SBIR-STTR Award

HPV is the United States' most prevalent sexually transmitted infection and the high-risk subtypes are of significant public health interest given that high-risk HPV (HR-HPV) infections have been conclusively linked to the development of certain cancers. Cervical intraepithelial neoplasias (CIN), caused by persistent HR-HPV infection, are categorized by grade, with high grades 2 and 3 being considered precancerous and grade 4, carcinoma in situ. While there are an estimated 250,000 to 1 million women diagnosed with CIN annually in the U.S., there are no minimally invasive therapies with direct antiviral activity for the treatment of CIN and excisional procedures are often associated with pain, fertility issues and recurrence. Despite the success of the prophylactic HPV vaccines, the incidence of HPV-induced cancer is steadily increasing, due to (a) the inability of the vaccine to cure preexisting infections; (b) a great majority 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 in localized formulations. Novan's nitric oxide (NO)-releasing drug candidates have demonstrated the ability to inhibit papillomavirus amplification and replication in nonclinical models, as well safety and efficacy in a Phase 2 trial of external genital warts. The goal of this Fast-Track research plan is to develop a new formulation of a nitric oxide-releasing gel that can be self-administered by the patient, intravaginally, as a treatment for cervical HPV infections in women. If successful, such an approach may be instrumental in reducing the number of locally destructive 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 gel formulation suitable for intravaginal administration and ensure the NO release profiles of the gel replicate profiles previously demonstrated to have antiviral effects. Go-no go criteria to transition from Phase I to Phase II is minimum stability of the formulation intended for clinical use in the U.S. (25?C for 12 weeks) and an NO release profile that matches the high C-max and short half-life release profile previously demonstrated to have antiviral activity when delivered topically. The Phase II portion is designed to assess the gel formulation's 1) in vitro toxicology: tumor promotion capabilities and effect on vaginal flora; 2) in vivo toxicology: safety, tolerability and toxicokinetics following application to mucosal surfaces via intravaginal administration in a 7-day pilot and a GLP 28-day repeat-dose toxicology study in rabbits necessary to submit an Investigational New Drug (IND) application; 3) pharmacology - ability to reduce vaginal papillomavirus infections and regress cervical neoplasias in a mouse model; and, 4) virology: evaluation of NO's antiviral activity and mechanism of action against HPV-16 infected cells. The body of this work constitutes the foundational nonclinical studies necessary to submit an Investigational New Drug (IND) application to the FDA.

Public Health Relevance Statement:
PROJECT NARRATIVE Persistent high-risk human papillomavirus (HR-HPV) infection is the most important risk factor for the development of cervical intraepithelial neoplasias (CIN) in women and the subsequent progression to cervical cancer. While there are an estimated 250,000 to 1 million women diagnosed with CIN annually in the U.S., there are no minimally invasive therapies with direct antiviral activity for the treatment of CIN. Excisional treatment procedures are associated with increased risk of pre-term birth in future pregnancies as well as anxiety, pain and bleeding. Novan is developing a nitric oxide-releasing antiviral gel for the treatment cervical HPV infections and the prevention of downstream malignancies in women.

