Preclinical testing of a novel non-hormonal intravaginal ring to prevent pregnancy and sexually transmitted infections

项目二--摘要 在全球，每年发生8500万次意外怀孕，100多万人通过性传播 感染(STI)每天都在发生，强调了对改进避孕措施和 防止性传播感染。目前为妇女提供的多用途预防技术(MPT)产品 联合避孕和抗艾滋病毒/性传播感染预防仅限于女性和男性避孕套。避孕药 MPTS中的选择主要是荷尔蒙方法。考虑到激素避孕药的副作用 和许多性传播感染的高比率，非激素MPT可能对一些女性有吸引力，并将是一种新的和 在MPT开发管道中迫切需要的创新领域，以更好地提供一系列选择和 增加摄取量。在与几个大学合作伙伴的合作下，人口理事会正在开发一种新的 30天阴道内环(IVR)，以防止意外怀孕和性传播感染(单纯疱疹病毒、淋病、 衣原体，可能还有艾滋病毒)，同时促进阴道健康。IVR释放铜、醋酸锌(Za)和 丙交酯(CZL-IVR)。项目2的首要目标是完成这一独特的 以确定我们的CZL-IVR的目标原料药释放和整体安全性和有效性。这个项目 将确定我们将追求的关键临床适应症以及这种新型三元原料药的最佳剂量 组合。CZL-IVR将使用三种原料药，使项目2能够校准剂量以最大限度地减少毒性和 最大限度地发挥功效。原料药是低成本、容易获得的化学品，具有现有的安全概况，这将 缓解与包含多个原料药的产品相关的监管挑战。项目2包括 在体外(目标1)和在小鼠和兔体内(目标2)进行避孕和抗性传播感染活性测试； 在绵羊体内的药代动力学(PK)和局部毒性研究(AIM 3)；以及深入的安全性/PK和抗- 细菌性阴道病的体内效应评估(阴道微生物区系、转录组和免疫介质) 恒河猴(目标4)。该项目将与项目1密切协调，以通知IVR加载和 IVR导联的选择。我们的多学科协作团队是唯一有资格推动 这种新型MPT IVR的开发。CZL-IVR将解决非激素避孕药的一个关键缺口 景观，填补了用户想要的利基市场，并提供了重要的公共卫生干预。在怀孕期间 预防将是定义我们的CZL-IVR，即三活性原料药的监管方法的主要标志 战略提供了更广泛的抗菌益处，使我们的TPP有别于其他正在开发的TPP，并开放了 寻求对避孕以外的适应症进行监管批准的途径。而我们理想的产品将 提供对广泛的性传播感染的保护，我们选择的具体次要适应症将是 基于我们的临床前数据、监管考虑和我们咨询委员会的建议。

PROJECT II – ABSTRACT Globally, 85 million unintended pregnancies occur per year and more than 1 million sexually transmitted infections (STIs) are acquired every day, emphasizing a clear unmet need for improved contraception and protection against STIs. Currently available multipurpose prevention technology (MPT) products for women that combine contraception and anti-HIV/STI prevention are limited to female and male condoms. The contraception options within MPTs are dominated by hormonal methods. Given the side effects of hormonal contraceptives and high rates of many STIs, non-hormonal MPT may be appealing for some women and would be a new and critically needed area of innovation in the MPT development pipeline to better provide a range of options and increase uptake. In collaboration with several university partners, the Population Council is developing a novel 30-day intravaginal ring (IVR) to prevent unintended pregnancy and STIs (herpes simplex virus, gonorrhea, chlamydia, and possibly HIV) while promoting vaginal health. The IVR releases Copper, Zinc acetate (ZA) and Lactide (CZL-IVR). The overarching goal of Project 2 is to complete preclinical testing for this unique product to determine the target API release and the overall safety and efficacy of our CZL-IVR. This project will define the critical clinical indications that we will pursue and the optimal dosing for this novel triple-API combination. The CZL-IVR will utilize three APIs, enabling Project 2 to calibrate dosages to minimize toxicity and maximize efficacy. The APIs are low-cost, easy-to-obtain chemicals with existing safety profiles, which will mitigate the regulatory challenges associated with products containing multiple APIs. Project 2 includes contraceptive and anti-STI activity testing in vitro (Aim 1) and in vivo in mice and rabbits (Aim 2); pharmacokinetics (PK) and local toxicity studies in vivo in sheep (Aim 3); and in-depth safety/PK and anti- bacterial vaginosis effect assessments (vaginal microbiota, transcriptome and immune mediators) in vivo in rhesus macaques (Aim 4). This project will be closely coordinated with Project 1 to inform IVR loading and selection of the lead IVR. Our multidisciplinary collaborative team is uniquely qualified to advance the development of this novel MPT IVR. The CZL-IVR will address a critical gap in the non-hormonal contraceptive landscape, fill a niche that users want and deliver an important public health intervention. While pregnancy prevention will be the primary indication defining the regulatory approach for our CZL-IVR, the triple-active API strategy offers broader antimicrobial benefits, distinguishes our TPP from others under development, and opens avenues for pursuing regulatory approval for indications beyond contraception. While our ideal product will provide protection from a broad range of STIs, the specific secondary indications we chose to pursue will be based on our preclinical data, regulatory considerations, and advice from our advisory committees.