A novel vaginal ring to prevent HIV and HSV-2 infection, as well as pregnancy

一种预防 HIV 和 HSV-2 感染以及怀孕的新型阴道环

基本信息

批准号：
8264696
负责人：
Melissa J Robbiani
金额：
$ 23.05万
依托单位：
POPULATION COUNCIL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8264696
关键词：
Acquired Immunodeficiency Syndrome Address Anti-HIV Agents Antiviral Agents Binding Biological Assay Biological Markers Cessation of life Chemistry Contraceptive Agents Data Development Dose Drug Delivery Systems Drug Formulations Drug resistance Drug toxicity Ethinyl Estradiol Ethylenes FDA approved Female Condoms Future Gel HIV HIV drug resistance HIV therapy High Pressure Liquid Chromatography Human Human Herpesvirus 2 Implant In Vitro Infection Levonorgestrel Macaca Male Condoms Measurement Measures Medical Mirena Mus Norplant Oral Contraceptives Oryctolagus cuniculus Pharmaceutical Preparations Phase Phase III Clinical Trials Polymers Population Pregnancy Prevention Process Progesterone Receptors Progestins Radioligand Assay Reproductive Health Resistance profile Respiratory Diaphragm Risk Running Salts Science System TMC120-R147681 Technology Tenofovir Testing Time Toxic effect Unplanned pregnancy Vagina Vaginal Ring Vaginal delivery procedure Woman Zinc Zinc Acetate arm contraceptive microbicide design drug resistant virus efficacy testing experience immunoreactivity in vivo microbial alkaline proteinase inhibitor microbicide non-nucleoside reverse transcriptase inhibitors novel particle pill prevent programs prototype receptor binding research clinical testing scale up simian human immunodeficiency virus vinyl acetate virucide

项目摘要

DESCRIPTION (provided by applicant): Multipurpose prevention technologies that block HIV acquisition and pregnancy are urgently needed. We plan to develop a novel EVA (ethylene vinyl acetate) vaginal ring that releases two anti-HIV agents (1 of 2 novel NNRTIs and zinc acetate, ZA) and a low dose progestin only contraceptive (Levonorgestrel, LNG). EVA is the polymer used in the FDA-approved product NuvaRing; MIV-150 and MIV-160 are potent NNRTIs not used in current HIV treatments; ZA prevents SHIV-RT and HSV-2 infection in vivo; and LNG is the most widely used progestin in approved oral contraceptives (in combination with ethinyl estradiol or alone in low dose progestin only contraceptives). We have shown that repeated application of a ZA gel significantly protects macaques against SHIV-RT; a MIV-150/ZA combination gel is even more effective. Recent studies also revealed that EVA rings releasing either MIV-150 or MIV-160 protect macaques against SHIV-RT infection. We propose that combination of MIV-150 or MIV-160 with ZA in a vaginal ring will represent a potent and broad-acting sustained release microbicide. In addition, the WHO-sponsored Phase 3 trial with a vaginal ring releasing 20 mg/d of LNG showed it to be a highly effective contraceptive. We hypothesize that a vaginal ring releasing MIV-150 or MIV- 160, ZA, and LNG will be a novel microbicide/contraceptive drug delivery system that will prevent HIV and HSV-2 infection, as well as release sufficient amounts of LNG to prevent pregnancy. The combination of a potent NNRTI that is not used to treat HIV with ZA represents a unique antiviral strategy to limit drug resistance issues, which will ultimately arise with rings including only one drug against HIV (e.g. dapivirine/LNG or tenofovir/LNG). In the R21 phase of the application we will run in vitro and in vivo studies to determine if combinations of the neat and formulated APIs are stable and effective. Concurrently, we will manufacture EVA rings loaded with the three API combinations and measure release rates and API interactions over time. In the R33 phase, we will transfer the ring technology to a CRO to develop a robust process to manufacture optimized prototype rings. PK/PD, biomarker, and antiviral efficacy studies will be performed in macaques. The formulation chemistry (R21 and R33) and macaque testing (R33) will guide the decision of which NNRTI/ZA/LNG combination ring to move forward for scale up and future clinical testing. This proposal addresses a critical unmet medical need; reducing a woman's simultaneous risk of unplanned pregnancy and HIV/HSV-2, lowering both the number of unplanned pregnancies and deaths due to HIV and complications with pregnancy. PUBLIC HEALTH RELEVANCE: We plan to develop a safe and effective vaginal ring comprising two anti-HIV agents and a contraceptive to protect women from HIV, HSV-2, and unplanned pregnancy. We expect this unique ring will be more effective, particularly in limiting the spread of drug-resistant HIV, than products in development elsewhere that contain only one anti-HIV agent and a contraceptive.