Project Terms:
Intravaginal Administration; Vaginal Administration; Antiviral Agents; anti-virals; anti-viral drugs; anti-viral agents; Antivirals; Antiviral Drugs; Anxiety; Malignant Neoplasms; neoplasm/cancer; malignancy; Malignant Tumor; Cancers; Carcinoma in Situ; in situ cancer; Preinvasive Carcinoma; Intraepithelial Carcinoma; cell culture; Cell Culture Techniques; Cell Body; Cells; Uterine Cervix Cancer; Malignant Uterine Cervix Tumor; Malignant Uterine Cervix Neoplasm; Malignant Tumor of the Cervix Uteri; Malignant Tumor of the Cervix; Malignant Neoplasm of the Cervix; Malignant Cervical Tumor; Malignant Cervical Neoplasm; Cervix Cancer; Cervical Cancer; Malignant neoplasm of cervix uteri; Uterine Cervix Tumor; Uterine Cervix Neoplasm; Cervix Uteri Tumor; Cervix Uteri Neoplasm; Cervix Tumor; Cervical Tumor; Cervical Neoplasms; Cervical Neoplasia; Cervix Neoplasms; climatic; Meteorological Climate; Climate; Venereal Warts; Genital Warts; Condylomata Acuminata; Condyloma Accuminata; Anogenital venereal warts; Diagnosis; Investigational New Drugs; Investigational Drugs; Environment; Fecundity; Fecundability; Fertility; Foundations; Future; Gel; Goals; Half-Life; blood loss; Bleeding; Hemorrhage; Modern Man; Human; In Vitro; Incidence; Infection; wart virus; Infectious Human Wart Virus; Human Papilloma Virus; HPV; Human Papillomavirus; Mucosal Tissue; Mucosa; Mucous Membrane; Murine; Mice Mammals; Mice; Mus; neoplastic growth; neoplasia; Neoplasms; endothelial cell derived relaxing factor; Nitrogen Protoxide; Nitrogen Monoxide; Mononitrogen Monoxide; Endothelium-Derived Nitric Oxide; Endogenous Nitrate Vasodilator; Nitric Oxide; Oxides; Painful; Pain; Papillomaviridae; Papilloma Viruses; Papillomavirus; Patients; Pharmacology; Population Growth; Gestation; Pregnancy; Public Health; Rabbits Mammals; Rabbits; Domestic Rabbit; Oryctolagus cuniculus; Recurrent; Recurrence; Research; Research Proposals; Risk; Risk Factors; Safety; Self-Administered; Self Administration; Venereal Infections; Venereal Disorders; Venereal Diseases; Sexually Transmitted Infection; Sexually Transmitted Disorder; Sexually Transmitted Diseases; Technology; Toxicology; United States; Vaccines; Vaginal; Vagina; virology; virus multiplication; viral replication; viral multiplication; Virus Replication; Woman; Work; Measures; promotor; promoter; preterm delivery; premature delivery; premature childbirth; Preterm Birth; Prematurely delivering; Premature Birth; Investigational New Drug Application; In Situ Hybridization; in situ Hybridization Staining Method; in situ Hybridization Genetics; Procedures; Cervical; Surface; Solid; Clinical; Phase; Adolescent; juvenile human; juvenile; Adolescent Youth; Cervical Intraepithelial Neoplasia; Uterine Cervix Intraepithelial Neoplasia; Cervix Uteri Intraepithelial Neoplasia; Cervix Intraepithelial Neoplasia; Cervical Intraepithelial Neoplasms; Link; Ensure; Evaluation; Funding; chemical property; Toxicokinetics; Phase II Clinical Trials; phase II protocol; phase 2 trial; Phase 2 Clinical Trials; Human papilloma virus infection; Human papillomavirus infection; HPV infection; vaginal fluid; prophylactic; Operative Surgical Procedures; surgery; Surgical Procedure; Surgical Interventions; Surgical; Operative Procedures; interest; Infection prevention; Prevent infection; success; Pharmacology and Toxicology; Excision; resection; Surgical Removal; Removal; Extirpation; Abscission; carcinogenicity; Modeling; response; Papillomavirus Infections; papilloma virus Infections; Human papillomavirus 16; type 16 Human papillomavirus; type 16 Human papilloma virus; human papilloma virus 16; Human papillomavirus type 16; Human papilloma virus type 16; HPV16; HPV-16; HPV 16; microbicide; microbicidal; Phase Transition; Dose; Human Papilloma Virus Vaccine; Human papillomavirus Vaccine; HPV Vaccine; Premalignant; precancerous; Pre-Malignant; in vivo; Tumor Promotion; Development; developmental; HPV-High Risk; High risk Human papilloma virus; High risk Human Papillomavirus; High risk HPV; High Risk Oncogenic HPV; design; designing; Population; mouse model; murine model; prototype; high risk; minimally invasive; effective therapy; effective treatment; anti-viral efficacy; antiviral efficacy; drug candidate; Regimen; Formulation; Oncoproteins; Oncogene Proteins; Oncogene Products; vaginal microbiota; vaginal microflora; vaginal microbial community; vaginal flora; vagina microbiota

