Research Project
9777229
1 PROJECT SUMMARY 2 HPV is the United States? most prevalent sexually transmitted infection and the high-risk subtypes are of 3 significant public health interest given that high-risk HPV (HR-HPV) infections have been conclusively linked 4 to the development of certain cancers. Cervical intraepithelial neoplasias (CIN), caused by persistent HR-HPV 5 infection, are categorized by grade, with high grades 2 and 3 being considered precancerous and grade 4, 6 carcinoma in situ. While there are an estimated 250,000 to 1 million women diagnosed with CIN annually in the 7 U.S., there are no minimally invasive therapies with direct antiviral activity for the treatment of CIN and 8 excisional procedures are often associated with pain, fertility issues and recurrence. Despite the success of the 9 prophylactic HPV vaccines, the incidence of HPV-induced cancer is steadily increasing, due to (a) the inability 10 of the vaccine to cure preexisting infections; (b) a great majority of adolescent populations is not vaccinated; and 11 (c) high rate of population growth. 12 Novan?s platform technology enables the delivery of nitric oxide in a solid form, on demand and in localized 13 formulations. Novan?s nitric oxide (NO)-releasing drug candidates have demonstrated the ability to inhibit 14 papillomavirus amplification and replication in nonclinical models, as well safety and efficacy in a Phase 2 trial 15 of external genital warts. The goal of this Fast-Track research plan is to develop a new formulation of a nitric 16 oxide-releasing gel that can be self-administered by the patient, intravaginally, as a treatment for cervical HPV 17 infections in women. If successful, such an approach may be instrumental in reducing the number of locally 18 destructive surgical procedures in the U.S. and, ultimately, cervical cancers attributable to HPV. 19 The Phase I portion of this research proposal is designed to formulate a stable gel formulation suitable for 20 intravaginal administration and ensure the NO release profiles of the gel replicate profiles previously 21 demonstrated to have antiviral effects. Go-no go criteria to transition from Phase I to Phase II is minimum 22 stability of the formulation intended for clinical use in the U.S. (25?C for 12 weeks) and an NO release profile 23 that matches the high C-max and short half-life release profile previously demonstrated to have antiviral activity 24 when delivered topically. The Phase II portion is designed to assess the gel formulation?s 1) in vitro toxicology: 25 tumor promotion capabilities and effect on vaginal flora; 2) in vivo toxicology: safety, tolerability and 26 toxicokinetics following application to mucosal surfaces via intravaginal administration in a 7-day pilot and a 27 GLP 28-day repeat-dose toxicology study in rabbits necessary to submit an Investigational New Drug (IND) 28 application; 3) pharmacology ? ability to reduce vaginal papillomavirus infections and regress cervical 29 neoplasias in a mouse model; and, 4) virology: evaluation of NO?s antiviral activity and mechanism of action 30 against HPV-16 infected cells. The body of this work constitutes the foundational nonclinical studies necessary 31 to submit an Investigational New Drug (IND) application to the FDA.
