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

关键路径 IND 支持研究、监管和产品开发

• 批准号: 8405106
• 负责人: Robert Walter Buckheit
• 金额: $ 94.2万
• 依托单位: IMQUEST BIOSCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-22 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8405106
• 关键词: AIDS prevention; Anti-Retroviral Agents; Antiviral Agents; Binding Sites; Biological Assay; Chemicals; Chemistry; Clinical; Clinical Research; Contracts; Critical Pathways; Development; Drug Combinations; Ensure; Evaluation; GMP lots; Gel; Goals; HIV; HIV Infections; Human; In Vitro; Individual; Infection; Infectious Agent; Instruction; International; Local Microbicides; Manufacturer Name; Modality; Modeling; Molecular Weight; Oryctolagus cuniculus; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Placebos; Polymerase; Preparation; Prevention; Production; Qualifying; Route; Safety; Sampling; Secure; Sexually Transmitted Diseases; Source; Staging; Structure; Tenofovir; Testing; Toxicology; Vagina; Validation; Viral; base; drug development; experience; fitness; irritation; lot production; meetings; method development; microbicide; novel; pre-clinical; product development; programs; rectal; research clinical testing; safety testing; stability testing; success; transmission process

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.

该项目(项目6)的目标是进行关键的IND导向路径活动，以推动两种适用于阴道或直肠间隔的新型双室局部杀微生物剂凝胶进入IND阶段，为预阶段1临床试验做准备。活性药物成分(API)将是IQP-0528，这是一种有效的小分子抗病毒化合物，已被证明可以完全消毒体外HIV感染模型，阻止感染在培养中的建立和传播。IQP-0528的独特之处在于它具有两种不同的抗艾滋病毒作用机制：阻止病毒进入和通过与非核苷结合位点相互作用抑制病毒聚合酶，原则上构成单一原料药中的药物组合。正在开发的其中一种凝胶将含有IQP-0528作为唯一的原料药，第二种凝胶将在 该药将同时含有IQP-0528和替诺福韦(TFV)，这是一种具有良好特性的抗逆转录病毒化合物，被批准用于系统控制感染者体内的艾滋病毒复制，在局部杀菌剂环境中作为单一制剂也取得了一些成功。在本项目中提出的对两种外用杀菌剂凝胶进行的关键路径使能研究是(1)合成， GMP IQP-0528原料药的释放和稳定性测试，(2)作为建议的一部分，在ImQuest开发的候选双室凝胶的GMP生产、释放和稳定性，(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 用于阴道和直肠间室中每种凝胶的临床研究的IND包，以及(6)用于评估非处方药凝胶的填充支撑物，目的是确定用于直肠间室中使用的凝胶的用户可接受性参数。