Investigational new drug enabling studies for the development of a topical fixed dose combination drug product to treat actinic keratosis and prevent cutaneous squamous cell carcinoma.

PROJECT SUMMARY / ABSTRACT 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.