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日益增加的负担突出了对新型安全有效的预防策略的迫切需要，如局部杀微生物剂。我们假设，一个真正安全有效的杀微生物剂将需要持续的，本地交付的药物组合，目标在艾滋病毒生命周期的不同步骤和交付系统，解决与遵守有关的挑战。安全的杀微生物剂不应干扰宿主防御，也不应增加选择耐药病毒的风险。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。该迭代计划的目标是开发一种通过阴道环（IVR）递送的复合杀微生物剂，以预防艾滋病毒的性传播。这将通过IVR制剂的双重活性单一药物，嘧啶二酮，这是一个强大的逆转录酶和进入抑制剂，或通过结合两种不同的抗逆转录病毒（ARV）药物。我们将通过联合阿昔洛韦和抗逆转录病毒药物来提供局部持续的HSV抑制，来解决HIV和HSV之间生物协同作用的重要性。杀微生物剂和制剂的安全性将使用设计用于评估其对上皮屏障和粘膜免疫的影响的新型测定法进行探索。将进行探索性临床研究，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，以检查三种不同聚氨酯环的安全性和耐受性，以确定用于配制杀微生物剂环的最佳组成。本研究的结果将指导我们的先导药物的IVR制剂，其将用于进一步的安全性和监管研究，包括猕猴PK和安全性研究。提出了一项I期前临床研究，以评估我们的主要IVR配制的杀微生物剂的PK和安全性，并使用加标策略确定释放的药物是否保留其抗病毒活性。 相关性：这些研究将为开发安全有效的IVR联合杀微生物剂预防HIV和抑制HSV提供重要信息。这些研究还将解决杀微生物剂科学的关键空白，重点是开发持续输送系统和安全生物标志物。 项目1：多靶向组合杀微生物剂预防HIV和HSV的有效性和安全性（赫罗尔德，B） 项目1描述（由申请人提供）：局部杀微生物剂，一种女性控制的预防艾滋病毒的策略，在阻止大流行方面至关重要。最佳的杀微生物剂应该保护免受感染，而不破坏粘膜环境或其宿主防御介质。该项目的重点是联合杀微生物剂的临床前评价，目的是确定安全有效的预防策略。将优先考虑针对艾滋病毒生命周期中至少两个步骤的组合，从而提供针对循环耐药病毒的保护，并降低药物选择耐药变体的风险。这将通过单一抗逆转录病毒药物（ARV）的双重活性来实现，嘧啶二酮是一种有效的逆转录酶抑制剂，也可以阻止艾滋病毒进入，或者通过结合两种不同的ARV杀微生物剂来实现。HIV和HSV之间的生物协同作用将通过评估阿昔洛韦与ARV杀微生物剂联合给药以提供局部持续抑制HSV复制的可能性来解决。关注HSV抑制的基本原理反映了发展中国家预先存在的HSV-2高患病率（60-90%），以及压倒性的生物学和流行病学证据表明，亚临床HSV复发（非常常见）增加了HIV感染的风险。杀微生物剂开发的关键差距是缺乏可预测安全性和有效性的生物标志物。该项目将通过开发和扩大新的检测方法来解决这些差距，该方法侧重于杀微生物剂和阴道环境之间的相互作用，使用原代细胞，外植体培养物，双室培养系统和小鼠模型。拟定的安全性模型侧重于持续给药对上皮完整性和生殖道粘膜免疫的影响。通过检查双重培养模型中HIV穿过上皮屏障能力的变化和小鼠生殖器疱疹易感性的变化，评估任何观察到的变化的生物学意义。从这些研究中获得的结果将为新型安全有效的复合杀微生物剂的发展提供重要信息。

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.