Continuing Preclinical Development of PPCM Vaginal Contraceptive MPT to IND

PPCM 阴道避孕药 MPT 至 IND 的持续临床前开发

• 批准号: 9889971
• 负责人: Ann E. Jerse
• 金额: $ 98.48万
• 依托单位: YASO THERAPEUTICS INC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-05 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889971
• 关键词: Atopobium vaginae; Binding; Biological Assay; Bone Marrow; Characteristics; Chlamydia trachomatis; Clinical Trials; Clinical Trials Design; Contraceptive Agents; Cyclic GMP; Data; Development; Dose; Economics; Epidemic; Feedback; Fertilization; Formulation; Funding; Future; Gel; Grant; Guidelines; HIV; Herpes Simplex Infections; High Prevalence; Human; Hyaluronan; In Vitro; Incidence; Infection prevention; Lead; Medical; Micronucleus Tests; National Institute of Allergy and Infectious Disease; National Institute of Child Health and Human Development; Neisseria gonorrhoeae; Oral; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phase I/II Clinical Trial; Phase I/II Trial; Phase II Clinical Trials; Placebos; Plasma; Preclinical Testing; Pregnancy; Prevention; Prevention trial; Production; Protocols documentation; Rattus; Resources; Safety; Seminal fluid; Services; Sexually Transmitted Diseases; Simplexvirus; Small Business Innovation Research Grant; Specific qualifier value; Technology; Toxicology; United States; Vagina; Vaginal Gel; Validation; Virus Diseases; Woman; Work; analytical method; animal efficacy; base; cervicovaginal; commercialization; condoms; contraceptive efficacy; design; efficacy study; genotoxicity; human tissue; improved; in vitro Assay; in vivo; manufacturing process; mouse model; novel; novel therapeutics; pathogen; phase 1 designs; preclinical development; prevent; product development; programs; prophylactic; response; scale up; social; stem; trend; unintended pregnancy; virology

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.

在所有经济、社会和文化环境中的妇女都遭受着高比率的非计划怀孕，同时沿着性传播疾病的高流行率和发病率。美国和欠发达经济体的趋势正在朝着错误的方向发展。提供单一的多用途预防产品（MPT），防止意外怀孕和一种或多种最流行的性传播疾病，是NICHD和NIAID的优先事项。Yaso-GEL是一种阴道凝胶制剂，其开发将成为首批提供妊娠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在性交前阴道应用，具有受精前避孕作用，是非激素和非全身性的。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期资助的主要目的是完成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，聚亚苯基羧基亚甲基（PPCM）在阴道避孕凝胶（Yaso-GEL）作为一种多用途预防技术（MPT），根据R44 HD 092206。在临床前试验中，PPCM抑制广谱性传播感染（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），此外还具有避孕活性。在此资助下，我们将完成启动IND所需的工作，包括：a）根据cGMP扩大Yaso- GEL的规模，为临床试验提供申请人，并建立3年的稳定性研究; B）完成大鼠作为第二物种的毒理学研究; c）完成最后的遗传毒性研究; d）验证人类宫颈阴道分泌物和血浆中的生物测定; e）设计I期和II期临床试验的安全性和避孕功效，利用新的避孕活性的体外测定来建立最佳剂量反应; f）提交IND。其次，将在小鼠模型中评价Yaso-GEL预防淋病奈瑟菌（Ng）和沙眼衣原体（Ct）感染的效果。如果有效，未来可能会进行临床试验，以评估这些重要的性病病原体在人类中的预防。

项目成果

Polyphenylene carboxymethylene (PPCM) microbicide repurposed as antiviral against SARS-CoV-2. Proof of concept in primary human undifferentiated epithelial cells.

• DOI: 10.1016/j.antiviral.2021.105162
• 发表时间: 2021-10
• 期刊: Antiviral research
• 影响因子: 7.6
• 作者: Escaffre O;Freiberg AN
• 通讯作者: Freiberg AN

Evaluation of the novel vaginal contraceptive agent PPCM in preclinical studies using sperm hyaluronan binding and acrosome status assays.

• DOI: 10.1111/andr.13110
• 发表时间: 2022-03
• 期刊: Andrology
• 影响因子: 4.5
• 作者: North BB;Weitzel MB;Waller DP;Birch WX;Feathergill KA;Birch LA;De Jonge CJ;Prins GS
• 通讯作者: Prins GS