Systematic Development of Antiretroviral Intravaginal Rings for HIV Prevention

描述(申请人提供)：高效抗逆转录病毒疗法(HAART)，其中抗逆转录病毒(ARV)药物联合给予，已成为治疗艾滋病毒/艾滋病的标准。越来越多的人达成共识，认为抗逆转录病毒药物的组合对于预防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。这一IPCP-MBP的首要目标是开发基于ARV组合的阴道内环(IVR)配方，以预防艾滋病毒的性传播，强调发展中国家妇女的需求。到目前为止，许多障碍阻碍了安全有效的局部联合NBP产品的开发，包括：缺乏选择最佳组合的可靠筛选过程；难以制定局部给药的组合；在临床试验阶段推进新型候选药物的时间很长；对复杂给药平台的可制造性和制造规模的担忧；以及临床试验中混淆疗效和安全性确定的依从性问题。该方案由5个项目和2个核心项目组成，旨在克服这些障碍，采用一种创新战略，通过系统和合理的筛选渠道推进多药静脉注射受体资料库。富马酸替诺福韦双丙酯(TDF)和恩曲他滨(FTC)的初始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)和替代疗效(项目3)。同时，TDF-FTC Lead和8种替代ARV IVR配方将在一种新的筛选过程中进行评估，该程序使用定量指标，使用定义明确的定量“通过/不通过”标准，从安全性和有效性方面选择表现最好的候选药物。制造临床cGMP的方法和能力许多性能最好的组合IVR将在支持IND的关键路径项目(项目5)中开发，使最安全和最有效的候选药物在IPCP结束时迅速进入I期临床试验。并行筛查和临床方法加速了最终导联向IPCP后I期临床试验的过渡：如果选择TDF-FTC，则在IPCP内完成启用IND的关键路径，并可以开始I期试验；如果选择替代组合，则制造和临床程序已经到位，可以将最终、最安全和最有效的导联IVR快速推进到I期临床试验。这项工作的成功完成具有特别重要的意义，因为它采用了系统、科学的流水线战略，以明确、定量的决策点为基础，加速、合理地开发用于艾滋病毒预防的抗逆转录病毒IVR先导组合，并减少多年后认识到应该推进TDF-FTC以外的组合。

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.