Pre-Clinical HPV16 Antiviral Compound Development

描述（由申请人提供）：人乳头瘤病毒（HPV）16是迄今为止宫颈不典型增生和宫颈癌的主要原因，但没有有效的治疗方法。CDC和/或WHO撰写的关于HPV 16感染妇女治疗的主要综述和调查通常将“随访”观察和手术干预作为唯一可用的选择，甚至很少表明抗病毒药物可能很快提供治疗的希望。我们提出临床前开发抗病毒化合物，我们已经发现在低纳摩尔范围内的抗病毒效力用于治疗人细胞培养物中的HPV 16。这些化合物靶向HPV复制起点（ori），并在NIAID-AT-STTR第1阶段资助的支持下设计，合成和测试，在细胞中具有特殊的抗病毒活性。它们作为抗病毒剂具有相当大的潜力，这将增加一个重要的工具来补充HPV疫苗，使HPV+和HPV-患者都能得到治疗。该提案提出了5个具体目标和一个全面的化学计划，完成后，将为GMP合成最佳药物配方和向FDA提交研究性新药申请（IND）奠定基础。该提案概述了与NanoVir顾问和斯坦福大学国际研究所（SRI）密切合作开发的Milestival和Go/No Go决策点，SRI是一家GLP批准的机构，在开发阴道给药药物方面具有相当的历史和专业知识，是许多NIAID检测的承包商。该计划描述了所需的一系列临床前开发研究。具体而言，在拟议的工作中，我们将：1）根据体外和体内的有效性和先导毒性，选择一种商业先导化合物（CL）和一种备用化合物; 2）CL和一个备份的放大合成，制备CL的25个制剂，通过在单层和筏培养中的体外功效和递送测试来鉴定CL的五个最佳局部制剂，3）选择CL制剂进行额外的初步毒性和药代动力学研究，包括阴道刺激和精子活力测定; 4）CL的放大化学合成和配制，确定CL的GLP检验报告（COA），以及先导局部制剂和IV制剂的GLP制备; 5）完成GLP药代动力学和毒性测试。这些研究的完成将有助于我们为GMP合成和提交IND进行人体试验做好准备。商业化计划量化了市场机会，并描述了产品上市前的步骤。这些研究的成功完成为目前感染HPV的主要致癌形式的数百万妇女提供了治疗的希望。公共卫生相关性：目前没有抗病毒治疗或治愈人类乳头瘤病毒（HPV）16，这种病毒导致世界上大多数宫颈癌病例。该提案中描述的工作旨在治疗HPV 16，这是该病毒最普遍的致癌形式。有效的HPV 16抑制剂在第1阶段被确定;在第2阶段的工作中，我们试图在向FDA提交研究性新药申请和启动临床研究之前完成FDA要求的大部分测试。

DESCRIPTION (provided by applicant): Human Papillomavirus (HPV) 16 is by far the major cause of cervical dysplasia and cancer, but no effective treatment for the virus is available or anticipated. Major CDC- and/or WHO-authored reviews and surveys of treatments for women infected by HPV16 typically refer to "follow up" observation and surgical intervention as the only options available, and rarely even suggest that antivirals might soon provide hope for treatment. We propose preclinical development of antiviral compounds we have discovered that posses potency in the low nanomolar range for treatment of HPV16 in human cell culture. These compounds, which target the HPV origin of replication (ori) and were designed, synthesized and tested with the support of an NIAID-AT-STTR Phase 1 grant, possess exceptional antiviral activity in cells. They hold considerable potential as antiviral agents that will add an important tool to complement the HPV vaccines, allowing both HPV+ and HPV- patients to be treated. The proposal puts forward 5 specific aims and a comprehensive chemistry plan that, when completed, will have laid the ground work for GMP synthesis of an optimal drug formulation and filing of an Investigational New Drug application (IND) with the FDA. The proposal outlines Milestones and Go/No Go decision points that have been developed in close collaboration with NanoVir consultants and the Stanford Research Institute, International (SRI), a GLP-approved facility with considerable history and expertise in the development of vaginally-delivered drugs and contractor for many NIAID assays. The plan describes a required series of preclinical development studies. Specifically, in the proposed work we will: 1) select one Commercial Lead compound (CL) and one back-up based on efficacy and pilot toxicity in vitro and in vivo; 2) scale-up synthesis of the CL and one back-up, prepare 25 formulations of the CL, identify the five best topical formulations of the CL via in vitro efficacy and delivery testing in monolayer and raft cultures, and demonstrate effective cervical delivery via vaginal administration in rabbits; 3) select CL formulations for additional pilot toxicity and pharmacokinetic studies, including vaginal irritation and sperm motility assays; 4) scale-up chemical synthesis and formulation of the CL, determination of a GLP Certificate of Analysis (COA) for the CL, and GLP preparation of the lead topical formulation and an IV formulation; 5) complete GLP pharmacokinetic and toxicity testing. Completion of these studies will help prepare us for GMP synthesis and submission of an IND for testing in humans. The Commercialization Plan quantifies the market opportunity and describes the steps preceding market launch of the product. Successful completion of these studies offers the hope of treatment for millions of women currently infected by the primary cancer-causing form of HPV. PUBLIC HEALTH RELEVANCE: There is currently no antiviral treatment or cure for Human Papillomavirus (HPV)16 , the virus that causes most cases of cervical cancer in the world. The work described in this proposal is designed to lead to a treatment for HPV16, the most prevalent, cancer causing form of the virus. Potent HPV16 inhibitors were identified in Phase 1; in this Phase 2 work, we seek to complete most of the tests required by the FDA prior to submission of an Investigational New Drug Application to the FDA and initiation of clinical studies.