Intravaginal Ring Delivery of Safe & Effective Microbicides to Prevent HIV & HSV

描述（由申请人提供）：日益严重的艾滋病毒流行病及其对妇女的负担日益增加，突出表明迫切需要新的安全有效的预防战略，如局部杀微生物剂。我们假设，一种真正安全有效的杀微生物剂将需要针对HIV生命周期中不同阶段的药物组合的持续、局部递送，以及解决与依从性相关的挑战的递送系统。安全的杀菌剂不应干扰宿主防御，也不应增加选择耐药病毒的风险。要实现这一目标，需要对杀微生物剂进行更严格的临床前和临床评估，重点关注它们与生殖道粘膜环境的相互作用。这个迭代项目的目标是开发一种通过阴道内环（IVR）传递的联合杀微生物剂，以防止艾滋病毒的性传播。这将通过一种双活性单药嘧啶二酮的IVR配方来实现，嘧啶二酮既是一种有效的逆转录酶抑制剂，也是一种进入抑制剂，或者通过联合两种不同的抗逆转录病毒（ARV）药物来实现。我们将通过将阿昔洛韦与抗逆转录病毒药物联合使用来提供局部持续的HSV抑制，从而解决HIV与HSV之间生物协同作用的重要性。杀菌剂和配方的安全性将使用新的测定方法来评估它们对上皮屏障和粘膜免疫的影响。将开展探索性临床研究，以评估卢旺达妇女的生殖道粘膜环境，因为确定健康的生殖道环境将为建立杀微生物剂安全性的临床生物标志物提供关键信息。将进行初步研究，检查三种不同聚氨酯环的安全性和耐受性，以确定配制杀微生物环的最佳成分。这项研究的结果将指导我们的先导药物的IVR配方，并将推进进一步的安全性和监管研究，包括猕猴PK和安全性研究。一项I期前临床研究建议评估我们的主要IVR配方杀微生物剂的PK和安全性，并确定释放的药物是否使用尖峰策略保持其抗病毒活性。

DESCRIPTION (provided by applicant): The growing HIV pandemic and its increasing burden on women highlights the urgent need for novel safe and effective preventative strategies such as topical microbicides. We hypothesize that a truly safe and effective microbicide will require sustained, local delivery of a combination of drugs that target different steps in the HIV life cycle and a delivery system that addresses the challenges related to adherence. A safe microbicide should not interfere with host defenses nor increase the risk of selecting for drug resistant viruses. Achieving this goal requires more stringent pre-clinical and clinical evaluation of microbicides, focusing on their interactions with the genital tract mucosal environment. The goal of this iterative Program is to develop a combination microbicide delivered via intravaginal ring (IVR) to prevent the sexual transmission of HIV. This will be accomplished either through IVR formulation of a dual-active single agent, a pyrimidinedione, which is both a potent reverse transcriptase and entry inhibitor, or by combining two distinct antiretroviral (ARV) drugs. We will address the importance of the biological synergy between HIV and HSV by also combining acyclovir with ARV drugs to provide local sustained suppression of HSV. The safety of the microbicides and formulations will be explored using novel assays designed to assess their impact on the epithelial barrier and mucosal immunity. Exploratory clinical studies to evaluate the genital tract mucosal environment of Rwandan women will be conducted as defining the healthy genital tract environment will provide crucial information for establishing clinical biomarkers of microbicide safety. Pilot studies to examine the safety and tolerability of three different polyurethane rings will be conducted to identify the optimal composition for formulation of microbicide rings. Results of this study will guide the IVR formulation of our lead drugs, which will be advanced for further safety and regulatory studies including macaque PK and safety studies. A pre-Phase I clinical study is proposed to evaluate PK and safety of our lead IVR formulated microbicide and to determine if the released drug retains its antiviral activity using a spiking strategy. RELEVANCE: These studies will provide crucial information for advancement of safe and effective IVR combination microbicides to prevent HIV and to suppress HSV. These studies will also address critical gaps in microbicide science focusing on the development of sustained delivery systems and safety biomarkers. PROJECT 1: Efficacy & Safety of Multitargeted Combination Microbicides to Prevent HIV & HSV (Herold, B) PROJECT 1 DESCRIPTION (provided by applicant): Topical microbicides, a female-controlled strategy to prevent HIV, are crucial in stemming the pandemic. An optimal microbicide should protect against infection without disrupting the mucosal environment or its mediators of host defense. This project focuses on the preclinical evaluation of combination microbicides with the goal of identifying safe and effective prevention strategies. Combinations that target at least two steps in the HIV life cycle will be prioritized, thus providing protection against circulating resistant viruses and reducing the risk that the drugs will select for resistant variants. This will be accomplished through the dual activities of a single antiretroviral drug (ARV), a pyrimidinedione, which is a potent reverse transcriptase inhibitor and also blocks HIV entry, or by combining two different ARV microbicides. The biological synergy between HIV and HSV will be addressed by evaluating the possibility of delivering acyclovir in combination with the ARV microbicides to provide local sustained suppression of HSV replication. The rationale for focusing on HSV suppression reflects the pre-existing high prevalence of HSV-2 (60-90%) in the developing world and the overwhelming biological and epidemiological evidence demonstrating that subclinical HSV recurrences, which are quite common, increase the risk for HIV acquisition. Critical gaps in microbicide development are the lack of biomarkers predictive of safety and efficacy. This project will address these gaps by developing and expanding novel assays, which focus on the interactions between microbicides and the vaginal environment, using primary cells, explant cultures, and a dual chamber culture system and murine models. The proposed safety models focus on the impact of sustained drug delivery on epithelial integrity and genital tract mucosal immunity. The biological significance of any observed changes will be assessed by examining changes in the ability of HIV to traverse the epithelial barrier in the dual culture model and changes in the susceptibility to genital herpes in the mouse. Results obtained from these studies will provide crucial information for the advancement of novel safe and effective combination microbicides.