Ph1/2 Study of FCX-007 for Treatment of RDEB IND 16582 Protocolv4.1 (11/23/2016)

项目描述（项目概要/摘要） 大疱性表皮病是一组遗传性遗传性水疱性皮肤病。严重的EB 由VII型胶原基因（COL 7A 1）内突变引起的亚型，隐性营养不良 大疱性表皮病（RDEB）是一种常染色体隐性遗传性皮肤病。有这种病的人 疾病有缺陷或缺乏正常的VII型胶原蛋白，这有助于粘附的 表皮或皮肤的外层到皮肤的内真皮层。述疾病是 以皮肤和粘膜上疼痛的水泡和伤口为特征。的后遗症 水泡和伤口常常使人衰弱、毁容，有时甚至是致命的。RDEB患者有 预期寿命缩短，因感染、器官衰竭或鳞状细胞癌而过早死亡 癌（SCC）。RDEB是美国公认的孤儿和儿科罕见疾病。 美国食品药品监督管理局（FDA）。目前RDEB的治疗仅限于姑息性伤口护理 因为目前没有治愈性治疗方法，也没有批准用于RDEB的药物。纤维细胞 技术公司（Fibrocell）正在开发FCX-007，一种基因修饰的离体自体 成纤维细胞疗法，其将VII型胶原蛋白递送至RDEB受试者的皮肤。Fibrocell具有 FCX-007的开放研究性新药申请（IND 016582）。 在这项拨款申请中，Fibrocell建议继续其干预性，开放标签的1/2期 评估FCX-007的安全性、有效性和作用持续时间的研究。目标适应症为 FCX-007是治疗经遗传学证实的RDEB患者的皮肤起泡病变， 试验.通过以下方式减小伤口尺寸并促进伤口闭合将具有临床意义： 预防或降低感染、疼痛、瘢痕形成、畸形或鳞状细胞癌的发生率 carcinoma. Fibrocell预计FCX-007在临床上是安全的，因为其具有自体性质。 治疗，并基于动物的临床前长期毒性和致瘤性数据。临床 将通过检测是否存在VII型可复制慢病毒（RCL）来评估安全性 胶原蛋白自身抗体分析，用于对VII型胶原蛋白的免疫反应以及物理免疫反应。 考试FCX-007的有效性和耐久性将通过存在/增加类型 VII胶原蛋白正确定位于基底膜区，并掺入到 超微结构正常的锚定纤维。FCX-007已被授予孤儿药资格， 儿科罕见病认定和FDA快速通道认定，用于治疗 RDEB的主题。这笔赠款将用于协助完成1/2期临床试验 这可能导致对RDEB受试者的潜在有效的基于细胞的基因治疗。纤维细胞 预计将与FDA密切合作，设计3期临床试验， 目前正在进行1/2期试验。这项拨款提案实现了FDA孤儿项目的目标。 产品部资助计划，以支持用于罕见疾病的产品的临床开发 目前没有治疗方法的疾病。

Project Description (Project Summary/Abstract) Epidermolysis bullosa (EB) is a group of inherited genetic blistering skin disorders. A severe EB subtype caused by mutations within the type VII collagen gene (COL7A1), recessive dystrophic epidermolysis bullosa (RDEB), is an autosomal recessive, inherited skin disease. People with this disease have defective or lack normal type VII collagen, which facilitates adhesion of the epidermis, or outer layer of the skin, to the inner dermal layers of the skin. The disease is characterized by painful blisters and wounds on skin and mucous membranes. The sequelae of blisters and wounds are often debilitating, disfiguring, and sometimes fatal. RDEB patients have a reduced life expectancy with early death resulting from infection, organ failure or squamous cell carcinoma (SCC). RDEB is acknowledged as an orphan and pediatric rare disease by the U.S. Food and Drug Administration (FDA). Current therapy for RDEB is limited to palliative wound care as there are currently no curative treatments and no approved drugs for RDEB. Fibrocell Technologies, Inc. (Fibrocell) is developing FCX-007, a gene-modified ex-vivo autologous fibroblast therapy that will deliver type VII collagen to the skin of RDEB subjects. Fibrocell has an open Investigational New Drug Application (IND 016582) for FCX-007. In this grant application, Fibrocell proposes to continue its interventional, open-label Phase 1/2 study to evaluate the safety, efficacy and duration of effect of FCX-007. The target indication for FCX-007 is the treatment of skin-blistering lesions in patients with RDEB confirmed by genetic testing. Reducing wound size and facilitating wound closure will be clinically meaningful by preventing or decreasing the rate of infection, pain, scarring, deformity or squamous cell carcinoma. Fibrocell expects FCX-007 to be clinically safe given the autologous nature of the therapy, and based on preclinical long-term toxicity and tumorigenicity data in animals. Clinical safety will be assessed by testing for presence of replication-competent lentivirus (RCL), type VII collagen autoantibody analysis for immune reactions to type VII collagen as well as physical examinations. Efficacy and durability of FCX-007 will be assessed by presence/increase in type VII collagen protein correctly localized to the basement membrane zone and incorporated into ultra-structurally normal anchoring fibrils. FCX-007 has been granted orphan designation, pediatric rare disease designation and fast track designation by the FDA for the treatment of subjects with RDEB. This grant will be used to assist in completing the Phase 1/2 clinical trial which may lead to a potentially effective cell-based gene therapy for RDEB subjects. Fibrocell expects to work closely with the FDA in designing the Phase 3 clinical trial while data from the current Phase 1/2 trial is being gathered. This grant proposal fulfills the goal of FDA’s Orphan Product Division grant program to support the clinical development of products for use in rare diseases where no current therapy exists.