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和怀孕的多功能预防技术。我们计划开发一种新型的EVA（乙烯基乙烯酯）阴道环，该环释放了两种抗HIV药物（1种新型NNRTIS和乙酸锌，Za）和仅剂量孕激素避孕剂（左甲虫孕激素，LNG，LNG）。 EVA是FDA批准的产品中使用的聚合物； MIV-150和MIV-160是当前HIV治疗中未使用的有效NNRTI。 ZA可防止Shiv-RT和HSV-2体内感染；液化天然气是批准的口服避孕药中使用最广泛的孕激素（结合乙醇雌二醇或仅在低剂量孕激素避孕药中）。我们已经证明，重复应用ZA凝胶可显着保护猕猴免受Shiv-Rt的影响。 MIV-150/ZA组合凝胶更加有效。最近的研究还表明，释放MIV-150或MIV-160的EVA环可保护猕猴免受SHIV-RT感染。我们建议，在阴道环中，MIV-150或MIV-160与ZA的组合将代表有效且宽阔的持续释放菌心。此外，WHO赞助的3阶段试验具有阴道释放20 mg/d的LNG，表明它是一种非常有效的避孕药。我们假设释放MIV-150或MIV-160，ZA和LNG的阴道环将是一种新型的杀菌剂/避孕药递送系统，可防止HIV和HSV-2感染，并释放足够量的LNG以防止妊娠。不使用ZA治疗HIV的有效NNRTI的组合代表了一种限制耐药性问题的独特抗病毒策略，最终将出现仅包括一种针对HIV的药物（例如， dapivirine/lng或tenofovir/lng）。在应用程序的R21阶段，我们将在体外和体内进行研究，以确定整洁和配方API的组合是否稳定且有效。同时，我们将生产带有三种API组合的EVA环，并随着时间的推移测量释放率和API相互作用。在R33阶段，我们将把环技术转移到CRO中，以开发出强大的过程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NNRTI/ZA/LNG组合环的决定，以向前迈进，以进行扩展和将来的临床测试。该提案解决了至关重要的未满足医疗需求；降低了妇女同时出现计划外怀孕和艾滋病毒/HSV-2的风险，从而减少了由于艾滋病毒和怀孕并发症而导致的计划外怀孕和死亡的数量。 公共卫生相关性：我们计划开发一个安全有效的阴道环，包括两种抗HIV药物和一种保护妇女免受艾滋病毒，HSV-2和计划外怀孕的避孕药。我们希望这种独特的环将更有效，尤其是在限制抗药性HIV的传播方面，与仅包含一种抗HIV剂和一种避孕药的其他地方的产品相比。