Pre-Clinical HPV16 Antiviral Compound Development

描述（由申请人提供）：人乳头瘤病毒（HPV） 16是迄今为止导致宫颈发育不良和癌症的主要原因，但目前尚无有效的治疗方法。疾病预防控制中心和/或世卫组织撰写的关于感染HPV16的妇女治疗的主要评论和调查通常将“随访”观察和手术干预作为唯一可用的选择，甚至很少提出抗病毒药物可能很快就会带来治疗的希望。我们建议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具有治疗人类细胞培养中的HPV16的效力。这些靶向HPV复制起源（ori）的化合物是在NIAID-AT-STTR 1期资助的支持下设计、合成和测试的，在细胞中具有卓越的抗病毒活性。它们作为抗病毒药物具有相当大的潜力，将为HPV疫苗补充一个重要的工具，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，将为最佳药物配方的GMP合成和向FDA提交新药研究申请（IND）奠定基础。该提案概述了与NanoVir顾问和斯坦福国际研究所（SRI）密切合作制定的里程碑和Go/No Go决策点。斯坦福国际研究所是一家经glp批准的机构，在开发阴道给药方面具有相当长的历史和专业知识，也是许多NIAID检测的承包商。该计划描述了一系列必要的临床前开发研究。具体而言，在拟议的工作中，我们将：1)根据体外和体内的功效和中试毒性选择一种商业先导化合物（CL）和一种备用化合物；2)按比例合成氯胺酮和1个备用制剂，制备25种氯胺酮制剂，通过体外单层和raft培养的疗效和给药测试，确定5种最佳的氯胺酮外用制剂，并通过家兔阴道给药证明其有效的宫颈给药；3)选择CL配方进行额外的中试毒性和药代动力学研究，包括阴道刺激和精子活力分析；4)扩大化学合成和配制CL，确定CL的GLP分析证书（COA）， GLP制备主要外用制剂和静脉制剂；5)完成GLP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进行人体试验做准备。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原发性致癌型HPV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。本提案中描述的工作旨在找到一种治疗HPV16的方法，HPV16是最普遍的致癌病毒形式。在1期研究中发现了有效的HPV16抑制剂；在第二阶段的工作中，我们寻求在向FDA提交新药研究申请和开始临床研究之前完成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.