Contact Pathway Inhibitor to Prevent Vascular Access Failure

接触途径抑制剂以防止血管通路失败

• 批准号: 10604057
• 负责人: Christina U Lorentz
• 金额: $ 99.85万
• 依托单位: ARONORA, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10604057
• 关键词: Achievement; Acute; Addendum; Address; Adverse event; African American; Agreement; American Society of Hematology; Anticoagulants; Anticoagulation; Arteriovenous fistula; Authorization documentation; Award; Binding; Biotechnology; Black race; Blood; Blood Vessels; Blood coagulation; C-reactive protein; Cardiovascular system; Catheters; Chemistry; Chronic; Clinical; Clinical Data; Clinical Trials; Coagulation Process; Complex; Complication; Contact Inhibition; Data; Development; Dialysis procedure; Dose; Double-Blind Method; Drug Kinetics; Drug toxicity; End stage renal failure; Evaluation; Event; Exposure to; Factor XI; Factor XII; Factor XII Deficiency; Failure; Feedback; Female; Fibrinolytic Agents; Freeze Drying; Goals; Guidelines; Hemodialysis; Hemorrhage; Hemostatic Agents; Human; Hyperplasia; Implant; Incidence; Industry; Infection; Inflammation; Inflammatory; Interruption; Intervention; Kidney Failure; Lead; Legal patent; Life; Longevity; Marketing; Measures; Medical; Morbidity - disease rate; No-Observed-Adverse-Effect Level; Outcome; Outcome Measure; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Phase II Clinical Trials; Placebos; Plasma; Population; Primates; Procedures; Prosthesis; Randomized; Rattus; Recommendation; Recovery; Regimen; Renal Replacement Therapy; Research; Risk; Safety; Secure; Serum; Site; Small Business Innovation Research Grant; Sprague-Dawley Rats; Stenosis; System; Therapeutic; Therapeutic antibodies; Thrombin; Thrombosis; Thrombus; Toxic effect; Venous; arteriovenous graft; authority; clinical development; drug candidate; efficacy outcomes; efficacy study; efficacy trial; health care disparity; inhibitor; innovation; male; meetings; mortality; neutralizing antibody; novel strategies; patient population; placebo controlled study; preclinical safety; prevent; product development; safety study; side effect; success; targeted treatment; thrombotic; treatment duration

Project Summary End-stage renal disease (ESRD) patients must maintain chronic vascular access to perform life-saving hemodialysis (HD); however, the HD access portal is extremely vulnerable to infection, stenosis, and thrombo- occlusion. While vascular access options include the placement of central veinous catheters, arteriovenous (AV) fistulas, and AV grafts, superior outcomes have been established with the use of AV fistulas (AVFs). Despite national vascular access guidelines promoting the use of AVFs over synthetic arteriovenous grafts (AVGs) for dialysis due to their lower occlusion rates and longer survival, AVGs are still utilized in ~17% of all chronic HD patients (~85,000 in the U.S.). Regrettably, significant healthcare disparities exist within this patient population. Indeed, in chronic HD patients, the rate of AVG use is 77% higher in the Black/African American versus white population, while AVG use among females is 69% greater than in males. Thus, an important unmet need exists to address AVG patency and longevity. This SBIR Fast-Track project directly addresses the critical need by developing a unique antithrombotic agent, AB023 (xisomab 3G3), to help maintain chronic AVG access patency. To this end, we have recently completed a single-dose pilot phase 2a clinical trial (NCT03963895) in ESRD patients to evaluate whether this approach may be safe and effective. Our early clinical data suggests that xisomab 3G3 is indeed safe in this medically complex patient population, with no drug-related adverse events and no increased bleeding observed at the vascular access site (Lorentz, et. al. Blood, 2021). A single dose of xisomab 3G3 limited systemic markers of both thrombosis and inflammation, and also reduced severe dialysis circuit blood clotting events. During this proposed Phase I/II SBIR project, we propose to extend these studies into repeat, every other week drug administration to determine if this new approach to anticoagulation is safe and effective in chronic HD patients with AVGs, who generally have an elevated risk of both thrombosis and bleeding and no satisfactory options for therapeutic anticoagulation. Since xisomab 3G3 specifically targets coagulation factor XI (FXI) activation by factor XII (FXII) without inhibiting the FXI feedback activation by thrombin, our innovative drug candidate is entirely unique in the growing armamentarium of FXI inhibitors under development. Accordingly, since FXII deficiency in humans does not result in any known bleeding side-effects, xisomab 3G3 could be an effective antithrombotic strategy that is exceptionally safe. As such, xisomab 3G3 represents a fundamentally unique anticoagulation concept. Success of the proposed research and achievement of our critical milestones will lead directly to subsequent and definitive safety/efficacy trials in ESRD patients with chronically implanted AVGs, who are in desperate need of safe thromboprophylaxis.

项目摘要 末期肾脏疾病（ESRD）患者必须维持慢性血管恢复生命 血液透析（HD）；但是，高清访问门户非常容易受到感染，狭窄和动脉粥样硬化的影响。 阻塞。虽然血管通道选项包括放置中央钢丝导管，而动静脉 （AV）瘘管和AV移植物，通过使用AV瘘（AVF）建立了出色的结果。 尽管国家血管通道指南促进了在合成动脉植入的移植物上使用AVF （AVG）由于透析率较低而生存率较长，因此AVG仍在所有量中的17％中使用 慢性高清患者（美国约85,000例）。遗憾的是，该患者中存在重大医疗保健差异 人口。实际上，在慢性高清患者中，黑人/非裔美国人的AVG使用率高77％ 与白人人口相对，而女性中的AVG使用比男性大69％。因此，一个重要 存在未满足的需求，以解决AVG通畅和寿命。这个SBIR快速轨道项目直接解决 通过开发独特的抗强化剂AB023（Xisomab 3G3）来帮助维持慢性 AVG访问通畅。为此，我们最近完成了一项单剂量试验阶段2A临床试验 （NCT03963895）在ESRD患者中评估这种方法是否安全有效。我们的早期 临床数据表明，在此医学复杂的患者人群中，Xisomab 3G3确实是安全的，没有 在血管通道部位观察到与药物有关的不良事件，没有观察到的出血增加（Lorentz等。 血，2021）。单剂量的xisomab 3g3有限的血栓形成和炎症的系统标记， 还减少了严重的透析回路血液凝结事件。在此拟议的I/II阶段SBIR项目中，我们 建议将这些研究扩展为重复一次，每隔一周的药物管理 抗凝方法在慢性高清患者中是安全有效的，他们通常患有 血栓形成和出血的风险升高，没有令人满意的治疗抗凝治疗选择。自从 Xisomab 3G3特异性地靶向固定因子XI（FXI）通过因子XII（FXII）激活而不抑制 FXI反馈激活凝血酶，我们的创新药物候选人在增长中完全是独一无二的 FXI抑制剂正在开发中。因此，由于人类的FXII缺乏症 导致任何已知的出血副作用，xisomab 3g3可能是有效的抗血栓形成策略， 非常安全。因此，Xisomab 3G3代表了一个根本独特的抗凝概念。 拟议的研究和实现我们关键里程碑的成功将直接导致随后的 ESRD患者的慢性AVG患者的确保/功效试验，他们绝望 需要安全的血栓预防。