Critical Path IND-enabling Studies, Regulatory, and Product Development

本项目（项目6）的目标是开展关键的IND导向路径活动，将两种适用于阴道或直肠隔室的新型双隔室局部杀微生物剂凝胶推进到IND阶段，为1期临床试验前做准备。活性药物成分（API）将是IQP-0528，一种有效的小分子量抗病毒化合物，已显示可完全杀灭体外HIV感染模型，阻断培养物中感染的建立和传播。IQP-0528的独特之处在于其具有两种不同的抗HIV作用机制：通过与非核苷结合位点相互作用阻断病毒进入和抑制病毒聚合酶，原则上构成单一API中的药物组合。其中一种正在开发的凝胶将含有IQP-0528作为唯一的API，第二种凝胶将在 依序方式，将含有IQP-0528和替诺福韦（TFV），一种充分表征的抗逆转录病毒化合物，其被批准用于感染个体中HIV复制的系统控制，其也已成功地作为单一药剂用于局部杀微生物剂环境中。本项目中提出的将对两种局部杀微生物剂凝胶进行的关键路径IND使能研究是（1）合成， GMP IQP-0528 API的放行和稳定性检测，（2）作为提案一部分在ImQuest开发的候选双室凝胶的GMP生产、放行和稳定性，（3）生产用于非临床安全性和毒理学研究的非GMP双室凝胶产品，（4）进行适当的非临床GLP和非GLP安全性和毒理学研究，（5）提交可批准的 IND包装，用于阴道和直肠隔室中每种凝胶的临床研究，以及（6）生产灌装支持，用于评价非处方凝胶，以定义直肠隔室中展开的凝胶的用户可接受性参数。

The goal of the this project (Project 6) is to perform the critical IND-directed path activities necessary to advance two novel dual compartment topical microbicide gels that are suitable for use in either the vaginal or rectal compartments to the IND stage in preparation for pre-Phase 1 clinical testing. The active pharmaceutical ingredient (API) will be IQP-0528, a potent, small molecular weight antiviral compound that has been shown to completely sterilize an in vitro HIV infection model, blocking the establishment and spread of infection in the culture. IQP-0528 is unique in that it possesses two distinct mechanisms of anti-HIV action; blockade of viral entry and inhibition of the viral polymerase through interaction with a non-nucleoside binding site, in principle, constituting a combination of drugs in a single API. One of the gels being developed will contain IQP-0528 as the only API, the second gel, which will be developed in a sequential fashion, will contain both IQP-0528 and tenofovir (TFV), a well characterized anti-retroviral compound that is approved for systemic control of HIV replication in infected individuals that has also been used with some success as a single agent in the topical microbicide setting. The critical path IND-enabling studies proposed in this project that will be executed for two topical microbicide gel are (1) synthesis, release and stability testing of GMP IQP-0528 API, (2) GMP production, release and stability of the candidate dual compartment gel developed at ImQuest as part of the proposal, (3) production of non-GMP dual compartment gel products for use in nonclinical safety and toxicology studies, (4) conduct of the appropriate nonclinical GLP and non-GLP safety and toxicological studies, (5) submission of a approvable IND package for the clinical study of the each gel in both the vaginal and rectal compartments, and (6) manufacturing filling support for the evaluation of over-the-counter gels for the purpose of defining user acceptability parameters for gels deployed in the rectal compartment.