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 新感染艾滋病毒的妇女中有一半是由于无保护的阴道性交， 被感染的伴侣宫颈阴道粘膜是HIV进入女性的主要入口。 由于性关系的不平衡，妇女往往无法保护自己。长期 该项目的目标是开发一种安全有效的产品，以防止妇女感染艾滋病毒 既受女性控制又不依赖性交为了实现这一目标，我们正在开发 一种新的方法，利用阴道微生物组的保护特性， 感染.保护作用主要是由拮抗 阴道病原体，包括艾滋病毒，通过产生乳酸和其他代谢产物。MucoCept-CVN 是一种独特的重组活双歧杆菌产品（LBP）， 已被基因增强以分泌有效的HIV进入抑制剂的詹森氏菌株，经修饰 氰威菌素-N（mCV-N）。该菌株沿着阴道粘膜的定植， 预期mCV-N的分泌减少女性生殖道中的HIV获得。的目标 本项目旨在完成MucoCept-mCVN的开发并满足FDA要求， 进行1期临床试验。研究性新药（IND）申请已提交给 MucoCept-CVN片剂处方的FDA。在进行临床试验之前，FDA 要求我们重新配制MucoCept-mCVN产品，并在家兔阴道中重新试验 刺激模型（RVI），原因是担心无活性片剂辅料的潜在阴道刺激。 该SBIR II提案描述了两种新的 MucoCept-CVN制剂基于我们使用另一种阴道给药LBP的经验 在先进的临床开发。该计划旨在减轻制造和监管 风险，并最大限度地提高产品的安全性，以确保FDA在最短的时间内批准 和成本效益的方式。具体而言，我们将重新配制MucoCept-CVN片剂， 羟丙基甲基纤维素胶囊和使用该胶囊的预填充阴道施用器 中间粉末和生产小批量的cGMP产品用于RVI和临床测试。 将在RVI模型中检测并比较两种MucoCept-CVN制剂和安慰剂 车辆控制。具有最低总体阴道刺激潜力的制剂将是 选择用于临床研究。将修订IND，以纳入新的安全性和制剂 并提交给FDA。一旦FDA批准，我们将进行首次人体试验 这一重要产品的临床研究。