Novel pre-coital, non-hormonal multipurpose prevention technology (MPT)

摘要 新出现的证据表明，妇女更有可能使用多用途预防技术（MPT）， 预防怀孕和艾滋病毒/性传播感染的产品要比预防怀孕或艾滋病毒/性传播感染的产品多。的 MPT的发展空间主要是含有一种或多种激素避孕药的产品， 许多妇女，包括哺乳期妇女，不能或不愿使用。Amphora凝胶是个例外。双头藻属 是由Evofem Biosciences开发的一种非激素，阴道作用的女性避孕产品 Inc.它的工作原理是保持阴道的低pH值，这对精子、细菌和病毒是有害的。Evofem最近 完成了Amphora的3期避孕有效性试验，表明典型使用有效性为86.0%， 方案有效性（完美使用）为98.7%，与最常用形式的 激素避孕口服药Amphora目前正在2b期试验中进行测试，用于预防 妇女泌尿生殖道衣原体和淋病，并准备进行预防细菌性淋病复发的试验 阴道病（BV），已完成入组。QGRFT是非抗逆转录病毒（non-ARV）的稳定类似物 抗HIV凝集素griffithsin（GRFT）。我们完成了阴道给药GRFT凝胶的1期试验， 与PATH一起开发了一种新的阴道给药GRFT快速溶解插入物（FDI）， 预防猕猴中的猿猴人类免疫缺陷病毒（SHIV）感染以及 小鼠我们的长期目标是为少女和广大妇女开发Amphora/QGRFT FDI， 包括母乳喂养的妇女，提供非激素避孕，并减少获得 广泛的病毒性和细菌性性传播感染。在此，我们将评估两种药物的可行性、安全性和体内疗效。 创新的MPT原型：一个Amphora/QGRFT FDI，可以避孕和抗HIV/STI/BV 具有避孕和抗性传播感染/细菌性阴道病特性的Amphora-only FDI。的 将制造原型，然后在一系列体外试验、生理化学试验和生物化学试验中进行评价。 性质/稳定性评价，以及体内研究，以证明FDI崩解，药物在阴道中的保留， 安全性、抗HIV活性（猕猴模型中的药效学研究和猕猴体内疗效）和 抗HSV-2活性（鼠模型）。Amphora/QGFRT FDI可提供比Amphora/QGFRT FDI更有效的抗HSV-2活性。 由于QGRFT的抗HSV-2活性，单独使用Amphora。利用这些研究中获得的数据，我们将选择一个外国直接投资 推进兔子避孕效果测试和大鼠IND毒理学研究。小说 这里提出的非激素FDI可以（i）消除与激素避孕药相关的副作用，（ii） 满足性生活不频繁或正在哺乳的妇女的需要，以及（iii）减少性行为的发生， 艾滋病毒/性传播感染的获得和抗逆转录病毒药物耐药艾滋病毒的出现。这种由妇女发起的外国直接投资有可能 改善妇女健康，推进MPT领域。一旦获得批准，外国直接投资将是第一个非激素， 按需和事件驱动的MPT，具有避孕和广谱抗/HIV/STI特性。

ABSTRACT Emerging evidence indicates that women are more likely to use a multipurpose prevention technology (MPT) for pregnancy and HIV/STI infection prevention than a product for pregnancy or HIV/STI infection prevention. The MPT development space is dominated by products that contain one or more hormonal contraceptives, which many women, including breastfeeding women, cannot or will not use. Amphora gel is an exception. Ampphora is a non-hormonal, vaginally-acting contraceptive product for women being developed by Evofem Biosciences Inc. It works by maintaining a low vaginal pH that is hostile to sperm, bacteria, and viruses. Evofem recently completed a Phase 3 contraceptive efficacy trial of Amphora that indicated typical use efficacy of 86.0% and per protocol efficacy (perfect use) of 98.7%, comparable to the efficacy of the most commonly used forms of hormonal contraception, oral pills. Amphora is currently being tested in Phase 2b trials for prevention of urogenital chlamydia and gonorrhea in women and preparing for trials for prevention of recurrent bacterial vaginosis (BV), which has completed enrollment. QGRFT is a stable analog of the non-antiretroviral (non-ARV) anti-HIV lectin griffithsin (GRFT). We completed a Phase 1 trial of a vaginally administered GRFT gel, and with PATH developed a novel vaginally administered GRFT fast dissolving insert (FDI) that significantly prevented simian human immunodeficiency virus (SHIV) infection in macaques and HSV-2 and HPV infection in mice. Our long term goal is to develop an Amphora/QGRFT FDI for adolescent girls and a wide range of women, including breastfeeding women, which provides non-hormonal contraception and reduces the risk of acquiring a broad range of viral and bacterial STIs. Herein we will evaluate the feasibility, safety, and in vivo efficacy of two innovative MPT prototypes: an Amphora/QGRFT FDI that could have contraceptive and anti-HIV/STI/BV properties and an Amphora-only FDI that could have contraceptive and anti-STI/BV properties. The prototypes will be manufactured and then evaluated in a series of in vitro assays, physiochemical property/stability evaluations, and in vivo studies to demonstrate FDI disintegration, drug retention in the vagina, safety, anti-HIV activity (pharmacodynamics studies in a macaque model and in vivo efficacy in macaques) and anti-HSV-2 activity (murine model). The Amphora/QGFRT FDI may offer more potent anti-HSV-2 activity than Amphora alone due to QGRFT’s anti-HSV-2 activity. Using data obtained in these studies, we will select one FDI to advance into contraceptive efficacy testing in rabbits and IND-enabling toxicology studies in rats. The novel non-hormonal FDI proposed here could (i) eliminate side effects associated with hormonal contraceptives, (ii) meet the needs of women who have infrequent sex or who are breastfeeding, and (iii) reduce the sexual acquitision of HIV/STIs and the emergence of ARV-resistant HIV. This woman-initiated FDI has the potential to improve women’s health and advance the MPT field. When approved, the FDI would be the first non-hormonal, on-demand and event-driven MPT with both contraceptive and broad spectrum anti/HIV/STI properties.