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

• 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
• 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

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的EVA(乙烯-乙酸乙烯酯)阴道环，它可以释放两种抗HIV药物(两种新型NNRTI中的一种和醋酸锌，ZA)和一种低剂量的仅限孕激素的避孕药(左旋诺孕酮，LNG)。EVA是FDA批准的产品NuvaRing中使用的聚合物；MIV-150和MIV-160是目前艾滋病毒治疗中未使用的有效NNRTIs；ZA在体内防止SHV-RT和HSV-2感染；LNG是已批准的口服避孕药中使用最广泛的孕激素(与炔雌二醇联合使用或在仅限低剂量孕激素的避孕药中单独使用)。我们已经证明，重复使用ZA凝胶可以显著保护猕猴免受Shiv-RT的感染；MIV-150/ZA组合凝胶甚至更有效。最近的研究还表明，释放MIV-150或MIV-160的EVA环可以保护猕猴免受Shiv-RT感染。我们认为，MIV-150或MIV-160与ZA在阴道环中的组合将是一种有效的、广效的缓释杀菌剂。此外，世界卫生组织赞助的3期临床试验显示，每天释放20毫克液化天然气的阴道环是一种高效的避孕药。我们推测，释放MIV-150或MIV-160、ZA和LNG的阴道环将是一种新型的杀微生物剂/避孕药物输送系统，将防止HIV和HSV-2感染，并释放足够数量的LNG以防止怀孕。一种不用于治疗艾滋病毒的有效NNRTI与ZA的组合代表了一种独特的抗病毒战略，以限制耐药性问题，最终将出现只包括一种抗艾滋病毒药物的环(例如， 达匹韦林/液化天然气或替诺福韦/液化天然气)。在应用的R21阶段，我们将进行体外和体内研究，以确定整洁和配方原料药的组合是否稳定和有效。同时，我们将生产装载了三种原料药组合的EVA环，并测量随着时间的推移释放率和原料药相互作用。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。将在猕猴身上进行PK/PD、生物标记物和抗病毒效果研究。配方化学(R21和R33)和猕猴测试(R33)将指导决定NNRTI/ZA/LNG组合环推进规模扩大和未来的临床测试。这项建议解决了一个关键的未得到满足的医疗需求；降低了妇女同时发生意外怀孕和艾滋病毒/单纯疱疹病毒2型的风险，降低了意外怀孕和因艾滋病毒以及妊娠并发症而死亡的人数。 公共卫生相关性：我们计划开发一种安全有效的阴道环，由两种抗艾滋病毒药物和一种避孕药组成，以保护妇女免受艾滋病毒、HSV-2和意外怀孕的影响。我们预计这一独特的环将比其他地方只含有一种抗艾滋病毒药物和避孕药的产品更有效，特别是在限制抗药性艾滋病毒的传播方面。