Systematic Development of Antiretroviral Intravaginal Rings for HIV Prevention

用于预防艾滋病毒的抗逆转录病毒阴道环的系统开发

• 批准号: 8765700
• 负责人: Marc Michael Baum
• 金额: $ 327.49万
• 依托单位: OAK CREST INSTITUTE OF SCIENCE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-11 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8765700
• 关键词: AIDS prevention; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adherence; Anatomy; Animals; Anti-Retroviral Agents; Antiviral Agents; Benchmarking; Biological Assay; Blood; CD4 Positive T Lymphocytes; Cell Culture System; Cell Culture Techniques; Cellular Structures; Cessation of life; Clinical; Clinical Research; Clinical Trials; Complex; Consensus; Critical Pathways; Cyclic GMP; Cytomegalovirus Retinitis; Data; Development; Devices; Dosage Forms; Dose; Drug Delivery Systems; Drug Exposure; Drug Formulations; Drug Interactions; Drug Kinetics; Environment; Enzymes; Epithelial Cells; Epithelium; Evaluation; FDA approved; Failure; Future; Goals; HIV; HIV Infections; HIV therapy; Highly Active Antiretroviral Therapy; Human; Imaging Techniques; In Situ; Individual; Integrase Inhibitors; Knowledge; Lead; Leadership; Learning; Libraries; Light; Liquid substance; Macaca; Malaria; Manufacturer Name; Measures; Membrane Transport Proteins; Methods; Metric; Microbial Biofilms; Modeling; Monitor; Mus; Oral; Outcome; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Preparation; Prevention; Prevention strategy; Procedures; Process; Prophylactic treatment; Protease Inhibitor; Regimen; Role; Safety; Sampling; Sheep; Tenofovir disoproxil fumarate; Testing; Time; TimeLine; Tissue Model; Tissues; Toxic effect; Triplet Multiple Birth; Tuberculosis; Vagina; Vaginal Ring; Vaginal delivery procedure; Virus; Woman; Work; World Health; base; cervicovaginal; clinical efficacy; drinking water; empowered; emtricitabine; experience; improved; in vivo; industry partner; inhibitor/antagonist; innovation; manufacturing scale-up; microbicide; mouse model; non-nucleoside reverse transcriptase inhibitors; novel; pharmacodynamic model; pharmacokinetic model; prevent; product development; programs; public health relevance; research clinical testing; response; screening; simian human immunodeficiency virus; spatiotemporal; transmission process

DESCRIPTION (provided by applicant): Highly Active Antiretroviral Therapy (HAART), where antiretroviral (ARV) drugs are given in combination, has become the standard in treatment of HIV/AIDS. There is growing consensus that combinations of ARV drugs will be essential for an optimally effective non-vaccine biomedical prevention (nBP) product against HIV. The overarching goal of this IPCP-MBP is to develop intravaginal ring (IVR) formulations based on ARV combinations for prevention of sexual HIV transmission, emphasizing the needs of women in the developing world. A number of obstacles have thus far prevented the development of a safe and effective topical combination nBP product, including: lack of an reliable screening process to select an optimal combination; difficulty in formulating combinations for topical delivery; long timelines to advance novel candidates through the clinical trial phase; concern with manufacturability and manufacturing scale-up for complex delivery platforms; and issues with adherence confounding determination of efficacy and safety in clinical trials. This Program, consisting of 5 Projects and 2 Cores, aims to overcome these obstacles by applying an innovative strategy to advance a library of multidrug IVRs through a systematic and rational screening pipeline. An initial lead combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) will undergo a (pre-Phase I) Exploratory Clinical Trial (Project 4) in healthy women to assess pharmacokinetics (Project 1), safety (Project 2), and surrogate efficacy (Project 3). Concurrently, the TDF-FTC lead and 8 alternative ARV IVR formulations will be assessed in a novel screening process using quantitative metrics to select the best-performing candidate, in terms of safety and efficacy, using well-defined, quantitative "go/no-go" criteria. Methods and capacity to manufacture clinical cGMP lots of the best-performing combination IVR will be developed in the IND-enabling critical path Project (Project 5), allowing rapid advancement of the safest and most efficacious candidate into Phase I clinical trials at the conclusion of the IPCP. The parallel screening and clinical approach accelerates transition of the final lead to post-IPCP Phase I clinical trials: If TDF-FTC is selected, the IND- enabling critical path is completed within the IPCP and Phase I trials can begin; if an alternative combination is selected, the manufacturing and clinical procedures are in place for rapid advancement of the final, safest and most efficacious lead combination IVR into Phase I clinical trials. Successful completion of this work is of exceptional significance because it uses a systematic, scientific pipeline strategy, based on clear, quantitative decision points, for the accelerated, rational development of a lead combination ARV IVR for HIV prevention, and mitigates against learning, years later, that combinations other than TDF-FTC should have been advanced.

描述（由申请人提供）：高效抗逆转录病毒疗法（HAART），即联合给予抗逆转录病毒（ARV）药物，已成为治疗艾滋病毒/艾滋病的标准。人们越来越一致认为，抗逆转录病毒药物的组合对于针对艾滋病毒的最佳有效非疫苗生物医学预防 (nBP) 产品至关重要。该 IPCP-MBP 的总体目标是开发基于 ARV 组合的阴道环 (IVR) 制剂，用于预防 HIV 性传播，强调发展中国家妇女的需求。迄今为止，许多障碍阻碍了安全有效的局部组合 nBP 产品的开发，包括： 缺乏可靠的筛选过程来选择最佳组合；难以制定局部给药组合；推进新候选药物进入临床试验阶段的时间较长；关注复杂交付平台的可制造性和制造规模；以及依从性问题混淆了临床试验中有效性和安全性的确定。该计划由 5 个项目和 2 个核心组成，旨在通过应用创新策略，通过系统且合理的筛选流程推进多药 IVR 库，从而克服这些障碍。富马酸替诺福韦二吡呋酯 (TDF) 和恩曲他滨 (FTC) 的初始先导组合将在健康女性中进行（第一阶段前）探索性临床试验（项目 4），以评估药代动力学（项目 1）、安全性（项目 2）和替代功效（项目 3）。同时，TDF-FTC 主要制剂和 8 种替代 ARV IVR 制剂将在新颖的筛选过程中使用定量指标进行评估，以选择安全性和有效性方面表现最佳的候选药物，并使用明确的定量“通过/不通过”标准。临床 cGMP 批次的最佳性能组合 IVR 的生产方法和能力将在支持 IND 的关键路径项目（项目 5）中开发，以便在 IPCP 结束时将最安全、最有效的候选药物快速推进到 I 期临床试验。并行筛选和临床方法加速了最终线索向 IPCP 后 I 期临床试验的过渡：如果选择 TDF-FTC，则 IND 关键路径在 IPCP 内完成，I 期试验可以开始；如果选择替代组合，则生产和临床程序已到位，可将最终、最安全和最有效的先导组合 IVR 快速推进至 I 期临床试验。这项工作的成功完成具有特殊意义，因为它采用了基于明确、定量决策点的系统、科学的管道策略，以加速、合理地开发用于预防艾滋病毒的先导组合抗逆转录病毒药物 IVR，并减轻数年后人们认为应该推进 TDF-FTC 以外的组合的情况。