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 终末期肾病(ESRD)患者必须保持慢性血管通路以进行救命 血液透析(HD)；然而，HD入口极易受到感染、狭窄和血栓的影响。 遮挡。虽然血管通路的选择包括放置中央静脉导管，但动静脉 在房室瘘和房室移植物方面，房室瘘(AVF)的使用已经建立了优越的结果。 尽管国家血管通路指南促进动静脉动静脉移植物使用动静脉曲张 (AVGs)用于透析由于其较低的闭塞率和较长的存活期，约17%的患者仍在使用AVGs 慢性HD患者(美国约8.5万人)。令人遗憾的是，这位患者体内存在显著的医疗保健差异。 人口。事实上，在慢性血液透析患者中，黑人/非裔美国人的AVG使用率高出77% 与白人人群相比，女性的AVG使用量比男性高69%。因此，一个重要的 存在未得到满足的需求，以解决AVG的通畅性和寿命问题。该SBIR快速通道项目直接针对 迫切需要开发一种独特的抗血栓药物AB023(Xisomab 3G3)来帮助维持慢性 平均访问通畅性。为此，我们最近完成了单剂中试阶段2a临床试验。 (NCT03963895)，以评估该方法是否安全有效。我们的早期 临床数据表明，在这个医学上复杂的患者群体中，xisomab 3G3确实是安全的，没有 在血管通路部位观察到与药物相关的不良事件和出血增加(Lorentz，et.艾尔 血，2021年)。单剂xisomab 3G3限制了血栓形成和炎症的系统标志物， 还可以减少严重的血液透析回路凝血事件。在这项拟议的第I/II期SBIR项目中，我们 建议将这些研究延长到重复，每隔一周给药一次，以确定这一新的 对于患有动静脉曲张的慢性血液透析患者来说，抗凝治疗是安全有效的，他们通常有 血栓形成和出血的风险增加，治疗抗凝没有令人满意的选择。自.以来 Xisomab 3G3特异性靶向凝血因子XI(FXI)激活凝血因子XII(FXII)而不抑制 凝血酶反馈激活FXI，我们的创新候选药物在不断增长的 正在开发的FXI抑制剂药库。因此，由于人类的FXII缺陷不会 导致任何已知的出血副作用，xisomab 3G3可能是一种有效的抗血栓策略，即 非常安全。因此，xisomab 3G3代表了一个从根本上独特的抗凝概念。 拟议研究的成功和我们关键里程碑的实现将直接导致后续 对长期植入动静脉曲张的终末期肾病患者进行明确的安全性/有效性试验，这些患者处于绝望之中 需要安全的血栓预防措施。