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: 10223989
• 负责人: Laurel A. Lagenaur
• 金额: $ 46.37万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223989
• 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; Female genitalia; 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.

项目概要 一半的新艾滋病毒感染发生在女性中，是由于与男性进行无保护的阴道性交而导致的。 被感染的伙伴。宫颈阴道粘膜是女性艾滋病毒进入的主要门户。 由于性关系的不平衡，女性常常无法保护自己。长期来看 该项目的目标是开发一种安全有效的产品来预防女性感染艾滋病毒 这既是女性控制的，又是性交独立的。为了实现这一目标，我们正在开发 一种利用阴道微生物组的保护特性来预防的新方法 感染。保护作用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物来抑制阴道病原体，包括艾滋病毒。 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 菌株经过基因增强，可分泌有效的 HIV 进入抑制剂，经过修饰 氰基病毒素-N (mCV-N)。该菌株在阴道粘膜上的定殖以及持续的 mCV-N 的分泌有望减少女性生殖道中的 HIV 感染。目标是 该项目旨在完成 MucoCept-mCVN 的开发并满足 FDA 的要求 启动一期临床试验。新药研究 (IND) 申请已提交给 FDA 批准 MucoCept-CVN 片剂配方。在进行临床测试之前，FDA 要求我们重新配制并在兔阴道中重新测试 MucoCept-mCVN 产品 由于担心非活性片剂赋形剂潜在的阴道刺激，刺激模型（RVI）。 该 SBIR II 提案描述了两种新药物的并行开发和临床前测试 MucoCept-CVN 配方基于我们对另一种阴道给药 LBP 的经验 处于高级临床开发阶段。该计划旨在减轻制造和监管压力 风险并最大限度地提高产品的安全性，以确保在最短时间内获得 FDA 批准 和成本有效的方式。具体来说，我们将重新配制 MucoCept-CVN 片剂作为 羟丙基甲基纤维素胶囊以及使用其作为预填充阴道施药器 中间粉末并生产小批量 cGMP 产品用于 RVI 和临床测试。 两种 MucoCept-CVN 制剂和安慰剂将在 RVI 模型中进行测试并进行比较 到车辆控制。总体阴道刺激潜力最低的配方是 被选用于临床研究。 IND 将进行修订，以包括新的安全性和配方 信息并提交给FDA。一旦 FDA 批准，我们将继续进行首次人体试验 这一重要产品的临床研究。