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.

项目摘要/摘要 光化性角化病(AKs)是一种癌前角质形成细胞，是皮肤鳞状细胞的前体细胞 癌症(CSCC)，这是一种非黑色素瘤皮肤癌，是第二种最常见的癌症，当 转移性，具有与黑色素瘤相当的死亡率。非黑色素瘤皮肤癌是一种不断增长的 公共卫生挑战，每年花费美国医疗保健系统超过10亿美元。核可 外用药物在治疗AKs方面只显示出适度的疗效，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，正在计划开发 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包含一种组合 骨化三醇(CPO)和5-氟尿嘧啶(5-FU)作为治疗AK和预防CSCC的处方药。 这种SBIR的产品将是一种稳定的、具有良好特性的处方固定剂量组合乳膏 治疗AK并降低免疫能力人群中发生CSCC的风险。该产品是 创新是因为它通过诱导CD4+T细胞介导的免疫反应而获得疗效。 长期目标是开发一种稳定的、耐受性良好的外用乳膏，利用这种力量 治疗AKs和预防与皮肤癌相关的发病率和死亡率。 一期SBIR等效性研究证实了仅4天(n=)或6天(n=18)治疗的可行性 使用原型CPO/5-FU乳膏在AK患者中耐受性良好，导致AK完全清除率为 79.6%，连续3年降低CSCC的发生风险。临床评估的原型配方是 不适合商业开发，因为它不稳定，会导致CPO快速降解。 在目标1中，将开发两种稳定和特性良好的固定剂量组合乳膏，并交付 人体身体皮肤上的活性成分被确定。里程碑将是两个稳定的发展 和特征良好的配方，其中一个表现出与原型相当的渗透曲线和一个 第二种药物在皮肤中的浓度是前者的两倍。在目标2中，延迟接触敏化 这些制剂将在豚鼠身上进行评估，体外刺激性潜力在牛角膜混浊中进行评估。 渗透性分析和FDA的反馈将在IND前的会议上征求。里程碑将会发现 新开发的配方将至少与原型一样好，原型已经被发现 对AK患者有良好的耐受性。 预期结果：铅配方将至少稳定一年，得分与原型相同 在皮肤和眼睛刺激性的IND测试中评估时。这些配方有望发挥作用 以及在临床评估和本SBIR范围之外的原型。A 505(B)(2)监管 预计将获得美国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.