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HIV感染和怀孕的多用途预防技术。我们计划开发一种新型EVA（醋酸乙烯酯）阴道环，该环释放两种抗hiv药物（2种新型NNRTIs和醋酸锌中的1种）和一种低剂量仅孕激素避孕药（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是目前HIV治疗中未使用的强效nnrti；ZA在体内可预防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黄体酮（与乙炔雌二醇联合使用或单独使用低剂量黄体酮避孕药）。我们已经证明，反复使用ZA凝胶可以显著保护猕猴免受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hiv -150或hiv -160的EVA环可以保护猕猴免受SHIV-RT感染。我们认为，在阴道环中将MIV-150或MIV-160与ZA联合使用将是一种有效的广效缓释杀菌剂。此外，世卫组织发起的阴道环释放20mg /d液化天然气的3期试验表明，它是一种非常有效的避孕药。我们假设一种释放MIV-150或MIV- 160、ZA和LNG的阴道环将成为一种新型的杀微生物剂/避孕药输送系统，可以预防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的强效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，耐药性问题最终将出现在仅包含一种抗HIV药物的环中(例如。

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.