描述（由申请人提供）：迫切需要阻止艾滋病毒感染和怀孕的多用途预防技术。我们计划开发一种新型 EVA（乙烯醋酸乙烯酯）阴道环，可释放两种抗 HIV 药物（两种新型 NNRTI 中的一种和醋酸锌，ZA）和一种低剂量纯孕激素避孕药（左炔诺孕酮，LNG）。 EVA是FDA批准的产品NuvaRing中使用的聚合物； MIV-150 和 MIV-160 是有效的 NNRTI，目前未用于 HIV 治疗； ZA 预防体内 SHIV-RT 和 HSV-2 感染； LNG 是经批准的口服避孕药中使用最广泛的孕激素（与乙炔雌二醇联合使用或单独在低剂量纯孕激素避孕药中使用）。我们已经证明，重复使用 ZA 凝胶可以显着保护猕猴免受 SHIV-RT 感染； MIV-150/ZA 组合凝胶更加有效。最近的研究还表明，EVA 环释放 MIV-150 或 MIV-160，可以保护猕猴免受 SHIV-RT 感染。我们建议 MIV-150 或 MIV-160 与 ZA 在阴道环中的组合将代表一种有效且广泛作用的缓释杀微生物剂。此外，世界卫生组织资助的第 3 期试验显示，阴道环每天释放 20 毫克液化天然气，这是一种高效的避孕方法。我们假设释放 MIV-150 或 MIV-160、ZA 和 LNG 的阴道环将成为一种新型杀菌剂/避孕药物输送系统，可预防 HIV 和 HSV-2 感染，并释放足够量的 LNG 来预防怀孕。不用于治疗 HIV 的有效 NNRTI 与 ZA 的组合代表了一种限制耐药性问题的独特抗病毒策略，这种策略最终将出现在仅包含一种抗 HIV 药物的环中（例如，达匹韦林/LNG 或替诺福韦/LNG）。在应用的 R21 阶段，我们将进行体外和体内研究，以确定纯 API 和配方 API 的组合是否稳定有效。同时，我们将制造装载有三种 API 组合的 EVA 环，并测量随时间推移的释放率和 API 相互作用。在 R33 阶段，我们将把环技术转让给 CRO，以开发稳健的工艺来制造优化的原型环。 PK/PD、生物标志物和抗病毒功效研究将在猕猴中进行。配方化学（R21 和 R33）和猕猴测试（R33）将指导决定哪种 NNRTI/ZA/LNG 组合环将继续扩大规模和未来的临床测试。该提案解决了未满足的关键医疗需求；降低妇女同时发生意外怀孕和 HIV/HSV-2 的风险，从而降低意外怀孕的数量以及因 HIV 和妊娠并发症导致的死亡人数。公共卫生相关性：我们计划开发一种安全有效的阴道环，其中包含两种抗 HIV 药物和一种避孕药，以保护女性免受 HIV、HSV-2 和意外怀孕的感染。我们预计这种独特的环将比其他地方正在开发的仅含有一种抗艾滋病毒药物和避孕药的产品更有效，特别是在限制耐药艾滋病毒的传播方面。