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

治疗人类感染的广谱抗病毒化合物的临床前开发

• 批准号: 7908130
• 负责人: CHRISTOPHER FISHER
• 金额: $ 100万
• 依托单位: NANOVIR, LLC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7908130
• 关键词: Abbreviations; Accounting; Ames Assay; Analytical Chemistry; Animals; Antiviral Agents; Anus; Biological Assay; Biological Availability; Biology; Bone Marrow; Cancer Etiology; Cell Culture Techniques; Cells; Centers for Disease Control and Prevention (U.S.); Cervical; Cervical dysplasia; Chemicals; Chemistry; Clinical; Clinical Research; Clinical Trials; Collaborations; Contractor; DNA; DNA biosynthesis; Data; Development; Disease; Dose; Drug Formulations; Drug Kinetics; Drug Stability; Episome; Epithelium; Genitourinary system; Genotype; Glossary; Grant; HPV-High Risk; High Pressure Liquid Chromatography; High-Risk Cancer; Human; Human Papilloma Virus Vaccine; Human Papillomavirus; Human papilloma virus 31; Human papilloma virus infection; Human papillomavirus 16; Human papillomavirus 18; In Vitro; Inhibitory Concentration 50; International; Intravaginal Administration; Investigational New Drug Application; Lead; Lymphoma; Malignant neoplasm of cervix uteri; Marketing; Maximum Tolerated Dose; Measures; Micronucleus Tests; Mus; National Institute of Allergy and Infectious Disease; Operative Surgical Procedures; Oryctolagus cuniculus; Pap smear; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacology and Toxicology; Pharmacy (field); Phase; Preparation; Process; Rattus; Recording of previous events; Records; Research; Research Institute; Safety; Solubility; Sperm Motility; Surveys; Testing; Time; Toxic effect; Toxicity Tests; Toxicogenetics; Toxicology; Vagina; Vaginal delivery procedure; Viral; Virus; Woman; Work; base; chemical synthesis; commercialization; design; drug candidate; effective therapy; experience; follow-up; high risk; in vivo; indexing; inhibitor/antagonist; irritation; keratinocyte; lymph nodes; malignant mouth neoplasm; meetings; novel; penis foreskin; pre-clinical; public health relevance; respiratory; scale up; solid solution; stability testing; tissue culture; uptake

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.

描述（由申请人提供）：该提案寻求支持广泛化合物的临床前开发以治疗人乳头瘤病毒（HPV）。 HPV是最常见的性传播病毒，是宫颈发育不良和宫颈癌的原因。它也与其他几种高增殖性疾病有关，例如口腔和肛门的癌症，以及上呼吸道和泌尿生殖道。在其任何高风险，致癌形式的任何高危病毒中均未有效治疗。 CDC和WHO文件，包括对HPV感染的妇女的治疗调查，通常将“后续观察”和后来的手术视为可用的最佳选择，并且很少提到可能开发抗病毒药物的可能性。我们发现，设计，合成和测试的抗病毒化合物在HPV18的NIAID-STTR 1阶段赠款的支持下具有3种不同的HPV高风险基因型的低纳莫尔范围内具有效力。这种广泛的频谱活性与HPV18，HPV16和HPV31维持人类细胞的病毒滴度显着降低有关。重要的是，用铅化合物对HPV+人体器官组织培养物的局部处理导致病毒滴度和细胞DNA合成的降低。这些新型化合物作为广泛活跃的HPV抗病毒剂具有巨大的潜力，因此为不打算使用HPV疫苗的感染患者提供了治疗选择。考虑到我们的化合物在3种高风险基因型中降低病毒滴度的效力，我们希望我们的化合物能够有效地针对引起疾病的其他HPV基因型。.提出了六个具体目的，包括化学计划，以及与FDA的预先启动会议，并将与FDA相遇，以启动用于申请研究的新药物应用程序（指标）。该提案提供了与Nanovir顾问密切合作开发的里程碑和GO/NO GO决策点，以及Stanford Research Institute，International（SRI），这是GLP批准的设施，在许多NIAID分析中具有相当大的历史和专业知识。研究计划描述了FDA所需的临床前开发研究，其中包括1）初始化学量表，非GLP毒理学和药代动力学研究； 2）使用临床试验中批准的成分或成分进行局部阴道递送的批准或成分，并开发了25种初始局部制剂的制定和药物稳定性研究； 3）在器官组织培养物中的体外递送和功效研究，以选择2-3种动物测试的制剂； 4）制备有足够的化合物用于pK/毒理学研究，并证明了兔子阴道分娩后体内宫颈摄取；在这些测试期间，还将遵循系统性暴露； 5）在2-3批中扩大临床铅化合物（CL）的化学合成和制定，以确定GLP的分析证书（COA），然后在GLP下进行CL制定； 6）FDA要求的GLP药代动力学和毒性测试，以证明高安全边缘将允许进展为临床试验。包括商业化计划，提供其他背景信息和基本原理，识别和衡量市场机会，并描述启动产品所需的步骤。这些研究的成功完成为数百万目前感染了HPV感染的人提供了希望，其中包括HPV16和18，占宫颈癌的65％。 公共卫生相关性：人类乳头瘤病毒（HPV）具有15种不同的高风险形式，这些形式引起了世界上大多数宫颈癌。该提案中描述的工作旨在导致HPV的广泛治疗。在第1阶段鉴定出有效的广谱抑制剂；在这一阶段2的工作中，我们试图在提交研究新药物的FDA和临床研究开始之前完成FDA所需的大多数测试。