Pre-Clinical HPV16 Antiviral Compound Development

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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.