Actinic Keratoses (AKs) are premalignant keratinocytes that are precursors to cutaneous squamous cell carcinoma (CSCC), which is a non-melanoma skin cancer, the second most common type of cancer, and when metastatic, has a mortality rate comparable to that of melanoma. Non-melanoma skin cancers are a growing public health challenge that cost the United States healthcare system in excess of $1 billion annually. Approved topical medications only exhibit modest efficacy in treating AKs and do not offer durable protection from CSCC. PHD Skin Care (PHD) is a clinical stage drug discovery and development company that is proposing to develop the first U.S. Food and Drug Administration (FDA) approved fixed dose topical cream containing a combination of calcipotriol (CPO) and 5-fluorouracil (5-FU) as a prescription drug to treat AK and prevent CSCC. The Product of this SBIR will be a stable and well characterized fixed dose combination cream that is prescribed to treat AK and reduce the risk of CSCC development in an immunocompetent population. The product is innovative because it derives efficacy by inducing a CD4+ T cell mediated immune response. The Long-Term Goal is the development of a stable and well-tolerated topical cream that harnesses the power of the immune system to treat AKs and prevent the morbidity and mortality associated with skin cancer. Phase I SBIR Equivalent Studies demonstrated the feasibility that just 4 (n=64) or 6 days (n=18) of treatment with a prototype CPO / 5-FU cream was well-tolerated in AK patients, caused an AK complete clearance rate of 79.6% and reduced the risk of CSCC development for 3 years. The clinically evaluated prototype formulation is not appropriate for commercial development because it is unstable and causes CPO to rapidly degrade. In Aim 1 two stable and well characterized fixed dose combination creams will be developed and the delivery of the active ingredients across human cadaver skin determined. Milestones will be the development of two stable and well characterized formulations where one exhibits a comparable penetration profile to the prototype and a second delivers twice the concentration of drugs into the skin. In Aim 2 the delayed contact sensitization of the formulations will be evaluated in guinea pigs, the in vitro irritancy potential evaluated in a bovine corneal opacity and permeability assay and FDA feedback will be solicited in a pre-IND meeting. Milestones will be finding that the newly developed formulations will score at least as favorably as the prototype, which was already found to be well-tolerated in AK patients. Expected outcome: The lead formulations will be stable for at least 1 year and score as well as the prototype when evaluated in IND-enabling assays of dermal and ocular irritation. The formulations are expected to perform as well as the prototype when evaluated clinically and outside the scope of this SBIR. A 505(b)(2) regulatory approval from the Food and Drug Administration is expected.
Public Health Relevance Statement: PROJECT NARRATIVE Non-melanoma skin cancers are a growing public health challenge that cost the United States (U.S.) healthcare system more than $1 billion in treatment costs annually. Actinic Keratoses are ultraviolet light induced premalignant keratinocytes that are precursors to cutaneous squamous cell carcinoma (CSCC). CSCC is the second most common type of cancer, is associated with significant morbidity, and results in more deaths than from melanoma in the U.S. each year. This resubmitted Direct Phase II SBIR proposal builds upon two successfully completed clinical trials and aims to develop a "go to market' prescription formulation containing calcipotriol and 5-fluoruracil as a topical fixed dose combination to treat AK patients and prevent CSCC.
Project Terms: After Care; After-Treatment; post treatment; Aftercare; Biological Assay; Assay; Bioassay; Biologic Assays; Cadaver; cadaveric; cadavers; Carcinoma; Epithelial cancer; Malignant Epithelial Neoplasms; Malignant Epithelial Tumors; epithelial carcinoma; Skin Cancer; Malignant Skin Neoplasm; malignant skin tumor; Cattle; Bovine Species; bovid; bovine; cow; Clinical Trials; Corneal Opacity; Leukoma; cornea opacity; Cessation of life; Death; Drug Combinations; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Investigational Drugs; Investigational New Drugs; Exhibits; Face; faces; facial; Feedback; Fluorouracil; 5-FU; 5-Fluracil; 5FU; Fluoro Uracil; Fluoruracil; Fluouracil; Goals; Healthcare Systems; Health Care Systems; Human; Modern Man; Immune system; Immunity; Immunotherapy; Immune mediated therapy; Immunologically Directed Therapy; immune therapeutic approach; immune therapeutic interventions; immune therapeutic regimens; immune therapeutic strategy; immune therapy; immune-based therapies; immune-based treatments; immuno therapy; In Vitro; Irritants; keratinocyte; Actinic keratosis; Actinic (Solar) Keratosis; Senile Hyperkeratosis; Solar Keratosis; senile keratosis; Lead; Pb element; heavy metal Pb; heavy metal lead; Marketing; melanoma; Malignant Melanoma; Metabolic Clearance Rate; clearance rate; Mission; Morbidity - disease rate; Morbidity; mortality; Patients; Permeability; Drug Prescriptions; Drug Prescribing; medication prescription; prescribed medication; Privatization; Public Health; Recurrence; Recurrent; Risk; CD4 Positive T Lymphocytes; CD4 Cells; CD4 T cells; CD4 helper T cell; CD4 lymphocyte; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; T4 Cells; T4 Lymphocytes; Testing; Toxicology; Ulcer; Ulceration; United States; United States Food and Drug Administration; Food and Drug Administration; USFDA; Calcipotriene; Daivonex; Dovonex; calcipotriol; Guinea Pigs; Guinea Pigs Mammals; Cavia; Treatment Cost; Caring; Skin Care; Investigational New Drug Application; improved; Clinical; Penetration; Phase; Series; Dermal; Dermatologist; Immunological response; host response; immune system response; immunoresponse; Immune response; Effector Cell; Disseminated Malignant Neoplasm; Metastatic Cancer; Metastatic Malignant Neoplasm; Knowledge; irritation; treatment duration; Treatment Period; treatment days; Benchmarking; Best Practice Analysis; benchmark; skin squamous cell carcinoma; Cutaneous Squamous Cell Carcinoma; Epidermoid Skin Carcinoma; hazard; technological innovation; Prevention; Skin Carcinoma; Non-Melanoma Skin Cancer; nonmelanoma skin cancer; drug development; Immunotherapeutic agent; immune drugs; immune-based therapeutics; immunologic therapeutics; immunotherapeutics; immunotherapy agent; drug discovery; Skin; reduce risk; reduce risks; reduce that risk; reduce the risk; reduce these risks; reduces risk; reduces the risk; reducing risk; reducing the risk; risk-reducing; Risk Reduction; preventing; prevent; cell mediated immune response; Patient Compliance; patient adherence; patient cooperation; therapy compliance; therapy cooperation; treatment compliance; compliance behavior; TSLP gene; TSLP; Thymic Stromal Lymphopoietin; Cream; Address; Dose; Data; Immunocompetent; immune competent; premalignant; precancer; precancerous; Randomized; randomisation; randomization; randomly assigned; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Development; developmental; open label; open label study; National Institute of Arthritis, and Musculoskeletal, and Skin Diseases; NIAMS; cost; UV radiation-induced; ultraviolet induced; ultraviolet light induced; ultraviolet radiation-induced; UV induced; designing; design; Outcome; Population; cancer type; innovate; innovative; innovation; commercial application; prototype; commercialization; product development; Randomization trial; randomized trial; screenings; screening; Double-blind trial; Formulation; adaptive immune response; clinical development; recruit; antitumor immune response; anti-tumor immune response; side effect; pre-Investigational New Drug meeting; Pre IND FDA meeting; Pre-IND mtg; pre-IND consultation; pre-IND discussion; pre-IND meeting; immune cell infiltrate; Immune infiltrates; commercial launch; commercial product launch
