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）：高度活跃的抗逆转录病毒疗法（HAART），其中抗逆转录病毒（ARV）结合使用，已成为HIV/AIDS治疗的标准。越来越多的共识是，ARV药物的组合对于针对HIV的最佳有效的非疫苗生物医学预防（NBP）产物至关重要。 IPCP-MBP的总体目标是基于预防性HIV传播的ARV组合来开发阴道内环（IVR）配方，强调了发展中国家妇女的需求。迄今为止，许多障碍都阻止了安全有效的局部组合NBP产品的发展，包括：缺乏可靠的筛选过程来选择最佳组合；难以制定局部交付的组合；长时间的时间表可以在临床试验阶段推进新型候选人；关注复杂交付平台的制造性和制造规模；以及依从性的问题，将疗效和安全性的确定混淆。该计划由5个项目和2个核心组成，旨在通过采用创新策略来克服这些障碍，以通过系统和理性的筛选管道来推进多饮用IVR库。替诺福韦富马酸苯甲酸苯甲甲酸酯（TDF）和Emtricerabine（FTC）的初始铅组合将在健康女性中接受（第I）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），（项目2）和替代效率（项目3）。同时，将使用定量指标在新的筛选过程中评估TDF-FTC铅和8种替代ARV IVR公式，以使用定义明确的定量，定量的“ GO/NO-GO”标准，使用定量指标选择最佳表现的候选者。制造临床CGMP的方法和能力最佳组合IVR将在INDANDAND的关键路径项目（项目5）中开发，从而使最安全，最有效的候选者在IPCP结束时迅速发展为I期临床试验。并行筛查和临床方法加速了最终导致IPCP后I期临床试验的过渡：如果选择了TDF-FTC，则可以在IPCP内完成指定的临界路径，并且可以开始I期试验；如果选择了替代组合，则可以快速发展最终，最安全，最有效的铅组合IVR IVR进入I期临床试验的制造和临床程序。这项工作的成功完成具有非凡的意义，因为它使用系统的，科学的管道策略，基于明确的定量决策点，用于加速的，合理的铅组合ARV IVR的合理发展，以减轻预防HIV，并在几年后的学习中进行缓解，以防止TDF-FTC以外的其他组合。