Systematic Development of Antiretroviral Intravaginal Rings for HIV Prevention

描述（由申请人提供）：高效抗逆转录病毒疗法（HAART），其中抗逆转录病毒（ARV）药物联合给药，已成为治疗艾滋病毒/艾滋病的标准。越来越多的人认为，抗逆转录病毒药物的组合将是最有效的非疫苗生物医学预防（nBP）产品对艾滋病毒至关重要。IPCP-MBP的总体目标是开发基于ARV组合的阴道环（IVR）制剂，以预防性传播艾滋病毒，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;难以配制用于局部递送的组合;通过临床试验阶段推进新候选物的时间较长;对复杂递送平台的可制造性和制造规模的担忧;以及在临床试验中与疗效和安全性的确定混淆的依从性问题。该计划由5个项目和2个核心组成，旨在通过应用创新战略来克服这些障碍，通过系统和合理的筛选管道来推进多药IVRs库。富马酸替诺福韦酯（TDF）和恩曲他滨（FTC）的初始先导组合将在健康女性中进行（I期前）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先导药物和8种替代ARV IVR制剂将在一种新的筛选过程中使用定量指标进行评估，以选择在安全性和有效性方面表现最佳的候选药物，使用明确定义的定量“通过/不通过”标准。将在IND关键路径项目（项目5）中开发生产最佳组合IVR临床cGMP批次的方法和能力，以便在IPCP结束时快速推进最安全和最有效的候选药物进入I期临床试验。平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启用关键路径在IPCP内完成，I期试验可以开始;如果选择了替代组合，则制造和临床程序已经到位，以快速推进最终，最安全、最有效的电极导线组合IVR进入I期临床试验。这项工作的成功完成具有特殊的意义，因为它使用了一个系统的，科学的管道战略，基于明确的，定量的决策点，加速，合理的开发一个领先的组合ARV IVR预防艾滋病毒，并减轻学习，多年后，其他组合比TDF-FTC应该已经推进。

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.