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.

项目总结