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.

研究性新药使研究能够开发局部固定剂量组合药物产品，以治疗光化性角化病和预防皮肤鳞状细胞癌。

• 批准号: 10482509
• 负责人: Andrew B Mahon
• 金额: $ 86.54万
• 依托单位: PHD SKIN CARE LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10482509
• 关键词: Actinic keratosis; Address; Aftercare; Benchmarking; Biological Assay; CCR; CD4 Positive T Lymphocytes; Cadaver; Calcipotriene; Carcinoma; Caring; Cattle; Cavia; Cessation of life; Clinical; Clinical Trials; Corneal Opacity; Cream; Data; Dermal; Dermatologist; Development; Disseminated Malignant Neoplasm; Dose; Double-blind trial; Drug Combinations; Drug Prescriptions; Effector Cell; Exhibits; Face; Feedback; Fluorouracil; Formulation; Goals; Healthcare Systems; Human; Immune response; Immune system; Immunity; Immunocompetent; Immunotherapeutic agent; Immunotherapy; In Vitro; Investigational Drugs; Investigational New Drug Application; Knowledge; Lead; Metabolic Clearance Rate; Mission; Morbidity - disease rate; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Outcome; Patients; Penetration; Permeability; Pharmaceutical Preparations; Phase; Population; Prevention; Public Health; Randomized; Recurrence; Risk; Series; Skin; Skin Cancer; Skin Carcinoma; Skin Care; Small Business Innovation Research Grant; TSLP gene; Testing; Toxicology; Treatment Cost; Tumor-infiltrating immune cells; Ulcer; Ultraviolet Rays; United States; United States Food and Drug Administration; adaptive immune response; anti-tumor immune response; cancer type; cell mediated immune response; clinical development; commercial application; commercialization; compliance behavior; cost; design; drug development; drug discovery; hazard; improved; innovation; irritation; keratinocyte; meetings; melanoma; mortality; open label; premalignant; prevent; product development; prototype; randomized trial; recruit; screening; side effect; skin squamous cell carcinoma; technological innovation; treatment duration

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.

项目概要/摘要 光化性角化病 (AK) 是癌前角质形成细胞，是皮肤鳞状细胞的前体 癌 (CSCC)，这是一种非黑色素瘤皮肤癌，是第二常见的癌症类型，当 转移性，死亡率与黑色素瘤相当。非黑色素瘤皮肤癌呈增长趋势 公共卫生挑战每年给美国医疗保健系统造成超过 10 亿美元的损失。得到正式认可的 局部药物在治疗 AK 方面仅表现出有限的疗效，并且不能提供针对 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，拟开发 第一个美国食品和药物管理局 (FDA) 批准的包含组合的固定剂量外用乳膏 卡泊三醇 (CPO) 和 5-氟尿嘧啶 (5-FU) 作为处方药治疗 AK 和预防 CSCC。 该 SBIR 的产品将是一种稳定且特性良好的固定剂量组合乳膏，按处方规定 在免疫功能正常的人群中治疗 AK 并降低发生 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来发挥功效。 长期目标是开发一种稳定且耐受性良好的外用乳膏，可利用其功效 免疫系统治疗 AK 并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 4 (n=64) 或 6 天 (n=18) 治疗的可行性 原型 CPO/5-FU 乳膏在 AK 患者中具有良好的耐受性，导致 AK 完全清除率 79.6%，并降低了3年发生CSCC的风险。临床评估的原型配方是 不适合商业开发，因为它不稳定并导致 CPO 快速降解。 在目标 1 中，将开发两种稳定且特征良好的固定剂量组合乳膏，并提供 确定了人体尸体皮肤上的活性成分。里程碑将是两个稳定的开发 和良好表征的配方，其中表现出与原型相当的渗透曲线和 第二次将两倍浓度的药物输送到皮肤中。在目标 2 中，延迟接触敏化 将在豚鼠中评估配方，在牛角膜混浊中评估体外潜在刺激性 渗透性测定和 FDA 反馈将在 IND 前会议上征求。里程碑将是发现 新开发的配方的得分至少与原型一样好，而原型已经被发现 AK 患者耐受性良好。 预期结果：先导制剂将稳定至少一年，并且评分与原型相同 在可进行 IND 的皮肤和眼部刺激测定中进行评估时。该配方预计能发挥 以及在本 SBIR 范围之外进行临床评估时的原型。 A 505(b)(2) 监管 预计将获得食品和药物管理局的批准。