Low Antigenicity Factor VIII

低抗原性因子VIII

• 批准号: 6537752
• 负责人: GARRETT E BERGMAN
• 金额: $ 41.3万
• 依托单位: OCTAGEN CORPORATION
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6537752
• 关键词: Macaca fascicularis; antigen antibody reaction; antigens; biotherapeutic agent; coagulation factor VIII; drug design /synthesis /production; drug screening /evaluation; hemophilia As; human subject; immunologic substance development /preparation; laboratory mouse; neutralizing antibody; patient oriented research; protein engineering; recombinant proteins

DESCRIPTION (Applicant's Description Verbatim): Our goal is to obtain registration of a low antigenicity recombinant fVIII product for the treatment of patients with neutralizing antibodies against human fVIII. Such inhibitor patients include those with hemophilia A who develop alloantibodies when treated with replacement human fVIII, as well as patients with "acquired hemophilia" who develop autoantibodies against endogenous fVIII. The development of an inhibitor to Will is a serious, potentially life threatening condition. Current treatment options are limited to so-called "bypassing" agents" and plasma derived porcine fVIII (Hyate:C). Bypassing agents are nonphysiologic and occasionally cause overdrive of the coagulation cascade. This may result in severe complications, such as disseminated intravascular thrombosis or myocardial infarction. Use of Hyate:C is currently limited by regulatory, treater and patient concerns arising from the plasma source of the product and side effects attributable to the relative impurity of the product. Applicant has exclusive access to recombinant porcine fVIII. Applicant has obtained substantial in vitro and in vivo data that supports the suitability of recombinant porcine Will for development as a low antigenicity fVIII product. Phase II of applicant's SBIR project shall include: completion of the preclinical development of the product, submission of an IND to the FDA, and initial safety and efficacy studies of the product in hemophilia A patients. In the preclinical stage, the safety and immunogenicity of the product will be studied in mice and cynomolgus monkeys. Pharmacokinetic data will be obtained in a highly predictive dog model of hemophilia A. After an ND is filed, the safety and pharmacokinetics of the product will be studied in a clinical trial in which approximately twelve inhibitor patients shall receive the product. PROPOSED COMMERCIAL APPLICATION: Approximately 26% of all hemophilia A patients develop antibodies. A significant portion cannot successfully be treated with human fVIII. A recombinant, low antigenicity fVIII product would compete well in the fVIII inhibitor patient market and be a first line therapy for "acquired hemophilia."

描述（申请人的逐字描述）：我们的目标是获得 用于治疗的低抗原性重组 fVIII 产品注册 具有抗人 fVIII 中和抗体的患者。此类抑制剂 患者包括患有 A 型血友病的患者，他们在以下情况下会产生同种抗体： 接受替代人 fVIII 治疗的患者，以及患有“获得性 血友病”，产生针对内源性 fVIII 的自身抗体。 意志抑制剂的发展是一种严重的、可能危及生命的疾病 健康）状况。目前的治疗方案仅限于所谓的“旁路” 剂”和血浆来源的猪 fVIII (Hyate:C)。旁路剂是 非生理性的，偶尔会导致凝血级联反应过度。 这可能会导致严重的并发症，例如播散性血管内 血栓形成或心肌梗塞。 Hyate:C 的使用目前受到以下限制 血浆源引起的监管、治疗和患者担忧 产品和由于产品的相对杂质而产生的副作用。 申请人拥有重组猪 fVIII 的独家使用权。申请人有 获得了大量的体外和体内数据，支持其适用性 重组猪 Will 开发为低抗原性 fVIII 产品。 申请人的 SBIR 项目第二阶段应包括： 产品的临床前开发，向 FDA 提交 IND，以及 该产品在甲型血友病患者中的初步安全性和有效性研究。在 临床前阶段，产品的安全性和免疫原性将受到影响 在小鼠和食蟹猴身上进行了研究。将获得药代动力学数据 在高度预测 A 型血友病的狗模型中。提交 ND 后， 产品的安全性和药代动力学将在临床试验中进行研究 其中大约十二名抑制剂患者将接受该产品。 拟议的商业应用： 大约 26% 的 A 型血友病患者会产生抗体。 很大一部分 不能成功地用人 fVIII 治疗。 重组、低抗原性 fVIII 该产品将在 fVIII 抑制剂患者市场上具有良好的竞争力，并成为一线疗法 对于“获得性血友病”。