Novel long-acting microbicide and contraceptive intrauterine system

描述(申请人提供)：全球约有3400万人感染了人类免疫缺陷病毒(HIV)，撒哈拉以南非洲地区是感染人数最多的地区。发病率仍然居高不下，每年新增感染250万人。在全球艾滋病毒/艾滋病大流行的同时，意外怀孕占全世界所有怀孕的近一半，每年由于不安全的堕胎以及妊娠和分娩并发症而导致近100 000名产妇死亡。唯一有概念验证数据的抗HIV杀微生物剂是替诺福韦阴道凝胶，间歇服用， 围产期养生法。在涉及每日给药方案的艾滋病毒预防研究中，遵守情况普遍较差。不能证明1%TFV凝胶有统计学意义的疗效 在声学试验中(每天用1%阴道TFV凝胶给药一次)是由于粘附性低。根据方案，只有不到30%的试验参与者使用该产品。同样，在Fem-PrEP试验中，产品依从性低很可能是无法证明口服富马酸替诺福韦(TDF)/恩曲他滨有效的原因。我们建议通过开发一种创新的宫内系统(IUS)来解决这些问题，该系统至少释放一年高效的替诺福韦(TFV)前体药物替诺福韦(TFV)，富马酸替诺福韦(TAF)。TAF是一种新型的、稳定的、淋巴靶向的TFV前药，正在进行晚期临床试验，作为一种口服HIV治疗。TAF的效力是TFV的1000倍，而且比前药TDF(ViRead(R))更稳定和有效。TAF将与来自IUS的铜(Cu)一起持续释放。铜宫内节育器是世界上使用和接受的最成熟和最具成本效益的长效可逆避孕药之一，它也提供非激素益处。一旦插入IUS，女性就会获得有效、谨慎的保护，并100%遵守，直到训练有素的提供者通过简单而快速的办公程序移除该系统。该项目的主要目标是证明TAF可以从IUS以提供有效水平的TFV-二磷酸(TFV-DP)的速率传递到局部生殖器组织(子宫内膜、宫颈和阴道)，并防止艾滋病毒在女性生殖道中的感染。药代动力学基准(PK)(例如，阴道淋巴细胞中TFV-DP浓度)将基于现有的活体数据。早期设备原型的安全性和PK将在兔模型中进行评估。在低剂量重复挑战非人类灵长类动物模型中，将与开发该模型的疾病控制中心团队合作，评估领先IUS的安全性、PK和有效性。拟议工作的成功将为妇女提供廉价、谨慎、长效的IUS，安全有效地预防意外/不合时宜的怀孕和艾滋病毒感染，并将导致艾滋病毒暴露前预防、避孕和妇女整体生殖健康领域的范式转变。

DESCRIPTION (provided by applicant): Globally, approximately 34 million people are infected with human immunodeficiency virus (HIV), and sub- Saharan Africa is the region with the highest prevalence of infections. The incidence rate remains stubbornly high at 2.5 million new infections each year. In parallel with the global HIV/AIDS pandemic, unplanned pregnancies account for nearly half of all pregnancies worldwide and lead to almost 100,000 maternal deaths per year as a result of unsafe abortions and complications of pregnancy and delivery. The only anti-HIV microbicide with proof of concept data is tenofovir vaginal gel, dosed in an intermittent, pericoital regimen. Adherence in HIV prevention studies involving daily dosing regimens has generally been poor. The inability to demonstrate statistically significant efficacy for TFV 1% gel in the VOICE trial (once daily dosing with vaginal TFV 1% gel) was due to low adherence. Less than 30% of trial participants used the product per protocol. Similarly, low product adherence was most likely responsible for the inability to demonstrate effectiveness of oral tenofovir disoproxil fumarate (TDF)/emtricitabine in the Fem-PrEP trial. We propose to address these problems by developing an innovative intrauterine system (IUS) releasing a highly potent prodrug of tenofovir (TFV), tenofovir alafenamide fumarate (TAF) for a minimum of 1 year. TAF is a new, stable, lymphoid-targeting prodrug of TFV, which is undergoing late-stage clinical testing as an oral HIV treatment. TAF is 1000 times more potent than TFV and more stable and potent than the prodrug TDF (Viread(R)). TAF will be released continuously in combination with copper (Cu) from the IUS. Cu IUSs are one of the most well-established and cost-effective long-acting reversible contraceptives used and accepted around the world, which also provide non-hormonal benefits. Once an IUS is inserted, women have effective, discreet protection with 100% adherence, until the system is removed by a trained provider in a simple and fast office procedure. The main goal of this project is to demonstrate that TAF can be delivered from an IUS at a rate that provides effective levels of TFV-diphosphate (TFV-DP), the active metabolite, to local genital tissues (endometrium, cervix and vagina) and prevents HIV infection in the female reproductive tract. Benchmarks for pharmacokinetics (PK) (e.g., TFV-DP concentrations in vaginal lymphocytes) will be based on existing in vivo data. Safety and PK of early device prototypes will be assessed in the rabbit model. Safety, PK and efficacy of a lead IUS will be assessed in the low-dose repeat challenge nonhuman primate model in collaboration with the Centers for Disease Control team who developed this model. Success of the proposed work will provide women with access to an inexpensive, discreet, long-acting IUS that is safe and effective to prevent unintended/mistimed pregnancy and HIV infection, and will lead to a paradigm shift in the fields of HIV pre-exposure prophylaxis, contraception, and women's overall reproductive health.