Contact Pathway Inhibitor to Prevent Catheter-Related Thrombosis - Project Summary Indwelling central venous catheters (CVCs), including peripherally inserted central catheters (PICCs) as well as implantable venous access ports, are commonly used for drug treatments or supportive care in a variety of disease conditions; however, central lines carry a risk of complications, including catheter-related infections and catheter-related thrombosis (CRT). Several risk factors can contribute to CRT including underlying diseases, many of which are conditions in which CVC placement is critical to patient care. For example, cytotoxic chemotherapy to treat cancer can create a hypercoagulable state that increases CRT risk. While both cancer and cancer directed therapy impart thrombotic risk, some also increase the risk of bleeding, including myelotoxic drugs. At present, antithrombotic drugs are not used for CRT prevention in cancer patients due to hemostatic impairment concerns and lack of efficacy data. Since CRT can have localized (device failure) or secondary (vessel occlusion, embolization) complications, an important unmet need exists for safe and effective CRT prevention in patients who need CVC placement. This SBIR Fast Track project directly addresses this critical need by developing a unique contact activation targeting antithrombotic and antiinflammatory agent, AB023 (gruticibart), to prevent CRT. We have recently conducted a small investigator- initiated phase 2 clinical study in cancer patients with CVCs to evaluate whether this approach may be safe and effective (NCT04465760). In this exploratory study, we found only 1 in 8 (12.5%) patients developed early CRT detected via ultrasound after AB023 administration. In a parallel observational study, we found that 4 in 10 (40%) cancer patients with a CVC had early CRT detected via ultrasound. Our early clinical safety data from this trial and from another trial in end stage renal disease patients on hemodialysis (NCT03612856) suggests that AB023 is safe in medically complex patient populations, with no drug-related adverse events observed in 42 treated individuals. During this Phase I/II SBIR project, we propose to conduct a powered, randomized, placebo-controlled, double blind clinical trial to evaluate the safety of CRT prevention in cancer patients who otherwise would not receive thromboprophylaxis. AB023 specifically targets prothrombotic coagulation factor XI (FXI) activation by factor XII (FXII), without inhibiting hemostatic feedback activation of FXI by thrombin. Therefore, AB023 is unique and has the potential to be exceptionally safe among other investigational FXI/FXIa targeting drugs in development. However, it is not yet entirely certain that blocking the FXI/FXII interaction has no unforeseen adverse effects on hemostasis. Therefore, as a long-term development strategy, we will also determine the potential utility of several drug reversal approaches to terminate the anticoagulant activity of AB023. Achievement of our critical milestones include: Aim 1- Identify one effective reversal or bypass agent for AB023, and Aim 2- Demonstrate that a single dose of AB023 is safe and reduces early CRT when administered to cancer patients at the time of CVC placement. Success of the proposed research will prompt subsequent definitive trials of AB023 to safely prevent CRT.
