A Pivotal Phase 3 Study of FCX-007 (Genetically-Modified Autologous Human Dermal Fibroblasts) for Recessive Dystrophic Epidermolysis Bullosa

7.项目总结/摘要 隐性营养不良性大疱性表皮病（RDEB）是一种常染色体隐性遗传性皮肤病， 由VII型胶原基因突变引起的疾病。该疾病的特征在于 皮肤和粘膜上的疼痛的水泡和伤口，由于缺乏粘附， 从表皮到皮肤的真皮内层。伤口的后遗症通常会使人衰弱， 毁容有时甚至致命RDEB患者的预期寿命缩短， 由感染、器官衰竭或鳞状细胞癌（SCC）引起。目前的治疗 RDEB仅限于姑息性伤口护理，因为目前没有批准用于RDEB的药物。 Fibrocell Technologies，Inc. (FTI)正在开发FCX-007，一种活的，离体的， 使用慢病毒基因修饰的自体人真皮成纤维细胞 载体（INXN-2004），其能够表达人VII型（C7）蛋白。FTI拥有 FCX-007的开放性研究新药申请（IND 016582）。 FTI建议继续其干预性、患者内随机化和对照、开放标签， 评价FCX-007的疗效、耐久性和安全性的III期研究。FTI工作 与FDA密切合作，根据从FDA收集的数据设计3期临床试验。 I/II期试验（FI-EB-001）。将由设盲研究者确定临床疗效 评估伤口完全闭合、反应的持久性、伤口表面积的变化， 一名患者报告了疼痛的结局。临床安全性将通过检测是否存在 可复制慢病毒（RCL），VII型胶原自身抗体免疫反应， 肿瘤（鳞状细胞癌（SCC）），以及体格检查和不良反应 不良事件（AE）。FCX-007的有效性和耐久性将通过伤口闭合进行评估 从第12周至第48周，FTI认为这代表了具有临床意义的获益 来研究课题鉴于FCX-007 I/II期，FTI预计FCX-007在临床上是安全的 临床数据（FI-EB-001）、临床前安全性数据和治疗的自体性质。 FCX-007已被授予孤儿，罕见儿科疾病和再生医学 FDA指定用于治疗RDEB受试者的高级治疗（RMAT）。 赠款资金将用于执行3期临床试验（FI-EB-002）， 涉及一种用于RDEB受试者的潜在有效的基于细胞的基因疗法。这份赠款提案满足了 FDA办公室孤儿产品开发资助计划的目标是支持临床 开发用于目前没有治疗方法的罕见疾病的产品。

7. PROJECT SUMMARY/ABSTRACT Recessive dystrophic epidermolysis bullosa (RDEB), is an autosomal recessive, inherited skin disease caused by mutations within the type VII collagen gene. The disease is characterized by painful blisters and wounds on skin and mucous membranes due to lack of adhesion of the epidermis to the inner dermal layers of the skin. The sequelae of 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). Current therapy for RDEB is limited to palliative wound care as there are currently no approved drugs for RDEB. Fibrocell Technologies, Inc. (FTI) is developing FCX-007, a suspension of live, ex-vivo, autologous human dermal fibroblast cells that have been genetically modified using a lentiviral vector (INXN-2004), which enables the expression of the human type VII (C7) protein. FTI has an open Investigational New Drug Application (IND 016582) for FCX-007. FTI proposes to continue its interventional, intra-patient randomized and controlled, open-label, Phase 3 study to evaluate the efficacy, durability, and safety of FCX-007. FTI has worked closely with the FDA in designing the Phase 3 clinical trial based on data gathered from the Phase 1/2 trial (FI-EB-001). Clinical efficacy will be determined by blinded investigator assessment of complete wound closure, durability of response, change in surface area of wound, and a patient reported outcome of pain. Clinical safety will be assessed by testing for presence of replication-competent lentivirus (RCL), type VII collagen autoantibody immune reactions, neoplasms (squamous cell carcinoma (SCC)), as well as physical examinations and adverse events (AEs). Efficacy and durability of FCX-007 will be assessed by the closure of wounds from Week 12 through Week 48, which FTI believes represents a clinically meaningful benefit to study subjects. FTI expects FCX-007 to be clinically safe given the FCX-007 Phase 1/2 clinical data (FI-EB-001), the preclinical safety data, and the autologous nature of the therapy. FCX-007 has been granted Orphan, Rare Pediatric Disease, and Regenerative Medicine Advanced Therapy (RMAT) designations by the FDA for the treatment of subjects with RDEB. The grant funding will be used to execute the Phase 3 clinical trial (FI-EB-002) which may lead to a potentially effective cell-based gene therapy for RDEB subjects. This grant proposal fulfills the goal of FDA's Office Orphan Product Development grant program to support the clinical development of products for use in rare diseases where no current therapy exists.