HPV is the United States' most prevalent sexually transmitted infection and the high-risk subtypes are of significant public health interest given that high-risk HPV (HR-HPV) infections have been conclusively linked to the development of certain cancers. Cervical intraepithelial neoplasias (CIN), caused by persistent HR-HPV infection, are categorized by grade, with high grades 2 and 3 being considered precancerous and grade 4, carcinoma in situ. While there are an estimated 250,000 to 1 million women diagnosed with CIN annually in the U.S., there are no minimally invasive therapies with direct antiviral activity for the treatment of CIN and excisional procedures are often associated with pain, fertility issues and recurrence. Despite the success of the prophylactic HPV vaccines, the incidence of HPV-induced cancer is steadily increasing, due to (a) the inability of the vaccine to cure preexisting infections; (b) a great majority 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 in localized formulations. Novan's nitric oxide (NO)-releasing drug candidates have demonstrated the ability to inhibit papillomavirus amplification and replication in nonclinical models, as well safety and efficacy in a Phase 2 trial of external genital warts. The goal of this Fast-Track research plan is to develop a new formulation of a nitric oxide-releasing gel that can be self-administered by the patient, intravaginally, as a treatment for cervical HPV infections in women. If successful, such an approach may be instrumental in reducing the number of locally destructive 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 gel formulation suitable for intravaginal administration and ensure the NO release profiles of the gel replicate profiles previously demonstrated to have antiviral effects. Go-no go criteria to transition from Phase I to Phase II is minimum stability of the formulation intended for clinical use in the U.S. (25˚C for 12 weeks) and an NO release profile that matches the high C-max and short half-life release profile previously demonstrated to have antiviral activity when delivered topically. The Phase II portion is designed to assess the gel formulation's 1) in vitro toxicology: tumor promotion capabilities and effect on vaginal flora; 2) in vivo toxicology: safety, tolerability and toxicokinetics following application to mucosal surfaces via intravaginal administration in a 7-day pilot and a GLP 28-day repeat-dose toxicology study in rabbits necessary to submit an Investigational New Drug (IND) application; 3) pharmacology - ability to reduce vaginal papillomavirus infections and regress cervical neoplasias in a mouse model; and, 4) virology: evaluation of NO's antiviral activity and mechanism of action against HPV-16 infected cells. The body of this work constitutes the foundational nonclinical studies necessary to submit an Investigational New Drug (IND) application to the FDA.

Public Health Relevance Statement:
PROJECT NARRATIVE Persistent high-risk human papillomavirus (HR-HPV) infection is the most important risk factor for the development of cervical intraepithelial neoplasias (CIN) in women and the subsequent progression to cervical cancer. While there are an estimated 250,000 to 1 million women diagnosed with CIN annually in the U.S., there are no minimally invasive therapies with direct antiviral activity for the treatment of CIN. Excisional treatment procedures are associated with increased risk of pre-term birth in future pregnancies as well as anxiety, pain and bleeding. Novan is developing a nitric oxide-releasing antiviral gel for the treatment cervical HPV infections and the prevention of downstream malignancies in women.

