Continuing Preclinical Development of PPCM Vaginal Contraceptive MPT to IND

在所有经济、社会和文化环境中，妇女的意外怀孕率很高，性传播疾病的流行率和发病率也很高。美国和欠发达经济体的趋势正朝着错误的方向发展。提供一种既能预防计划外怀孕又能预防一种或多种最普遍的性传播疾病的单一多用途预防产品是NICHD和NIAID的优先事项。Yaso-GEL是一种阴道凝胶配方，它的开发将提供首批同时提供怀孕和性传播感染保护的MPT产品之一，这种产品易于获得和使用，不需要医疗服务。此外，Yaso-GEL用于阴道性交前，具有受精前避孕作用，非激素和非系统性。这些特点避免了目前避孕药具使用者的许多安全问题。该2B期拨款的主要目的是完成FDA要求的CMC和毒理学研究，以提交Yaso-GEL的IND。其次，基于体外实验数据，我们希望在尖端小鼠模型中研究Yaso-GEL对两种常见性传播感染的预防潜力。我们正在开发一种新的药物——阴道避孕凝胶（Yaso-GEL）中的聚苯基羧基甲基（PPCM），作为R44HD092206下的多用途预防技术（MPT）。在临床前测试中，PPCM抑制广泛的性传播感染（sti），包括淋病奈瑟菌（Ng），沙眼衣原体（Ct），单纯疱疹病毒（HSV）和人类免疫缺陷病毒（HIV），除了具有避孕活性。在这笔资助下，我们将完成打开IND所需的工作。这包括：a)在cGMP下扩大Yaso- GEL的规模，填写临床试验申请并建立为期3年的稳定性研究；B)完成一项将大鼠作为第二物种的毒理学研究；C)完成最后一次遗传毒性研究；D)验证人宫颈阴道分泌物和血浆中的生物测定；e)设计安全性和避孕有效性的I期和2期临床试验，利用新的离体避孕活性测定来确定最佳剂量反应；其次，Yaso-GEL将在小鼠模型中进行预防淋病奈瑟菌（Ng）和沙眼衣原体（Ct）感染的评估。如果有效，未来的临床试验可能会进行，以评估这些重要的性传播感染病原体在人类中的预防。

Women in all economic, social, and cultural circumstances suffer from high rates of unplanned pregnancy, along with a high prevalence and incidence of sexually transmitted diseases. Trends in the United States and lesser developed economies are going in the wrong direction. The availability of a single multipurpose prevention product (MPT) that prevents both unplanned pregnancy and one or more of the most prevalent sexually transmitted diseases is a priority for both NICHD and NIAID. The development of Yaso-GEL, a vaginal gel formulation, will provide one of the first MPT products offering both pregnancy and STI protection, one that is easy to obtain and to use, that does not require medical services. In addition, Yaso-GEL is applied vaginally pre-coitally, has pre-fertilization contraceptive action, is non-hormonal and non-systemic. These characteristics avoid many safety concerns of current contraceptive users. The primary purpose of this Phase 2B grant is to complete CMC and toxicology studies required by FDA to submit an IND for Yaso-GEL. Secondarily, based on in vitro data, we wish to study the prophylactic potential of Yaso-GEL against two common sexually transmitted infections in cutting edge murine models. We are developing a new drug, polyphenylene carboxymethylene (PPCM) in a vaginal contraceptive gel (Yaso-GEL) as a multipurpose prevention technology (MPT) under R44HD092206. In preclinical testing, PPCM inhibits a broad spectrum of sexually transmitted infections (STIs) including Neisseria gonorrhoeae (Ng), Chlamydia trachomatis (Ct), Herpes simplex virus (HSV) and human immunodeficiency virus (HIV), in addition to having contraceptive activity. Under this grant, we will complete the work needed to open our IND. This includes: a) scale up Yaso- GEL under cGMP, fill applicators for clinical trials and establish a 3-year stability study; b) complete a toxicology study in rats as a second species; c) complete the last genotoxicity study; d) validate the bioassay in human cervicovaginal secretions and plasma; e) design Phase I and Phase 2 clinical trials for safety and contraceptive efficacy, utilizing a new ex vivo assay of contraceptive activity to establish optimal dose response; f) submit the IND. Secondarily, Yaso-GEL will be evaluated in murine models for prevention of infection with Neisseria gonorrhoeae (Ng) and Chlamydia trachomatis (Ct). If effective, future clinical trials may be conducted to evaluate prevention of these important STI pathogens in humans.