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

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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.