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，妇女都患有高度计划外的怀孕率，以及性传播疾病的高患病率和发病率。美国和较不发达经济体的趋势朝着错误的方向发展。 NICHD和NIAID的优先事项是，单一的多用途预防产品（MPT）可以防止计划外怀孕和最普遍的性传播疾病中的一种或多种最普遍的性疾病。阴道凝胶配方Yaso-Gel的开发将提供最早提供怀孕和STI保护的MPT产品之一，即易于获得和使用，不需要医疗服务。此外，Yaso-Gel被阴道前扎乳房施用，具有侵入前的避孕作用，是非激素和非系统性的。这些特征避免了当前避孕用户的许多安全问题。该阶段2B赠款的主要目的是完成FDA要求为Yaso-Gel提交IND所需的CMC和毒理学研究。其次，根据体外数据，我们希望研究Yaso-Gel对尖端鼠模型中两种常见的性传播感染的预防潜力。我们正在在R44HD092206下，在阴道避孕凝胶（YASO-GEL）中开发一种新药，即阴道避孕凝胶（YASO-GEL）作为多功能预防技术（MPT）的新药。在临床前测试中，PPCM抑制了包括淋病奈瑟氏菌（NG），沙眼衣原体（CT），单纯疱疹病毒（HSV）和人类免疫缺陷病毒（HIV）（HIV）的广泛传播感染（STIS）（ng），疱疹性疱疹（CT）。根据这笔赠款，我们将完成打开IND所需的工作。这包括：a）在CGMP下扩展Yaso-Gel，填充临床试验的涂药器并建立了为期3年的稳定性研究； b）在大鼠中完成第二种毒理学研究； c）完成最后一项遗传毒性研究； d）在人宫颈阴道分泌物和血浆中验证生物测定； e）设计I阶段和第2阶段的安全性和避孕功效临床试验，利用新的离体避孕活性测定法来建立最佳剂量反应； f）提交IND。其次，将在预防淋病奈瑟氏菌（NG）和沙眼衣原体（CT）的鼠模型中评估Yaso-Gel。如果有效，可以进行未来的临床试验，以评估人类这些重要的STI病原体的预防。

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