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- 合规原料药和制剂生产和放行，管理 临床前安全性和有效性研究，并制定和整合监管文件 向美国食品药品监督管理局提交研究性新药（IND）申请 美国食品药品监督管理局（FDA），以支持调查性临床试验。项目1将建立 新产品的制造方法，并帮助定义一个加速的 临床疗效证明和产品许可证的发展路径。 我们的杀微生物剂的新活性药物成分（API）是Griffithsin（GRFT）， 一种海藻天然蛋白质，我们已经开发并扩大了一种高效的 重组制造工艺。 GRFT是已知的最有效的HIV-1进入抑制剂，也具有高活性， 其他可能与HIV共传播的病毒，如HSV-2。通过我们 作为PREVENT计划的合作伙伴，我们已经生产了超过200 g的GRFT 并开发了高效、稳定的杀微生物剂凝胶剂型。 这些原型凝胶已在离体人体外植体中进行了初步安全性评价 系统、物理化学稳定性和API释放特性， 结果在本项目的目标1中，我们将应用迄今为止成功使用的方法 进一步优化API生产工艺，以获得最大产量和回收率。的 生产工艺将符合FDA cGMP指南， 以及支持文件。cGMP将使用合规API 生产核心B中优化的直肠凝胶最终剂型。目标2：安全 直肠凝胶产品的耐受性将在符合法规的 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。初步化学， 生产和控制（CMC）和安全性信息沿着以及临床草案 将在IND前会议上与FDA讨论方案。机构反馈将有助于 我们正在完成IND申请，FDA激活该申请将使我们能够启动 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.