Project Terms:
Intravaginal Administration; Vaginal Administration; Antiviral Agents; Antiviral Drugs; Antivirals; anti-viral agents; anti-viral drugs; anti-virals; Anxiety; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Carcinoma in Situ; Intraepithelial Carcinoma; Preinvasive Carcinoma; in situ cancer; Cell Culture Techniques; cell culture; Cells; Cell Body; Malignant neoplasm of cervix uteri; Cervical Cancer; Cervix Cancer; Malignant Cervical Neoplasm; Malignant Cervical Tumor; Malignant Neoplasm of the Cervix; Malignant Tumor of the Cervix; Malignant Tumor of the Cervix Uteri; Malignant Uterine Cervix Neoplasm; Malignant Uterine Cervix Tumor; Uterine Cervix Cancer; Cervix Neoplasms; Cervical Neoplasia; Cervical Neoplasms; Cervical Tumor; Cervix Tumor; Cervix Uteri Neoplasm; Cervix Uteri Tumor; Uterine Cervix Neoplasm; Uterine Cervix Tumor; Climate; Meteorological Climate; climatic; Anogenital venereal warts; Condyloma Accuminata; Condylomata Acuminata; Genital Warts; Venereal Warts; Diagnosis; Investigational Drugs; Investigational New Drugs; Environment; Fertility; Fecundability; Fecundity; Foundations; Future; Gel; Goals; Half-Life; Hemorrhage; Bleeding; blood loss; Human; Modern Man; In Vitro; Incidence; Infection; Human Papillomavirus; HPV; Human Papilloma Virus; Infectious Human Wart Virus; wart virus; Mucous Membrane; Mucosa; Mucosal Tissue; Mus; Mice; Mice Mammals; Murine; Nitric Oxide; Endogenous Nitrate Vasodilator; Endothelium-Derived Nitric Oxide; Mononitrogen Monoxide; Nitrogen Monoxide; Nitrogen Protoxide; endothelial cell derived relaxing factor; Pain; Painful; Papillomavirus; Papilloma Viruses; Papillomaviridae; Patients; Pharmacology; Population Growth; Pregnancy; Gestation; Public Health; Oryctolagus cuniculus; Domestic Rabbit; Rabbits; Rabbits Mammals; Recurrence; Recurrent; Research; Research Proposals; Risk; Risk Factors; Safety; Self Administration; Self-Administered; Sexually Transmitted Diseases; Sexually Transmitted Disorder; Sexually Transmitted Infection; Venereal Diseases; Venereal Disorders; Venereal Infections; Technology; Toxicology; United States; Vaccines; Vagina; Vaginal; virology; Virus Replication; viral multiplication; viral replication; virus multiplication; Woman; Work; Measures; promotor; promoter; Prematurely delivering; Preterm Birth; premature childbirth; premature delivery; preterm delivery; Premature Birth; Investigational New Drug Application; in situ Hybridization Genetics; in situ Hybridization Staining Method; In Situ Hybridization; Procedures; Cervical; Surface; Solid; Clinical; Phase; Adolescent Youth; juvenile; juvenile human; Adolescent; Cervical Intraepithelial Neoplasms; Cervix Intraepithelial Neoplasia; Cervix Uteri Intraepithelial Neoplasia; Uterine Cervix Intraepithelial Neoplasia; Cervical Intraepithelial Neoplasia; Link; Ensure; Evaluation; Funding; chemical property; Toxicokinetics; HPV infection; Human papillomavirus infection; Human papilloma virus infection; vaginal fluid; prophylactic; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; Operative Surgical Procedures; interest; Prevent infection; Infection prevention; success; Pharmacology and Toxicology; Topical Drug Administration; administer topically; apply topically; deliver topically; topical administration; topical delivery; topical drug application; topical treatment; topically administered; topically applied; topically delivered; topically treated; treat topically; Topical application; Abscission; Extirpation; Removal; Surgical Removal; resection; Excision; carcinogenicity; Modeling; response; papilloma virus Infections; Papillomavirus Infections; HPV 16; HPV-16; HPV16; Human papilloma virus type 16; Human papillomavirus type 16; human papilloma virus 16; type 16 Human papilloma virus; type 16 Human papillomavirus; Human papillomavirus 16; microbicidal; microbicide; Phase Transition; Dose; HPV Vaccine; Human papillomavirus Vaccine; Human Papilloma Virus Vaccine; precancerous; premalignant; in vivo; Tumor Promotion; developmental; Development; High Risk Oncogenic HPV; High risk HPV; High risk Human Papillomavirus; High risk Human papilloma virus; HPV-High Risk; designing; design; Population; murine model; mouse model; prototype; high risk; minimally invasive; effective treatment; effective therapy; antiviral efficacy; anti-viral efficacy; drug candidate; Regimen; phase 2 trial; phase II trial; Formulation; Oncogene Products; Oncogene Proteins; Oncoproteins; vagina microbiota; vaginal flora; vaginal microbial community; vaginal microflora; vaginal microbiota