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

描述（由申请人提供）：该申请寻求支持用于治疗人乳头瘤病毒（HPV）的广谱化合物的临床前开发。HPV是最常见的性传播病毒，是导致宫颈发育不良和宫颈癌的原因。它还与其他几种增生性疾病有关，如口腔癌、肛门癌、上呼吸道癌和泌尿生殖道癌。目前还没有针对任何高风险致癌形式的病毒的有效治疗方法。疾病预防控制中心和世卫组织的文件，包括对感染HPV的妇女的治疗方法的调查，通常将“随访”观察和后来的手术作为现有的最佳选择，很少提及开发抗病毒药物的可能性。在NIAID-STTR 1期资助的支持下，我们发现、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维持发作期的人类细胞的病毒滴度显著降低有关。重要的是，用铅化合物局部治疗HPV+人器官型组织培养物导致病毒滴度和细胞DNA合成降低。这些新型化合物具有相当大的潜力，可作为广泛活性的HPV抗病毒药物，从而为不打算接种HPV疫苗的感染患者提供治疗选择。考虑到我们的化合物在3种高危基因型中降低病毒滴度的效力，我们希望我们的化合物对其他致病的HPV基因型有效。提出了六个具体目标，包括化学计划，以及与FDA的IND前会议，这将为提交研究新药申请（IND）奠定基础。该提案提供了里程碑和Go/No Go决策点，这些决策点是与NanoVir顾问和斯坦福国际研究所（SRI）密切合作开发的。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。研究计划描述了FDA要求的临床前开发研究，包括1)初始化学放大、非glp毒理学和药代动力学研究；2)制剂前和药物稳定性研究，并开发25种初始外用制剂，使用已批准或目前正在临床试验中评估的成分用于阴道外用；3)器官型组织培养体外给药及功效研究，选择2-3个配方进行动物试验；4)制备足够的化合物用于前期PK/毒理学研究，并证明兔阴道分娩后体内宫颈摄取；在这些测试期间，还将进行系统性暴露；5)扩大化学合成和配制临床先导化合物（CL），分2-3批进行GLP测定，并获得分析证书（COA），然后在GLP下配制CL；6) FDA要求的GLP药代动力学和毒性测试，以证明其具有较高的安全边际，从而可以进行临床试验。商业化计划包括提供额外的背景信息和基本原理，确定和衡量市场机会，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，包括占宫颈癌65%的HPV16和hpv18。

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.