Project 1: PREVENT Program Critical Path Project

关键路径项目(CPP；项目1)的总体目标是协调cGMP- 合规药品和药品的生产、发放、管理 临床前安全性和有效性研究，并制定和整合管理文件 向美国食品和药物管理局提交研究新药(IND)申请 美国食品和药物管理局(FDA)，支持一项调查性临床试验。项目1将建立 新产品的制造方法，并帮助定义加速的 向临床疗效和产品许可展示的发展路径。 我们的杀微生物剂的新活性药物成分(API)是格里菲辛(GRFT)， 一种海洋藻类天然蛋白，我们已经为其开发并扩大了有效的 重组制造工艺。 GRFT是已知的最有效的HIV-1进入抑制剂，对 其他可能与艾滋病毒共同传播的病毒，如HSV-2。通过我们的 预防计划的合作者，我们已经生产了超过200克的GRFT 用于科研用途，并开发出有效稳定的杀菌剂凝胶剂型。 这些原型凝胶已经在人体外植体中进行了初步安全性评估。 系统、物理化学稳定性和原料药释放特性非常令人鼓舞 结果。在本项目的目标1中，我们将应用到目前为止已成功使用的方法 以进一步优化原料药的制造工艺，以实现最大的产量和回收率。这个 制造过程将符合FDA cGMP指南， 以及支持文件。将使用符合要求的API来控制GMP 制造直肠凝胶最终剂型在Core B中优化。在目标2中，安全性 并且直肠凝胶产品的耐受性将在符合规定的情况下确定 3种动物的毒理学，终点包括局部和全身安全性， 耐受性、刺激性、敏感性和免疫毒性。基础化学， 制造和控制(CMC)和安全信息以及临床草案 协议将在IND前会议上与FDA讨论。机构的反馈将有助于 美国正在敲定IND申请，FDA激活该申请将允许我们启动 项目3中GRFT杀微生物剂的首次人体临床试验。

The overall goal of the Critical Path Project ("CPP"; Project 1) is to coordinate cGMP- compliant Drug Substance and Drug Product manufacture and release, manage preclinical safety and efficacy studies, and develop and integrate regulatory documents for submission of an Investigational New Drug (IND) application to US Food and Drug Administration (FDA), in support of an investigative clinical trial. Project 1 will establish the manufacturing methodology for the new product and help define an accelerated development path towards demonstration of clinical efficacy and product licensure. The novel active pharmaceutical ingredient (API) of our microbicide is Griffithsin (GRFT), a marine algal natural protein for which we have developed and scaled an efficient recombinant manufacturing process. GRFT is the most potent HIV-1 entry inhibitor known and also has high activity against other viruses that may be co-transmitted with HIV, such as HSV-2. Through our collaborators in the PREVENT Program, we have produced more than 200 g of GRFT for research use, and developed effective and stable microbicide gel dosage forms. These prototype gels have been evaluated for initial safety in an ex vivo human explant system, physicochemical stability and API release characteristics with very encouraging results. In Aim 1 of this Project, we will apply methods we have successfully used to date to further optimize the API manufacturing process for maximum yield and recovery. The manufacturing process will be brought to compliance with FDA cGMP guidelines, together with supporting documentation. Compliant API will be used to cGMP manufacture the rectal gel final dosage form optimized in Core B. In Aim 2, the safety and tolerability of the rectal gel product will be determined in regulation-compliant toxicology in 3 animal species, with endpoints to include topical and systemic safety, tolerability, irritation, sensitivity and immunotoxicity. Preliminary Chemistry, Manufacturing and Controls (CMC) and safety information along with a draft clinical Protocol will be discussed with FDA in a pre-IND meeting. Agency feedback will assist us in finalizing an IND application, activation of which by FDA will allow us to initiate a first-in-humans clinical trial of the GRFT microbicide in Project 3.