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.

项目概要/摘要 光化性角化病（AKs）是一种癌前角化细胞，是皮肤鳞状细胞癌的前体。 癌（CSCC），这是一种非黑色素瘤皮肤癌，第二种最常见的癌症类型，当 转移性的，具有与黑素瘤相当的死亡率。非黑色素瘤皮肤癌是一种不断增长的 公共卫生挑战，美国医疗保健系统每年花费超过10亿美元。批准 局部药物在治疗AK中仅表现出适度的功效，并且不能提供对CSCC的持久保护。 PHD Skin Care（PHD）是一家临床阶段药物发现和开发公司， 第一个美国食品和药物管理局（FDA）批准的固定剂量局部乳膏， 卡泊三醇（CPO）和5-氟尿嘧啶（5-FU）作为治疗AK和预防CSCC的处方药。 该SBIR的产品将是一种稳定且充分表征的固定剂量复方乳膏， 治疗AK并降低免疫功能正常人群发生CSCC的风险。产品 其创新性在于其通过诱导CD4 + T细胞介导的免疫应答而获得功效。 长期目标是开发一种稳定且耐受性良好的外用乳膏， 免疫系统治疗AK和预防与皮肤癌相关的发病率和死亡率。 I期SBIR等效研究证明了仅治疗4天（n = 64）或6天（n = 18）的可行性 原型CPO/5-FU乳膏在AK患者中耐受良好，导致AK完全清除率为 79.6%，并降低了3年CSCC发展的风险。临床评价的原型制剂是 不适合商业开发，因为它不稳定并导致CPO快速降解。 在目标1中，将开发两种稳定且充分表征的固定剂量组合乳膏，并且将递送 测定了人尸体皮肤中的活性成分。小米将两个稳定发展 和充分表征的制剂，其中一种制剂表现出与原型相当的渗透曲线， 第二种是将两倍浓度的药物输送到皮肤中。在目标2中， 将在豚鼠中评价制剂，在牛角膜混浊中评价体外刺激潜力 将在IND前会议上征求渗透性试验和FDA反馈。米勒会发现 新开发的配方将至少与原型一样有利，已经发现原型 AK患者耐受性良好。 预期结果：先导制剂将稳定至少1年，评分与原型相同 当在皮肤和眼部刺激的IND启用试验中进行评价时。预期制剂的性能 以及在临床评估时的原型，超出了本SBIR的范围。A 505（B）（2）监管 预计将获得食品和药物管理局的批准。

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.