Phase II Amount
$2,817,681
Each year venous thromboembolism affects up to 2 million Americans and 24 million people worldwide.Patients with venous thromboembolism have blood clots in the legs (venous thrombosis) that may travel to thelungs (pulmonary embolism). Pulmonary embolism (PE) is a leading cause of hospital deaths. Pulmonaryemboli may acutely obstruct blood flow, causing right heart failure, circulatory collapse and death within hoursor days. Over a longer period of time, persistent pulmonary emboli may cause serious, disabling complicationssuch as chronic thromboembolic pulmonary hypertension and right heart failure For more than 85 years, anticoagulation has been standard therapy for PE. Anticoagulation does notdissolve thrombi and is an inadequate treatment for massive PE. However, treatment with a thrombus-dissolving agent, such as recombinant tissue plasminogen activator (r-tPA), dissolves pulmonary emboli toimprove heart pressures, reduce clot burden, increase the ability of the lung tissue to oxygenate the blood anddecrease post-thrombotic symptoms better than standard anticoagulation therapy. Nevertheless, r-tPA-likeagents cause severe or fatal hemorrhage and the benefit of r-tPA therapy exceeds the risk of bleeding only inpatients that face imminent death from massive PE. For the vast majority of patients, r-tPA therapy is not safe,even in those patients with intermediate-risk PE, which may have 30-day death rates as high as 10%.To savelives, reduce recurrent thrombosis and decrease long term complications in patients with PE, TranslationalSciences (TSI) seeks to develop a therapeutic a2AP-inactivating monoclonal antibody (a2AP-I) as the first newclass of safe, thrombus-dissolving agents since plasminogen activator therapy was first used in humans > 60years ago. This new therapy is targeted to neutralize a2AP, the major inhibitor of thrombus dissolution in vivo.Extensive research from our lab and others has shown that a2AP deficiency, or an a2AP-I removes the brakeson thrombus dissolution by activating endogenous fibrinolysis, causing venous thrombi and pulmonary embolito dissolve spontaneously without causing bleeding. Even in experimental stroke, where the ischemic brain is asensitive test of therapeutic risk, a2AP-I therapy enhances thrombus dissolution, reduces brain infarction,decreases brain hemorrhage and saves lives by comparison to r-tPA. An a2AP-I has extraordinary potential forimproving the treatment of PE. On the basis of pre-clinical data, we project that by comparison to currenttherapy, treatment with TS23 could significantly reduce right heart failure, improve survival, decrease recurrentthrombosis and prevent long-term disability in patients with pulmonary embolism. TSI currently holds an INDfor Phase II trial of TS23 in PE and now brings together leading investigators for an efficient trial to assess thesafety and efficacy of TS23 in patients with intermediate-risk pulmonary embolism.
Public Health Relevance Statement: When blood clots form in the veins, and travel to the lungs, they cause pulmonary embolism. Pulmonary embolism may obstruct blood flow, dangerously lower blood pressure, cause long term disability or lead to sudden death. Current anticoagulation therapy fails to address these complications because it does not dissolve and clear blood clots, but only prevents new clot formation. In this trial, will test a highly innovative approach to safely dissolving blood clots, to assess whether it can improve outcomes for patients with pulmonary embolism.
Project Terms: Affect ; inhibitor/antagonist ; inhibitor ; Monoclonal Antibodies ; Clinical Treatment Moab ; mAbs ; Anticoagulation ; Antiplasmin ; Plasmin Antiactivator ; alpha 2-Plasmin Inhibitor ; alpha-2-Antiplasmin ; Blood ; Blood Reticuloendothelial System ; Blood coagulation ; Blood Clotting ; Brain ; Brain Nervous System ; Encephalon ; Cardiovascular Diseases ; cardiovascular disorder ; Clinical Trials ; Critical Illness ; Critically Ill ; Dangerousness ; Cessation of life ; Death ; Sudden Death ; Double-Blind Method ; Double-Blind Study ; Double-Blinded ; Double-Masked Method ; Double-Masked Study ; Embolism ; Embolus ; Therapeutic Embolization ; Embolization Therapy ; Embolotherapy ; embolization ; Face ; faces ; facial ; Fibrinolysis ; Fibrinolyses ; Cyclic GMP ; Guanosine Cyclic Monophosphate ; cGMP ; Heart ; Heart failure ; cardiac failure ; Hemorrhage ; Bleeding ; blood loss ; Hospitals ; Human ; Modern Man ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Lung ; Lung Respiratory System ; pulmonary ; male ; United States National Institutes of Health ; NIH ; National Institutes of Health ; Patients ; Pharmacology ; Placebos ; Sham Treatment ; sham therapy ; Alteplase ; Recombinant Tissue Plasminogen Activator ; T-Plasminogen Activator ; Tissue Activator D-44 ; Tissue Plasminogen Activator ; Tissue-Type Plasminogen Activator ; t-PA ; Plasminogen Activator ; pressure ; Pulmonary artery structure ; Pulmonary Artery ; Pulmonary Embolism ; Recurrence ; Recurrent ; Research ; Research Personnel ; Investigators ; Researchers ; Risk ; Safety ; Shock ; Circulatory Collapse ; circulatory shock ; Stroke ; Apoplexy ; Brain Vascular Accident ; Cerebral Stroke ; Cerebrovascular Apoplexy ; Cerebrovascular Stroke ; brain attack ; cerebral vascular accident ; cerebrovascular accident ; Testing ; Thrombosis ; thrombotic disease ; thrombotic disorder ; Time ; Travel ; Veins ; Venous Thrombosis ; Phlebothrombosis ; Fibrin fragment D ; D-dimer ; D-dimer fibrin ; D-dimer fragments ; fibrin fragment D-dimer ; fibrin fragment D1 dimer ; fibrin fragment DD ; Thrombus ; Acute myocardial infarction ; Acute myocardial infarct ; Guidelines ; improved ; Acute ; Chronic ; Clinical ; Death Rate ; disability ; Blood flow ; nonhuman primate ; non-human primate ; Phase II Clinical Trials ; Phase 2 Clinical Trials ; phase II protocol ; Therapeutic ; Venous ; Hour ; Pulmonary Thromboembolism ; hemorrhagic stroke ; Brain hemorrhage ; American ; novel ; brain infarct ; Brain Infarction ; Lung Parenchyma ; Lung Tissue ; Structure of parenchyma of lung ; Ischemic Stroke ; Leg ; Lysis ; Cytolysis ; preventing ; prevent ; therapeutic testing ; therapeutic evaluation ; Clotting ; Coagulation ; Coagulation Process ; Address ; Dose ; Symptoms ; Data ; in vivo ; Clinical Data ; Patient-Focused Outcomes ; Patient outcome ; Patient-Centered Outcomes ; Serious Adverse Event ; Severe Adverse Event ; serious adverse experience ; serious adverse reaction ; Translational Research ; Translational Science ; translation research ; Ventricular ; Development ; developmental ; pre-clinical ; preclinical ; manufacturing process ; innovation ; innovate ; innovative ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; volunteer ; standard of care ; stability testing ; phase III trial ; phase 3 trial ; phase II trial ; phase 2 trial ; phase I trial ; phase 1 trial ; blood pressure reduction ; BP reduction ; lower BP ; lower blood pressure ; lowers blood pressure ; reduce BP ; reduce blood pressure ; reduction in BP ; reduction in blood pressure ; improved outcome ; reduce symptoms ; alleviate symptom ; ameliorating symptom ; decrease symptom ; fewer symptoms ; relieves symptoms ; symptom alleviation ; symptom reduction ; symptom relief ; chronic thromboembolic pulmonary hypertension ; venous thromboembolism ; limb ischemia ; ischemic limb ; COVID-19 treatment ; COVID-19 therapy ; COVID19 therapy ; COVID19 treatment ; SARS-CoV-2 therapy ; SARS-CoV-2 treatment ; coronavirus disease 2019 therapy ; coronavirus disease 2019 treatment ; severe acute respiratory syndrome coronavirus 2 therapy ; severe acute respiratory syndrome coronavirus 2 treatment ; treat COVID-19 ; treat COVID19 ; treat SARS-CoV-2 ; treat coronavirus disease 2019 ; treat severe acute respiratory syndrome coronavirus 2 ; thrombotic ; thrombotic complications ; thromboembolic complications ; thrombosis complications ; COVID-19 patient ; COVID infected patient ; COVID patient ; COVID positive patient ; COVID-19 infected patient ; COVID-19 positive patient ; COVID19 patient ; COVID19 positive patient ; SARS-CoV-2 infected patient ; SARS-CoV-2 patient ; SARS-CoV-2 positive patient ; coronavirus disease 2019 infected patient ; coronavirus disease 2019 patient ; coronavirus disease 2019 positive patient ; coronavirus disease infected patient ; coronavirus disease patient ; coronavirus disease positive patient ; coronavirus patient ; patient infected with COVID ; patient infected with COVID-19 ; patient infected with SARS-CoV-2 ; patient infected with coronavirus disease ; patient infected with coronavirus disease 2019 ; patient infected with severe acute respiratory syndrome coronavirus 2 ; patient with COVID ; patient with COVID-19 ; patient with COVID19 ; patient with SARS-CoV-2 ; patient with coronavirus disease ; patient with coronavirus disease 2019 ; patient with severe acute respiratory distress syndrome coronavirus 2 ; severe acute respiratory syndrome coronavirus 2 infected patient ; severe acute respiratory syndrome coronavirus 2 patient ; severe acute respiratory syndrome coronavirus 2 positive patient ;
