Development of a nitric oxide-releasing antiviral gel for the treatment of cervical HPV infections and prevention of downstream malignancies in women

HPV is the United States’ most prevalent sexually transmitted infection and thehigh-risk subtypes are of significant public health interest given that high-risk HPV (HR-HPV) infections have beenconclusively linked to the development of certain cancers. Cervical intraepithelial neoplasias(CIN), caused by persistent HR-HPV infection, are categorized by grade, with high grades 2and 3 being considered precancerous and grade 4, carcinoma in situ. While there are anestimated 250,000 to 1 million women diagnosed with CIN annually in the U.S., there are nominimally invasive therapies with direct antiviral activity for the treatment of CINand excisional procedures are often associated with pain, fertility issues and recurrence. Despitethe success of the prophylactic HPV vaccines, the incidence of HPV-induced cancer is steadilyincreasing, due to (a) the inability of the vaccine to cure preexisting infections; (b) a greatmajority of adolescent populations is not vaccinated; and (c) high rate of population growth. Novan’s platform technology enables the delivery of nitric oxide in a solid form, on demand and inlocalized formulations. Novan’s nitric oxide (NO)-releasing drug candidates havedemonstrated the ability to inhibit papillomavirus amplification and replication in nonclinicalmodels, as well safety and efficacy in a Phase 2 trial of external genital warts. The goal of thisFast-Track research plan is to develop a new formulation of a nitric oxide-releasing gel that canbe self-administered by the patient, intravaginally, as a treatment for cervical HPV infections inwomen. If successful, such an approach may be instrumental in reducing the number of locallydestructive surgical procedures in the U.S. and, ultimately, cervical cancers attributable to HPV. The Phase I portion of this research proposal is designed to formulate a stable gelformulation suitable for intravaginal administration and ensure the NO release profilesof the gel replicate profiles previously demonstrated to have antiviral effects. Go-nogo criteria to transition from Phase I to Phase II is minimum stability of theformulation intended for clinical use in the U.S. (25˚C for 12 weeks) and an NO release profilethat matches the high C-max and short half-life release profile previously demonstrated to haveantiviral activity when delivered topically. The Phase II portion is designed to assess the gelformulation’s 1) in vitro toxicology: tumor promotion capabilities and effect on vaginalflora; 2) in vivo toxicology: safety, tolerability and toxicokinetics following applicationto mucosal surfaces via intravaginal administration in a 7-day pilot and a GLP 28-day repeat-dosetoxicology study in rabbits necessary to submit an Investigational New Drug (IND) application; 3)pharmacology – ability to reduce vaginal papillomavirus infections and regress cervicalneoplasias in a mouse model; and, 4) virology: evaluation of NO’s antiviral activity and mechanismof action against HPV-16 infected cells. The body of this work constitutes the foundationalnonclinical studies necessary to submit an Investigational New Drug (IND) application to the FDA.