Contact Pathway Inhibitor to Prevent Vascular Access Failure

项目摘要 终末期肾病（ESRD）患者必须维持慢性血管通路以执行救生 血液透析（HD）;然而，HD入路入口极易受到感染、狭窄和血栓的影响， 闭塞虽然血管通路的选择包括放置中心静脉导管， (AV)瘘和AV移植物，使用AV瘘（AVF）已确立了上级结局。 尽管国家血管通路指南提倡使用AVF而不是人工动静脉移植物， 由于AVG的闭塞率较低且生存期较长，AVG仍在约17%的患者中使用 慢性HD患者（美国约85，000例）。令人遗憾的是，该患者存在显著的医疗差异 人口事实上，在慢性HD患者中，黑人/非裔美国人的AVG使用率高出77 与白色人群相比，女性中AVG的使用率比男性高69%。因此，重要的 存在解决AVG通畅性和寿命的未满足需求。这个SBIR快速通道项目直接解决了 通过开发一种独特的抗血栓形成药物AB 023（xisomab 3G 3）， 平均通路通畅率。为此，我们最近完成了一项单剂量试点2a期临床试验， （NCT 03963895），以评价该方法是否安全有效。我们早期 临床数据表明，Xisomab 3G 3在这一医学复杂患者人群中确实安全， 药物相关的不良事件，并且在血管进入部位没有观察到出血增加（Lorentz，et. al. Blood，2021）.单剂量xisomab 3G 3限制了血栓形成和炎症的全身标志物， 并且还减少了严重的透析回路血液凝固事件。在拟议的第I/II期SBIR项目期间，我们 我建议将这些研究扩展到重复，每隔一周给药一次，以确定这种新的 抗凝方法在伴有AVG的慢性HD患者中安全有效，这些患者通常有 血栓形成和出血的风险升高，并且没有令人满意的抗凝治疗选择。以来 xisomab 3G 3特异性靶向凝血因子Xi（FXi）被因子XII（FXII）激活，而不抑制 FXI通过凝血酶反馈激活，我们的创新候选药物在不断增长的 正在开发的FXI抑制剂的医疗器械。因此，由于人类中的FXII缺乏症不 导致任何已知的出血副作用，Xisomab 3G 3可能是一种有效的抗血栓形成策略， 非常安全。因此，xisomab 3G 3代表了一种基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随后的 在患有长期植入AVG的ESRD患者中进行的确定性安全性/有效性试验，这些患者处于绝望状态 需要安全的血栓预防。

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.