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 由于无保护的阴道性交与一个新的HIV感染发生 感染的伴侣。子宫颈阴道粘膜是妇女艾滋病毒的主要入口。 由于性关系失衡，妇女通常无法保护自己。长期 该项目的目标是开发安全有效的产品，以防止妇女的艾滋病毒收购 这既是女性控制的，又是独立的。为了实现这一目标，我们正在发展 一种利用阴道微生物组的保护特性的新方法，以防止 感染。保护主要是由拮抗的共生乳杆菌介导的 通过产生乳酸和其他代谢产物，包括HIV在内的阴道病原体。 Mucocept-CVN 是一种独特的重组实时生物治疗产品（LBP），其中包含阴道乳杆菌 遗传增强以分泌有效的HIV进入抑制剂的Jensenii菌株，修饰 Cyanovirin-N（MCV-N）。通过这种菌株以及连续的阴道粘膜定植 MCV-N的分泌有望减少女性生殖道中的HIV获取。目标 该项目是为了完成粘膜cvn的开发，并满足FDA要求 启用1期临床试验。提交了调查新药（IND）申请 粘液CVN片剂配方的FDA。在进行临床测试之前，FDA 要求我们在阴道中重新重新重新重新重新调整并重新测试Mucocept-MCVN产品 由于担心非活性片剂的潜在阴道刺激，刺激模型（RVI）。 该SBIR II提案描述了两个新的平行开发和临床前测试 Mucocept-CVN制剂基于我们与另一种阴道施用LBP的经验 在高级临床开发中。该计划旨在减轻制造和监管 风险并最大化产品的安全性，以确保最多的FDA批准 和经济高效的方式。具体而言，我们将把粘液CVN片剂重新制定为 羟丙基甲基纤维素胶囊和使用相同的预灌注的阴道涂抹器 中型粉末和生产用于RVI和临床测试的CGMP少量产品。 将在RVI模型中测试两个粘膜CVN公式和安慰剂，并比较 到车辆控制。总体阴道刺激潜力最低的配方将是 选择用于临床研究。 IND将被修订以包括新的安全和配方 信息并提交给FDA。经过FDA批准，我们将继续进行第一个人类 该重要产品的临床研究。