cGMP Recombinant FIX for IV & Oral Hemophilia B Therapy

描述（由申请人提供）：B型血友病是由先天性凝血蛋白因子IX缺乏引起的出血性疾病。如果没有最佳的治疗方法，患者会遭受严重的衰弱、慢性疼痛和认知障碍。目前只有一小部分美国患者可以使用最佳治疗方法——频繁给药以减少出血发作频率，这主要是因为成本和供应有限；世界上80%的血友病患者没有接受任何治疗。这项研究的长期目标是利用转基因猪奶中生产的重组人凝血蛋白，为全球血友病患者群体开发一种丰富、纯净、安全、有效的治疗方法。本提案描述了基于创新生物工程技术的研究，以改进和扩大临床级因子IX的生产，表征静脉注射剂型的产品，完成临床试验所需的动物研究，并最终开发一种口服剂型，为美国B型血友病患者提供最佳治疗。该方法利用现有的基因工程转基因猪，在牛奶中合成高达1000 IU/ml （4 g/L）的人因子IX，并初步证明这种纯化的因子IX在血友病B小鼠模型中具有良好的止血和药代动力学特性。由于已经完成的基础研究的健全性和发展状态以及团队优势的广度和互补性，预计成功的概率很高。ProGenetics LLC的J. Cooper博士将供应FDA和usda合规的Factor IX牛奶。在内布拉斯加大学林肯分校，M. Meagher博士在生物工艺工程和重组蛋白的现行良好生产规范生产方面提供专业知识；Drs。W. Velander和K. Van Cott在转基因动物工程和人类因子IX的表征方面贡献了专业知识。科罗拉多州立大学的M. Manning博士在口服和注射剂量的稳定液体和冻干蛋白质的配方方面带来了专业知识。LifeSci Partners的S. Abramson博士拥有20年的生物制药开发经验，包括临床，技术和监管专业知识，包括AlphaNine(r)SD（纯化血浆衍生因子IX）。Drs。北卡罗来纳大学教堂山分校的P. Monahan和T. Nichols对B型血友病小鼠和狗有独特的临床前经验，将用于测试Factor IX产品的安全性和有效性。

DESCRIPTION (provided by applicant): Hemophilia B is a bleeding disorder resulting from congenital deficiency of coagulation protein Factor IX. Without optimal therapy, patients suffer crippling debilitations, chronic pain, and cognitive impairment. Optimal therapy - frequent dosing with Factor IX to reduce bleeding episode frequency - is currently available to only a small fraction of U.S. patients, largely because of cost and limited supply; 80% of the world's hemophilia patients receive no therapy. The long-term goal of this research is development of an abundant, pure, safe, and effective therapy for the global hemophilia patient population using recombinant human coagulation proteins produced in the milk of transgenic pigs. This proposal describes studies that are based upon innovative bioengineering technologies to refine and scale-up production of clinical grade Factor IX, characterize product formulated for intravenous dosage, complete animal studies required for clinical trials, and ultimately develop an oral dosage form to provide optimal therapy for U.S. hemophilia B patients. This approach capitalizes on existing genetically engineered transgenic pigs that synthesize up to 1000 IU/ml (4 g/L) of human Factor IX in milk and preliminary evidence for favorable hemostatic and pharmacokinetic properties of this purified Factor IX in a hemophilia B mouse model. A high probability of success is expected because of the soundness and state of development of the basic research already completed and the breadth and complementarity of the strengths of the team. Dr. J. Cooper of ProGenetics LLC will supply FDA- and USDA-compliant Factor IX milk. At the Univ. Nebraska-Lincoln, Dr. M. Meagher provides expertise in bioprocess engineering and current Good Manufacturing Practices production of recombinant proteins; Drs. W. Velander and K. Van Cott contribute expertise in transgenic animal engineering and characterization of human Factor IX. Dr. M. Manning of Colorado State University brings expertise in the formulation of stabilized liquid and lyophilized proteins for oral and injectable dosing. Dr. S. Abramson of LifeSci Partners has two decades of biopharmaceutical development experience encompassing clinical, technical, and regulatory expertise, including AlphaNine(r)SD (purified plasma-derived Factor IX). Drs. P. Monahan and T. Nichols of UNC-Chapel Hill have unique preclinical experience with hemophilia B mice and dogs that will be used to test the safety and efficacy of the Factor IX products.