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

新型非激素阴道环预防怀孕和性传播感染的临床前测试

• 批准号: 10700070
• 负责人: Natalia Teleshova
• 金额: $ 40.27万
• 依托单位: POPULATION COUNCIL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700070
• 关键词: AIDS prevention; Adherence; Advanced Development; Advisory Committees; Andrology; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Area; Bacteria; Bacterial Vaginosis; Biological Response Modifiers; Biology; Blood; Calibration; Cells; Cervical; Cervix Mucus; Chemicals; Chlamydia; Clinical; Clinical Trials; Collaborations; Contraceptive Agents; Contraceptive methods; Copper; Copper Sulfate; Data; Development; Dose; Drug Kinetics; Evaluation; Female Condoms; Formulation; Goals; Gonorrhea; HIV; HIV-1; Health; Histology; Hormonal; Human; Human Herpesvirus 2; Immune; In Vitro; Ions; Lactic acid; Lactobacillus; Lead; Macaca mulatta; Male Condoms; Methods; Mus; Oryctolagus cuniculus; Penetration; Pharmaceutical Preparations; Pharmacologic Substance; Population; Positioning Attribute; Preclinical Testing; Pregnancy; Prevention; Prodrugs; Qualifying; Research; Research Personnel; Research Project Grants; STI prevention; Safety; Seminal Plasma; Sexually Transmitted Diseases; Sheep; Simplexvirus; Technology; Testing; Toxic effect; United States Food and Drug Administration; Universities; Vagina; Vaginal Ring; Viral; Woman; Zinc Acetate; antimicrobial; cell motility; cervicovaginal; college; combat; contraceptive efficacy; cost; design; dosage; efficacy testing; hormonal contraception; improved; in vitro activity; in vitro testing; in vivo; in vivo evaluation; innovation; lead candidate; microbiota; multidisciplinary; novel; pre-Investigational New Drug meeting; pre-clinical; pregnancy prevention; prevent; product development; prototype; public health intervention; rRNA Genes; research and development; safety assessment; side effect; skills; sperm cell; technology development; transcriptome; transcriptome sequencing; unintended pregnancy; uptake; vaginal fluid; vaginal microbiota

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.

项目二-摘要 在全球范围内，每年发生8500万次意外怀孕，100多万次性传播 每天都会发生感染（STI），这凸显了人们对改进避孕措施和 预防性传播感染。目前可供妇女使用的多用途预防技术产品， 联合收割机和抗艾滋病毒/性传播感染的预防仅限于女用和男用避孕套。避孕 MPT中的选择主要是激素方法。考虑到激素避孕药的副作用 和许多性传播感染的高发病率，非激素MPT可能对一些妇女有吸引力， MPT开发管道中急需的创新领域，以更好地提供一系列选择， 增加摄取。人口理事会与几个大学伙伴合作，正在编写一本小说， 30-日阴道环（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的总体目标是完成这种独特的临床前测试。 产品，以确定目标API释放和我们的CZL-IVR的总体安全性和有效性。这个项目 将确定我们将追求的关键临床适应症和这种新型三联API的最佳剂量 组合. CZL IVR将使用三种API，使项目2能够校准剂量以最大限度地减少毒性， 最大化功效。这些原料药是低成本、易于获得的化学品，具有现有的安全性，这将 减轻与含有多种API的产品相关的监管挑战。项目2包括 体外（目标1）和小鼠和家兔体内（目标2）避孕和抗STI活性试验; 绵羊体内药代动力学（PK）和局部毒性研究（目标3）;以及深入的安全性/PK和抗- 体内细菌性阴道病效应评估（阴道微生物群、转录组和免疫介质） 恒河猴（Aim 4）。该项目将与项目1密切协调，以通知IVR加载， 选择领导IVR。我们的多学科合作团队是唯一有资格推动 开发这种新型MPT IVR。CZL-IVR将解决非激素避孕药的关键差距 景观，填补用户想要的利基市场，并提供重要的公共卫生干预措施。虽然妊娠 预防将是定义我们的CZL-IVR（三效API）监管方法的主要适应症 该战略提供了更广泛的抗菌益处，将我们的TPP与其他正在开发的TPP区分开来， 寻求监管机构批准避孕以外的适应症的途径。虽然我们的理想产品将 提供保护免受广泛的性传播感染，我们选择追求的具体次要适应症将是 基于我们的临床前数据、监管考虑和咨询委员会的建议。