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)来治疗 预防怀孕和HIV/STI感染比预防怀孕或HIV/STI感染的产品要好。这个 MPT的开发空间主要由含有一种或多种激素避孕药的产品主导，这些产品 许多妇女，包括哺乳妇女，不能或不会使用。双胞胎凝胶是个例外。Ampphora 是一种由Evofem生物科学公司开发的非荷尔蒙、阴道作用的女性避孕药 它的工作原理是保持低的阴道pH值，对精子、细菌和病毒怀有敌意。最近的Evofem 完成了Amphora避孕效果的3期试验，显示典型使用效率为86.0%和 协议有效率(完美使用)为98.7%，可与最常用形式的疗效相媲美 荷尔蒙避孕药，口服药片。目前，安非洛拉正在进行2b期试验，以预防 女性泌尿生殖道衣原体和淋病以及预防复发细菌试验的准备 阴道病(BV)，已完成登记。QGRFT是非抗逆转录病毒(Non-ARV)的稳定类似物 抗HIV凝集素格里菲辛(GRFT)。我们完成了阴道给药的GRFT凝胶的第一阶段试验，并且 随着Path的开发，一种新的阴道给药GRFT快速溶解插入物(FDI)显著 预防猕猴感染人类免疫缺陷病毒(SHV)和预防HSV-2和HPV感染 老鼠。我们的长期目标是为青春期女孩和广泛的妇女发展Amphora/QGRFT外国直接投资， 包括哺乳妇女，这提供了非荷尔蒙避孕并降低了感染 广泛的病毒和细菌性传播感染。在这里，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：一种可用于避孕和抗HIV/STI/BV的Amphora/QGRFT FDI 一种可能具有避孕和抗性传播感染/BV特性的仅限Amphora的外国直接投资。这个 原型将被制造出来，然后在一系列的体外测试、物理化学测试中进行评估 性质/稳定性评估，以及体内研究，以证明外国直接投资的崩解，药物在阴道内的滞留， 安全性、抗艾滋病毒活性(猕猴模型的药效学研究和猕猴体内疗效)和 抗HSV-2活性(小鼠模型)。Amphora/QGFRT FDI可能提供比 清热还五汤具有抗单纯疱疹病毒2型的活性。利用这些研究中获得的数据，我们将选择一项外国直接投资 在兔身上进行避孕药效试验，在大鼠身上进行IND毒理学研究。这部小说 这里提出的非荷尔蒙FDI可以(一)消除与荷尔蒙避孕药相关的副作用，(二) 满足不经常发生性行为或正在哺乳的妇女的需要，以及(3)减少性行为 艾滋病毒/性传播感染的获得性和抗逆转录病毒艾滋病毒的出现。这种由女性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性的， 按需和事件驱动的MPT，具有避孕和广谱抗/艾滋病毒/性传播感染特性。

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.