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、社会和文化环境下，妇女的意外怀孕率都很高，性传播疾病的患病率和发病率也很高。美国和欠发达经济体的趋势正在朝着错误的方向发展。 NICHD 和 NIAID 的首要任务是提供一种能够预防意外怀孕和一种或多种最流行的性传播疾病的单一多用途预防产品 (MPT)。 Yaso-GEL（一种阴道凝胶制剂）的开发将提供首批提供妊娠和性传播感染保护的 MPT 产品之一，该产品易于获得和使用，不需要医疗服务。此外，Yaso-GEL在性交前阴道使用，具有受精前避孕作用，是非激素和非全身性的。这些特性避免了当前避孕药具使用者的许多安全问题。 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药，阴道避孕凝胶 (Yaso-GEL) 中的聚苯甲酰亚甲基 (PPCM)，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，还能抑制多种性传播感染 (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)。根据这笔拨款，我们将完成开设 IND 所需的工作。这包括： a) 根据 cGMP 扩大 Yaso-GEL 规模，填充涂药器进行临床试验并建立 3 年稳定性研究； b) 完成第二个物种大鼠的毒理学研究； c) 完成最后的遗传毒性研究； d) 验证人宫颈阴道分泌物和血浆中的生物测定； e) 设计 I 期和 2 期临床试验的安全性和避孕功效，利用新的体外避孕活性测定来建立最佳剂量反应； f) 提交IND。其次，Yaso-GEL 将在小鼠模型中进行评估，以预防淋病奈瑟菌 (Ng) 和沙眼衣原体 (Ct) 感染。如果有效，未来可能会进行临床试验来评估对人类这些重要的性传播感染病原体的预防。

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