Pre-clinical Development of a Broad Spectrum Antiviral Compound to Treat Human Pa

描述(申请人提供)：该提案寻求支持用于治疗人乳头状瘤病毒(HPV)的广谱化合物的临床前开发。HPV是最常见的性传播病毒，是导致宫颈不典型增生和宫颈癌的原因。它还与其他几种过度增殖的疾病有关，如口腔癌和肛门癌，以及上呼吸道和泌尿生殖道。目前还没有任何针对这种高风险、致癌形式的病毒的有效治疗方法可用或预计。美国疾病控制与预防中心和世界卫生组织的文件，包括对感染HPV的妇女的治疗情况的调查，通常将“后续”观察和后来的手术作为最佳选择，很少提到可能开发出抗病毒药物。我们在NIAID-STTRHPV18第一阶段资助下发现、设计、合成和测试的抗病毒化合物，对3种不同的HPV高危基因型具有低纳摩尔范围的效力。这种广谱活性与HPV18、HPV16和HPV31维持EB病毒的人类细胞的病毒滴度显著下降有关。重要的是，用铅化合物局部处理HPV+人类器官组织培养物可降低病毒滴度和细胞DNA合成。这些新化合物具有相当大的潜力作为广泛活性的HPV抗病毒药物，从而为HPV疫苗不是针对的感染患者提供了一种治疗选择。考虑到我们的化合物降低了3种高危基因类型的病毒滴度的效力，我们希望我们的化合物将对其他导致疾病的HPV基因型有效。提出了包括化学计划在内的六个具体目标，以及与FDA举行的IND前会议，这将为提交调查性新药申请(IND)奠定基础。该提案提供了里程碑和通过/不通过的决策点，这些点是与NanoVir顾问和斯坦福国际研究院(SRI)密切合作开发的，SRI是GLP批准的机构，在经阴道递送药物的开发和许多NIAID分析的承包商方面具有丰富的历史和专业知识。研究计划描述了FDA要求的临床前开发研究，包括1)初步的化学放大、非GLP毒理学和药代动力学研究；2)配方前和药物稳定性研究，以及使用已获批准的成分或目前正在进行的局部阴道给药临床试验的成分开发25个初始局部制剂；3)在器官组织培养中进行体外释放和疗效研究，以选择2-3个配方用于动物试验；4)为试点PK/毒理学研究准备足够的化合物，并在兔阴道分娩后演示体内宫颈摄取；在这些试验期间还将跟踪全身暴露；5)扩大临床先导化合物(CL)的化学合成和配方，分2-3批次用于GLP分析证书(COA)的测定，然后根据GLP的要求配制CL；6)FDA要求的GLP药代动力学和毒性试验，以证明高安全边际，使进入临床试验成为可能。包括一份商业化计划，该计划提供更多的背景信息和基本原理，识别和衡量市场机会，并描述推出产品所需的步骤。这些研究的成功完成为目前感染HPV的数百万人提供了治疗的希望，包括HPV16和HPV18，这两种病毒占宫颈癌的65%。 与公共卫生相关：人乳头瘤病毒(HPV)有15种不同的高危形式，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对HPV的广泛治疗。在第一阶段确定了有效的广谱抑制剂；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): The proposal seeks support for the pre-clinical development of broad spectrum compounds for treatment of human papillomavirus (HPV). HPV, the most common sexually-transmitted virus, is the cause of cervical dysplasia and cervical cancer. It has also been implicated in several other hyperproliferative diseases, such as cancers of the mouth and anus, as well as the upper respiratory and urogenital tracts. No effective treatment for the virus in any of its high-risk, cancer-causing forms, is available or anticipated. CDC and WHO documents, including surveys of treatments for women infected by HPV, typically refer to "follow up" observation and later surgery as the best options available, and rarely refer to the possibility that antiviral drugs might be developed. The antiviral compounds we have discovered, designed, synthesized and tested with the support of an NIAID-STTR Phase 1 grant for HPV18, possess potency in the low nanomolar range for 3 different HPV high-risk genotypes. This broad spectrum activity is associated with significant decreases in viral titer for HPV18, HPV16 and HPV31 episome-maintaining human cells. Importantly, topical treatment of HPV+ human organotypic tissue cultures with lead compounds resulted in reductions for both viral titer and cellular DNA synthesis. These novel compounds hold considerable potential as broadly-active HPV antiviral agents, thus providing a treatment option for infected patients for whom the HPV vaccines were not intended. Considering the potency at which our compounds reduced viral titer in 3 high-risk genotypes, we are hopeful our compounds will be efficacious against additional disease-causing HPV genotypes.. Six specific aims including a chemistry plan are proposed, as well as a pre-IND meeting with the FDA that will lay the ground work for filing an Investigational New Drug application (IND). The proposal provides both 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 Research Plan describes preclinical development studies required by the FDA and includes 1) initial chemical scale up, non-GLP toxicology and pharmacokinetic studies; 2) Pre-formulation and drug stability studies, and development of 25 initial topical formulations using ingredients approved or ingredients presently being evaluated in clinical trials for topical vaginal delivery; 3) In vitro delivery and efficacy studies in organotypic tissue cultures to select 2-3 formulations for testing in animals; 4) Preparation of sufficient compound for Pilot PK/toxicology studies and demonstration of in vivo cervical uptake following vaginal delivery in rabbits; systemic exposure will also be followed during these tests; 5) Scaling up chemical synthesis and formulation of the clinical lead compound (CL) in 2-3 batches for GLP determination of a Certificate of Analysis (COA) followed by formulation of the CL under GLP; 6) GLP pharmacokinetic and toxicity testing as required by the FDA to demonstrate a high safety margin that will allow progression to Clinical Trials. A Commercialization Plan is included that provides additional background information and rationale, identifies and measures the market opportunity and describes the steps required to launch the product. Successful completion of these studies offers the hope of treatment for millions of people currently infected by HPV, including HPV16 and 18 which account for >65% of cervical cancers. PUBLIC HEALTH RELEVANCE: Human Papillomavirus (HPV) has 15 different high-risk forms that cause most cases of cervical cancer in the world. The work described in this proposal is designed to lead to a broad spectrum treatment for HPV. Potent broad spectrum 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.