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

日益严重的艾滋病毒流行病及其给妇女带来的负担日益加重，突出表明迫切需要新的安全有效的预防战略，例如局部使用的杀微生物剂。我们假设，真正安全和有效的杀微生物剂将需要持续、当地提供针对艾滋病毒生命周期不同步骤的药物组合，以及解决与坚持相关的挑战的交付系统。一种安全的杀微生物剂不应干扰宿主防御，也不应增加选择抗药性病毒的风险。要实现这一目标，需要对杀菌剂进行更严格的临床前和临床评估，重点是它们与生殖道粘膜环境的相互作用。这一迭代计划的目标是开发一种通过阴道内环(IVR)传递的组合杀菌剂，以防止艾滋病毒的性传播。这将通过一种双重活性的单一试剂--嘧啶二酮的IVR配方来实现，它既是一种有效的逆转录酶，也是一种进入抑制剂，或者通过将两种不同的抗逆转录病毒(ARV)药物结合起来实现。我们还将通过将阿昔洛韦与抗逆转录病毒药物相结合来提供局部持续的单纯疱疹病毒抑制，从而解决艾滋病毒和单纯疱疹病毒之间生物协同作用的重要性。将使用旨在评估其对上皮屏障和粘膜免疫的影响的新的分析方法来探索这些杀菌剂和制剂的安全性。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菌剂安全性的临床生物标记物提供关键信息。将进行初步研究，检查三种不同的聚氨酯环的安全性和耐受性，以确定配制杀菌剂环的最佳成分。这项研究的结果将指导我们的主导药物的IVR配方，这将被推进到进一步的安全性和监管研究，包括猕猴PK和安全性研究。建议进行一项前期I期临床研究，以评估我们的领先IVR配方杀菌剂的PK和安全性，并使用添加策略确定释放的药物是否保持其抗病毒活性。

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.