Pre-Clinical HPV16 Antiviral Compound Development

描述(申请人提供)：人乳头瘤病毒(HPV)16是目前为止导致宫颈不典型增生和癌症的主要原因，但目前还没有有效的病毒治疗方法。美国疾病控制与预防中心和/或世卫组织撰写的关于感染HPV16的妇女治疗方法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，甚至很少有迹象表明抗病毒药物可能很快就会为治疗带来希望。我们提出了抗病毒化合物的临床前开发，我们发现这种化合物在低纳摩尔范围内具有治疗人类细胞培养中HPV16的效力。这些化合物以HPV复制起点(ORI)为目标，在NIAID-AT-STTR第一阶段拨款的支持下设计、合成和测试，在细胞中具有特殊的抗病毒活性。它们作为抗病毒药物具有相当大的潜力，将增加一个重要工具来补充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，一旦完成，将为GMP合成最佳药物配方和向FDA提交研究新药申请(IND)奠定基础。该提案概述了与NanoVir顾问和斯坦福国际研究院(SRI)密切合作开发的里程碑和通过/不通过的决策点。SRI是GLP批准的机构，在阴道给药和许多NIAID分析的承包商方面具有丰富的历史和专业知识。该计划描述了所需的一系列临床前开发研究。具体地说，在拟议的工作中，我们将：1)根据体外和体内的疗效和先导毒性选择一个商业先导化合物(CL)和一个后备化合物；2)放大合成CL和一个后备化合物，制备CL的25个配方，通过单层和RAFT培养的体外效力和递送测试确定CL的五个最佳外用配方，并证明通过阴道给药有效地给药；3)选择CL配方进行额外的先导毒性和药代动力学研究，包括阴道刺激性和精子活力分析；4)扩大CL的化学合成和配方，测定CL的GLP分析证书(COA)，以及制备铅外用制剂和静脉制剂的GLP；5)完成GLP的药代动力学和毒性试验。这些研究的完成将有助于我们为GMP合成和提交IND用于人体试验做准备。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了主要致癌形式的HPV的数百万妇女提供了治疗的希望。与公共卫生相关：目前还没有针对人类乳头瘤病毒(HPV)16的抗病毒治疗或治愈，这种病毒导致世界上大多数宫颈癌病例。这项提案中描述的工作旨在导致治疗HPV16，HPV16是该病毒最普遍的致癌形式。在第一阶段确定了有效的HPV16抑制剂；在第二阶段的工作中，我们寻求在向FDA提交研究性新药申请和启动临床研究之前完成FDA要求的大多数测试。

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.