Continuing Preclinical Development of PPCM Vaginal Contraceptive MPT to IND

在所有经济、社会和文化环境中，妇女遭受计划外怀孕的高比率，以及性传播疾病的高流行率和高发病率。美国和欠发达经济体的趋势正朝着错误的方向发展。NICHD和NIAID的优先事项是提供单一的多用途预防产品(MPT)，以防止计划外怀孕和一种或多种最流行的性传播疾病。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在性交前经阴道使用，具有受精前避孕作用，是非激素和非全身的。这些特点避免了当前避孕药使用者的许多安全担忧。这一2B阶段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，基于体外数据，我们希望研究Yaso-Gel在尖端小鼠模型中预防两种常见的性传播感染的可能性。我们正在开发一种新药，聚苯撑羧亚甲基(PPCM)阴道避孕凝胶(YASO-Gel)，作为R44HD092206下的多用途预防技术(MPT)。在临床前测试中，PPCM除了具有避孕活性外，还抑制广泛的性传播感染，包括淋球菌(Ng)、沙眼衣原体(Ct)、单纯疱疹病毒(HSV)和人类免疫缺陷病毒(HIV)。在这笔赠款下，我们将完成开设IND所需的工作。这包括：a)在cGMP下放大Yaso-Gel，为临床试验填充喷雾器，并建立为期3年的稳定性研究；b)作为第二个物种完成对大鼠的毒理学研究；c)完成最后一项遗传毒性研究；d)验证人宫颈阴道分泌物和血浆中的生物测定；e)设计第一阶段和第二阶段临床试验，以安全和避孕效果，利用新的避孕活性体外试验来建立最佳剂量反应；f)提交IND。其次，Yaso-Gel将在预防淋球菌(Ng)和沙眼衣原体(Ct)感染的小鼠模型中进行评估。如果有效，未来可能会进行临床试验，以评估这些重要的性传播感染病原体对人类的预防作用。

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.