD 研究、7 天非 GLP 狗研究或任何体外测定。注：MP1000 = SBS-1000 - MP1000 是原始资助申请中使用的实验室名称，SBS-1000 是 Sparian Biosciences 的新名称。