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

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伊娃（乙烯醋酸乙烯酯）阴道环，可释放两种抗HIV药物（2种新型NNRTI中的1种和醋酸锌，ZA）和一种低剂量仅含孕酮的避孕药（左炔诺孕酮，LNG）。伊娃是FDA批准的产品NuvaRing中使用的聚合物; MIV-150和MIV-160是目前HIV治疗中未使用的强效NNRTI; ZA可预防体内SHIV-RT和HSV-2感染; LNG是批准的口服避孕药中使用最广泛的炔雌醇（与炔雌醇组合或单独用于低剂量炔雌醇避孕药）。我们已经证明，重复应用ZA凝胶可显著保护猕猴免受SHIV-RT的侵害; 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的伊娃环保护猕猴免受SHIV-RT感染。我们提出，MIV-150或MIV-160与ZA在阴道环中的组合将代表有效且广泛作用的持续释放杀微生物剂。此外，世卫组织赞助的阴道环释放20 mg/d LNG的3期试验表明，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杀微生物剂/避孕药物递送系统，其将预防HIV和HSV-2感染，以及释放足够量的LNG以预防怀孕。不用于治疗HIV的有效NNRTI与ZA的组合代表了一种独特的抗病毒策略，以限制耐药性问题，这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）。在申请的R21阶段，我们将进行体外和体内研究，以确定纯API和配制API的组合是否稳定有效。同时，我们将生产装载三种API组合的伊娃环，并测量随时间推移的释放速率和API相互作用。在R33阶段，我们将把成形环技术转让给CRO，以开发一个稳健的工艺来制造优化的原型成形环。将在猕猴中进行PK/PD、生物标志物和抗病毒疗效研究。配方化学（R21和R33）和猕猴试验（R33）将指导决定哪种NNRTI/ZA/LNG组合环将继续进行规模扩大和未来的临床试验。该提案解决了一个关键的未得到满足的医疗需求;减少妇女同时发生计划外怀孕和艾滋病毒/HSV-2的风险，减少计划外怀孕和因艾滋病毒和妊娠并发症死亡的人数。 公共卫生相关性：我们计划开发一种安全有效的阴道环，包括两种抗艾滋病毒药物和一种避孕药，以保护妇女免受艾滋病毒、HSV-2和意外怀孕的侵害。我们预计这种独特的环将更有效，特别是在限制耐药艾滋病毒的传播方面，比其他地方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。

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.