Contact Pathway Inhibitor to Prevent Vascular Access Failure

接触途径抑制剂以防止血管通路失败

基本信息

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
项目类别：
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

项目摘要

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.

项目概要终末期肾病 (ESRD) 患者必须维持慢性血管通路才能挽救生命血液透析（HD）；然而，HD 入口极易受到感染、狭窄和血栓的影响闭塞。虽然血管通路选择包括放置中心静脉导管、动静脉导管 (AV) 瘘管和 AV 移植物，使用 AV 瘘管 (AVF) 已经取得了优异的结果。尽管国家血管通路指南提倡使用 AVF 而非合成动静脉移植物由于其较低的闭塞率和较长的生存率，AVG 仍用于透析，约 17% 的透析患者仍使用 AVG 慢性 HD 患者（美国约 85,000 名）。遗憾的是，该患者体内存在显着的医疗保健差异人口。事实上，在慢性 HD 患者中，黑人/非裔美国人的 AVG 使用率要高出 77% 与白人相比，女性的 AVG 使用量比男性高 69%。因此，一个重要的解决 AVG 通畅和寿命方面的需求尚未得到满足。该 SBIR 快速通道项目直接解决迫切需要开发一种独特的抗血栓剂 AB023（xisomab 3G3），以帮助维持慢性 AVG 访问通畅。为此，我们最近完成了单剂量试点2a期临床试验 (NCT03963895) 在 ESRD 患者中评估这种方法是否安全有效。我们早期的临床数据表明，xisomab 3G3 在这种医学复杂的患者群体中确实是安全的，没有任何副作用药物相关的不良事件，并且在血管通路部位没有观察到出血增加（Lorentz 等人，2017）。血，2021）。单剂量的 xisomab 3G3 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凝血事件。在这个拟议的第一阶段/第二阶段 SBIR 项目中，我们建议将这些研究扩展到每隔一周重复给药，以确定这种新的药物是否有效对于患有 AVG 的慢性 HD 患者来说，抗凝方法是安全有效的，他们通常有血栓形成和出血的风险增加，并且没有令人满意的抗凝治疗选择。自从 xisomab 3G3 特异性靶向凝血因子 XI (FXI) 通过因子 XII (FXII) 激活，而不抑制通过凝血酶激活 FXI 反馈，我们的创新候选药物在不断增长的药物中是完全独特的正在开发的 FXI 抑制剂的军备库。因此，由于人类缺乏 FXII 并不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异常安全。因此，xisomab 3G3 代表了一种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 AVG 的 ESRD 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。