MucoCept-CVN, a genetically enhanced vaginal Lactobacillus strain for the prevention of HIV acquisition in women: Finalization of formulation for the first-in-human clinical trial

MucoCept-CVN，一种基因增强的阴道乳杆菌菌株，用于预防女性感染艾滋病毒：首次人体临床试验的配方最终确定

• 批准号: 9905651
• 负责人: Laurel A. Lagenaur
• 金额: $ 100万
• 依托单位: OSEL, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905651
• 关键词: AIDS prevention; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adult; Age; Antiviral Agents; Atopobium vaginae; Biological Response Modifier Therapy; California; Cause of Death; Chemistry; Clinical; Clinical Investigator; Clinical Protocols; Clinical Research; Clinical Trials; Collaborations; Cyanovirin-N; Cyclic GMP; Development; Dosage Forms; Dose; Engineering; Ensure; Excipients; Female; Formulation; Funding; Goals; Grant; HIV; HIV Entry Inhibitors; HIV Infections; HIV-1; In complete remission; Infection; Infection prevention; Intervention; Investigational Drugs; Investigational New Drug Application; Irritants; Knowledge; Lactic acid; Lactobacillus; Letters; Macaca mulatta; Mediating; Methylcellulose; Modeling; Mucous Membrane; Organism; Oryctolagus cuniculus; Pamphlets; Pharmaceutical Preparations; Phase I Clinical Trials; Placebos; Population Study; Powder dose form; Preclinical Testing; Property; Proteins; Recombinants; Research Personnel; Risk; Safety; San Francisco; Site; Small Business Innovation Research Grant; Tablets; Technology; Testing; Time; Toxicology; United States National Institutes of Health; Universities; Update; Vaccines; Vagina; Woman; Work; base; capsule; cervicovaginal; clinical development; commensal bacteria; cost efficient; design; experience; first-in-human; inhibitor/antagonist; irritation; microbiome; next generation; novel; novel strategies; pathogen; phase I trial; preclinical development; preclinical safety; prevent; reproductive; reproductive tract; research clinical testing; safety study; sexual relationship; simian human immunodeficiency virus; tablet formulation; transmission process; vaginal lactobacilli; vaginal microbiome; vaginal microbiota; vaginal mucosa

Project Summary Half of new HIV infections occur in women as a result of unprotected vaginal intercourse with an infected partner. The cervicovaginal mucosa is the primary portal of entry for HIV in women. Women often cannot protect themselves due to imbalances in sexual relationships. The long-term goal of this project is to develop a safe and effective product to prevent HIV acquisition in women that is both female-controlled and coitally independent. To achieve this goal, we are developing a new approach that harnesses the protective properties of the vaginal microbiome to prevent infections. Protection is largely mediated by commensal Lactobacillus species that antagonize vaginal pathogens, including HIV, by producing lactic acid and other metabolites. MucoCept-CVN is a unique recombinant live biotherapeutic product (LBP) that contains a vaginal Lactobacillus jensenii strain that has been genetically enhanced to secrete a potent HIV entry inhibitor, modified cyanovirin-N (mCV-N). Colonization of the vaginal mucosa by this strain along with the continuous secretion of mCV-N is expected to reduce HIV acquisition in the female genital tract. The goal of this project is to complete the development of MucoCept-mCVN and satisfy FDA requirements to enable a Phase 1 clinical trial. An Investigational New Drug (IND) application was submitted to FDA for the MucoCept-CVN tablet formulation. Before clinical testing can proceed, FDA requested that we reformulate and retest the MucoCept-mCVN product in the rabbit vaginal irritation model (RVI) due to concerns about potential vaginal irritation by inactive tablet excipients. This SBIR II proposal describes the parallel development and preclinical testing of two new MucoCept-CVN formulations based on our experience with another vaginally administered LBP in advanced clinical development. This plan is designed to mitigate manufacturing and regulatory risks and to maximize the safety of the product in order to ensure FDA approval in the most time and cost efficient manner. Specifically, we will reformulate MucoCept-CVN tablet as a hydroxypropyl methylcellulose capsule and as a prefilled vaginal applicator using the same intermediate powder and manufacture small lots of the cGMP products for RVI and clinical testing. The two MucoCept-CVN formulations and placebos will be tested in the RVI model and compared to the vehicle control. The formulation with the lowest overall vaginal irritation potential will be selected for the clinical study. The IND will be amended to include the new safety and formulation information and submitted to FDA. Upon FDA approval, we will proceed with the first-in-human clinical study of this important product.

项目摘要 一半的新HIV感染发生在女性身上，这是由于与 受感染的伴侣。宫颈阴道粘膜是女性感染艾滋病毒的主要入口。 由于性关系的不平衡，女性往往无法保护自己。长期的 该项目的目标是开发一种安全有效的产品来预防妇女感染艾滋病毒 这既是女性控制的，也是性交独立的。为了实现这一目标，我们正在发展 一种新的方法，利用阴道微生物群的保护特性来预防 感染。保护在很大程度上是由共生乳杆菌介导的，这些乳杆菌可以对抗 阴道病原体，包括艾滋病毒，通过产生乳酸和其他代谢物。MucoCept-CVN 是一种独特的重组活生物治疗产品(LBP)，含有阴道乳杆菌 Jensenii菌株已经经过基因增强，可以分泌一种有效的艾滋病毒进入抑制因子，经过修饰 氰韦林-N(MCV-N)。该菌株在阴道黏膜上的定植与连续感染 MCV-N的分泌预计将减少女性生殖道获得艾滋病毒的机会。的目标是 该项目旨在完成MucoCept-mCVN的开发，并满足FDA的要求 启用一期临床试验。研究新药(IND)申请已提交至 FDA为MucoCept-CVN片剂配方。在进行临床测试之前，FDA 要求我们重新配制MucoCept-mCVN产品并在兔阴道中进行重新测试 刺激模型(RVI)，因为担心非活性片剂辅料可能对阴道产生刺激。 这份SBIR II提案描述了两种新的 基于我们对另一种阴道给药LBP的经验的MucoCept-CVN配方 在高级临床开发中。该计划旨在减轻制造业和监管部门的压力 并最大限度地提高产品的安全性，以确保在最短的时间内获得FDA的批准 和经济高效的方式。具体地说，我们将MucoCept-CVN片剂重新配方为 羟丙基甲基纤维素胶囊及其作为预充型阴道敷贴器的应用 中间粉和小批量生产用于RVI和临床试验的cGMP产品。 两种MucoCept-CVN配方和安慰剂将在RVI模型中进行测试和比较 到车辆控制中心。总体阴道刺激性潜力最低的配方将是 被选为临床研究对象。将对IND进行修订，以包括新的安全性和配方 信息，并提交给FDA。在FDA批准后，我们将继续进行第一例人类 这一重要产品的临床研究。