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

项目说明(项目摘要/摘要) 大疱性表皮松解症(EB)是一组遗传性水疱性皮肤病。一场严重的EB III型胶原基因(COL7A1)突变引起的隐性营养不良亚型 大疱性表皮松解症(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III型胶原，这有助于粘连 表皮，或皮肤的外层，到皮肤的内层真皮层。这种疾病是 以皮肤和粘膜上的疼痛水泡和伤口为特征。的后遗症 水泡和伤口通常使人虚弱、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而过早死亡 癌(SCC)。RDEB被美国确认为孤儿和儿科罕见疾病。 美国食品和药物管理局(FDA)。目前对RDEB的治疗仅限于姑息性伤口护理 因为目前还没有治愈RDEB的治疗方法，也没有批准的药物。纤维细胞 技术公司(Fibrocell)正在开发FCX-007，一种基因修饰的体外自体 成纤维细胞疗法，将向RDEB受试者的皮肤输送III型胶原。纤维细胞有一种 FCX-007型公开研究新药申请(IND 016582) 在这项赠款申请中，Fibrocell提议继续其干预性、开放标签的1/2阶段 评价FCX-007的安全性、有效性和持续时间。的目标指示 FCX-007是治疗RDEB患者皮肤起泡皮损的药物，经基因检测证实 测试。减小伤口大小并促进伤口闭合将具有临床意义 预防或降低感染、疼痛、疤痕、畸形或鳞状细胞的发生率 癌症。Fibrocell预计FCX-007在临床上是安全的，因为 治疗，并基于临床前的长期毒性和动物致瘤性数据。临床 安全性将通过检测是否存在复制能力强的VII型慢病毒(RCL)进行评估 胶原蛋白自身抗体分析对III型胶原免疫反应的影响 考试。FCX-007的有效性和耐用性将通过类型的存在/增加来评估 VII型胶原蛋白正确定位于基底膜带并整合到 超正常结构的锚定纤维。FCX-007已被授予孤儿称号， FDA对儿童罕见疾病的指定和快速通道指定用于治疗 RDEB的受试者。这笔赠款将用于协助完成1/2期临床试验。 这可能为RDEB受试者带来一种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，而来自 目前的1/2期试验正在收集中。这项拨款提案实现了FDA孤儿的目标 产品事业部资助计划，支持稀有药物的临床开发 目前尚无治疗方法的疾病。

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.