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Principal Investigator: Christina U Lorentz
Organization: ARONORA, INC.
Fiscal Year: 2024
Award: $493,999
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <Achievement><Achievement Attainment><Acute><Address><Adverse Experience><Adverse effects><Adverse event><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antibodies><Anticoagulant Agents><Anticoagulant Drugs><Anticoagulants><Anticoagulation><Antidotes><Antiplatelet Agents><Antiplatelet Drugs><Antithrombotic Agents><Antithrombotic Drugs><Award><Binding><Biocompatible Materials><Biological Agent><Biological Products><Biomaterials><Bleeding><Blood><Blood Clotting><Blood Coagulation Factor XI><Blood Coagulation FactorXI><Blood Plasma><Blood Reticuloendothelial System><Blood coagulation><Blood-coagulation factor XII><Bypass><C-reactive protein><Cancer Patient><Cancer Treatment><Cancers><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Catheters><Chimera><Chimera organism><Chronic><Clinical><Clinical Evaluation><Clinical Research><Clinical Study><Clinical Testing><Clinical Trials><Clotting><Coagulation><Coagulation Factor XI><Coagulation Factor XII><Coagulation Process><Complex><Cytotoxic Chemotherapy><Cytotoxic Therapy><Data><Dedications><Deep Vein Thrombosis><Deep-Venous Thrombosis><Detection><Development><Device Failures><Devices><Disease><Disorder><Dose><Dose Limiting><Double-Blind Method><Double-Blind Study><Double-Blinded><Double-Masked Method><Double-Masked Study><Drug Targeting><Drug Therapy><Drug usage><Drugs><ESRD><Embolism><Embolization Therapy><Embolotherapy><Embolus><Emergencies><Emergency Situation><End stage renal failure><End-Stage Kidney Disease><End-Stage Renal Disease><Equipment Malfunction><Event><Factor XI><Factor XII><Feedback><Fibrinolytic Agents><Fibrinolytic Drugs><Goals><Hageman Factor><Heart Vascular><Hemodialyses><Hemodialysis><Hemorrhage><Hemostasis><Hemostatic Agents><Hemostatic function><Hemostatics><Human><Hypercoagulability><Idiotype><Immunoglobulin Idiotypes><Impairment><Implantable venous access port><Incidence><Individual><Infection><Inflammatory><Intervention><Intervention Strategies><Investigators><Kallikreinogen><Legal patent><Life><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Marketing><Measures><Medical><Medical Device><Medication><Modern Man><Molecular Interaction><Monitor><Observation research><Observation study><Observational Study><Observational research><Operative Procedures><Operative Surgical Procedures><Outcome Measure><Patents><Pathway interactions><Patient Care><Patient Care Delivery><Patients><Peripheral><Pharmaceutical Preparations><Pharmacotherapy><Phase><Phase 2 Clinical Trials><Phase II Clinical Trials><Placebo Control><Placebos><Plasma><Plasma Prokallikrein><Plasma Serum><Plasma Thromboplastin Antecedent><Prekallikrein><Prevention><Primates><Primates Mammals><Proteins, specific or class, C-reactive><Randomized><Recombinants><Reporting><Research><Research Personnel><Researchers><Reticuloendothelial System, Serum, Plasma><Risk><Risk Factors><SBIR><Safety><Secure><Sepsis><Sham Treatment><Small Business Innovation Research><Small Business Innovation Research Grant><Stream><Subcutaneous Port><Supportive Therapy><Supportive care><Surgical><Surgical Interventions><Surgical Procedure><System><Testing><Therapeutic Agents><Therapeutic Embolization><Theriacs><Thrombase><Thrombin><Thrombolytic Agents><Thrombolytic Drugs><Thrombophilia><Thrombosis><Thrombus><Time><Toxic effect><Toxicities><Venous><anti-cancer therapy><antihemophilic factor C><antithrombotic medication><antithrombotics><biological material><biologics><biopharmaceutical><biotherapeutic agent><blocking factor><blood infection><blood loss><blood thinner><bloodstream infection><cancer therapy><cancer-directed therapy><care for patients><care of patients><caring for patients><catheter related infection><chimeras><circulatory system><clinical development><clinical relevance><clinical test><clinically relevant><developmental><drug candidate><drug treatment><drug use><drug/agent><efficacy outcomes><embolization><experience><fibrinogenase><inhibitor><innovate><innovation><innovative><interventional strategy><malignancy><measurable outcome><neoplasm/cancer><neutralizing antibody><novel><outcome measurement><pathway><patient population><phase 2 trial><phase II protocol><phase II trial><placebo controlled><placebo controlled study><preservation><prevent><preventing><product development><prophylactic><randomisation><randomization><randomly assigned><research clinical testing><safety outcomes><safety testing><sham therapy><side effect><success><surgery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><thrombopoiesis inhibitor><thrombotic><thrombotic disease><thrombotic disorder><trial planning><ultrasound>