Therapy and Prophylaxis for Genital Tract Infection

生殖道感染的治疗和预防

• 批准号: 10155414
• 负责人: DOMINICK AUCI
• 金额: $ 100万
• 依托单位: THERAPYX, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155414
• 关键词: Acute; Agreement; Antibiotics; Antibodies; Biological; Biological Sciences; Cardiovascular Physiology; Centers for Disease Control and Prevention (U.S.); Clinical Protocols; Clinical Trials; Collaborations; Communicable Diseases; Conscious; Databases; Development; Development Plans; Disease; Dose; Dose-Limiting; Drug Kinetics; Encapsulated; Excipients; Formulation; Frequencies; Future; Generations; Goals; Gonorrhea; Human; Immune response; Immunity; Immunotherapeutic agent; Immunotherapy; Incidence; Infection; Interleukin-12; Intravaginal Administration; Legal patent; Macaca fascicularis; Maximum Tolerated Dose; Measures; Mediating; Monkeys; Multi-Drug Resistance; Mus; NOEL; Nature; Neisseria gonorrhoeae; No-Observed-Adverse-Effect Level; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Pluronics; Polyethylene Glycols; Preparation; Primates; Process; Program Development; Prophylactic treatment; Public Health; Rattus; Readiness; Recombinant Interleukin-12; Recommendation; Reporting; Resistance; Rodent; Role; Safety; Science; Serum; Small Business Innovation Research Grant; Toxic effect; Toxicology; Treatment Protocols; Vaccines; Vagina; Woman; Work; base; clinical development; clinical toxicology; comparative; cytokine; design; drug development; first-in-human; immunological intervention; manufacturing process; manufacturing scale-up; meetings; mouse model; nonhuman primate; novel; novel strategies; novel therapeutics; particle; phase 1 study; postnatal development; pre-clinical; profiles in patients; programs; public health relevance; reproductive; reproductive tract; resistant strain; respiratory; response; telemetering; therapeutic vaccine; treatment optimization; vaccine development

PROJECT SUMMARY/ABSTRACT Genital tract infection with Neisseria gonorrhoeae does not induce a state of specific protective immunity and can be acquired repeatedly. Despite public health measures, the disease persists at an unacceptably high frequency; there is no vaccine against it, and resistance even to the latest generations of antibiotics continues to emerge. TherapyX, Inc. is advancing GneX12, a novel immune therapeutic that is designed to enhance antibiotic-mediated clearance of persistent Neisseria gonorrhoeae infection and induce long-term protection against subsequent exposure, i.e. a therapeutic vaccine. Specifically, GneX12 is the canonical type 1 cytokine interleukin-12 (IL-12) encapsulated in proprietary biodegradable sustained-release microparticles. Phase I studies in a murine model of gonoccal infection demonstrated that intra-vaginal administration of GneX12 achieved rapid disease clearance and induced the development of long-term protective immunity. Phase II work optimized treatment schedule; demonstrated the critical role of Th1 immunity in disease clearance; revealed that long-term protection was mediated by an anti-gonoccocal humoral response; that the antibodies were cross- protective; and that co-administration with antibiotics did not interfere with the induction of long-term protection. Additional Phase II work established scale-up manufacturing processes and completed a type C meeting with the FDA, garnering agency agreement with our single species primate toxicology plan to support an investigative new drug application (IND). The aims of the current Phase IIb application are based on agency recommendations communicated during that meeting. Specifically, Aim 1 studies will complete additional toxicology, including reproductive toxicology, assessment in rodents as recommend by FDA. In Aim 2, a large-batch “GMP-like” GneX12 drug product is manufactured in compliance with FDA drug substance and drug product release recommendations for use in IND-enabling, non-human primate toxicology studies. A meeting request and package, including final CMC and pre-clinical toxicology questions and finalized clinical protocols, will then be prepared and submitted for a Type B meeting with the FDA (Aim 3). Lastly, based on the FDA guidance obtained in Aim 3, initial tolerability and pK of GneX12 in non-human primates is established and IND readiness is assessed (Aim 4) in preparation for an open IND and first-in-man clinical trials. The long-term goal of this project is to develop a biologic, which when administered in conjunction with antibiotics, will not only enhance disease clearance but will also induce long-term protective immunity. No similar product currently exists.

项目摘要/摘要 生殖道感染了淋病奈瑟氏菌，不会诱导特定的保护性免疫和 可以反复获取。尽管采取了公共卫生措施，但这种疾病仍然存在着令人难以置信的高度 频率;没有疫苗，即使对最新一代的抗生素也有抵抗力继续 出现。 Therapyx，Inc。正在推进GNEX12，这是一种新型免疫疗法，旨在增强 抗生素介导的持续性淋病的清除和影响长期保护 反对随后的暴露，即治疗性疫苗。具体而言，gnex12是典型的1型细胞因子 白介素12（IL-12）封装在专有生物降解的持续释放微粒中。第一阶段 在淋球感染的鼠模型中的研究表明，gnex12的阴道内给药 达到了快速的疾病清除率，并诱导了长期保护免疫的发展。第二阶段的工作 优化的治疗时间表；证明了Th1免疫学在疾病清除率中的关键作用；揭示了这一点 长期保护是由抗肺炎局部体液反应介导的。抗体是交叉的 保护的;与抗生素共同给药并没有干扰诱导长期保护。 额外的第二阶段工作建立了扩大制造过程，并完成了C型会议 与我们的单一物种私人毒理学计划的FDA，获得代理机构协议，以支持调查 新药应用（IND）。当前IIB申请的目的是基于代理建议 在那次会议期间进行了交流。具体而言，AIM 1研究将完成其他毒理学，包括 生殖毒理学，根据FDA建议对啮齿动物的评估。在AIM 2中，一个大批量的“ GMP状” GNEX12药品是按照FDA药物和药物释放制造的 用于辅助，非人类灵长类动物毒理学研究的建议。会议请求和 套餐，包括最终的CMC和临床前毒理学问题和最终临床方案，然后将是 准备并提交了与FDA的B型会议（AIM 3）。最后，根据获得的FDA指南 在AIM 3中，建立了非人类隐私的GNEX12的初始耐受性和PK 评估（AIM 4）为开放的IND和人类临床试验做准备。该项目的长期目标 是要开发生物学，当生物学与抗生素结合使用时，不仅会增强疾病 清除，但也会引起长期保护的免疫力。目前没有类似的产品。