Occlusive arterial thrombosis leading to stroke and myocardial infarction contribute to ~13 million deaths around the world every year. Over the past two decades, recombinant tissue plasminogen activator (rTPA) has remained the only drug approved to treat acute ischemic stroke. Unfortunately, patients who receive rTPA have a significant increase in symptomatic hemorrhage with a conversion rate of 6.4%. Moreover, rTPA only achieves an average of ~30% recanalization in arterial thrombi, which are commonly platelet rich and are notoriously resistant to rTPA. Evidence for this was seen in a recent study in patients who presented with large vessel occlusion (LVO) stroke and received rTPA, demonstrated vessel recanalization only 10% of the time. The limitations of rTPA therapy result in only ~5% of patients actually receive the drug. Therefore, a critical need exists to develop anti-thrombotic agents that: 1) prevent occlusive thrombus formation, 2) recanalize acute arterial occlusions and 3) prevent restenosis, all with a superior safety profile than that of rTPA. Von Willebrand Factor (VWF) is an optimal target for anti-thrombotic therapy. Under high shear seen in thrombosis, VWF binds to glycoprotein Ib? (GPIb?) of the platelet receptor complex GPIb-IX-V (GPIb-IX-V) as well as to GPIIb-IIIa, resulting in platelet activation and aggregation. VWF also self-associates, extending into the vessel lumen where it serves not only as a scaffold for platelets but also red blood cells. These central processes ultimately result in arterial thrombosis as seen in ischemic stroke. Aptamers are an innovative class of drug molecules that consist of oligonucleotides that specifically and efficiently bind to and inhibit target proteins. Basking Biosciences Inc has developed an RNA aptamer that inhibits VWF, named DTRI-031. It has also designed a reversal oligonucleotide, named DTRI-025 that rapidly neutralizes DTRI-031 within minutes. DTRI-031 prevents thrombus formation, lyses fully formed arterial occlusions and reduces the radiographic burden of ischemia better than rTPA in small and large animal models of arterial thrombosis and stroke. It is currently in the final series of IND enabling studies. DTRI-025 rapidly reverses DTRI-031 activity in vitro and in vivo in small animal models. The overall goal of this proposal is to define the optimum dose of DTRI-025 to neutralize DTRI-031 in a large animal model and to develop a bioassay to perform GLP safety pharmacology and toxicity studies with GMP manufactured DTRI-025. The Aims of this proposal will allow Basking Biosciences to submit a Pre-IND application to FDA and ultimately lead to First In Human (FIH) trials in conjunction with DTRI-031.
Public Health Relevance Statement: PROJECT NARRATIVE Occlusive arterial thrombosis leading to stroke and myocardial infarction contribute to ~13 million deaths every year globally and although rTPA reduces morbidity and mortality and improves functional outcomes, stroke patients treated with rTPA experience restenosis, poor recanalization, symptomatic hemorrhage and 50% mortality. Basking Biosciences Inc has developed an RNA aptamer, DTRI-031 that binds to and inhibits von Willebrand Factor (VWF), which is essential for thrombus formation, and has also designed a reversal oligonucleotide, DTRI-025 that neutralizes DTRI-031 activity within minutes. As GLP PK/toxicity studies for DTRI-031 are nearing completion with plans to submit an IND application with the FDA by Q2 of 2020, this proposal will allow generation of pre-clinical data, development of a bioassay to perform genetic toxicology and GLP toxicology and safety pharmacology of DTRI-025.
Project Terms: Acute; acute stroke; Adhesions; Affect; Alteplase; Animal Experiments; Animal Model; Animals; aptamer; artery occlusion; base; Base Ratios; Binding; Biological Assay; Biological Sciences; Bleeding time procedure; Blood coagulation; Blood Platelets; Brain Injuries; Canis familiaris; Cerebral Thrombosis; Cerebrum; Cessation of life; Clinical; Clinical Data; Clinical Trials Design; Coagulation Process; commercialization; Contracts; design; Detection; Development; Diagnostic radiologic examination; Dose; Drug Kinetics; Elderly; Epilepsy; Erythrocytes; Evaluation; experience; Fibrin; Fibrinolytic Agents; first-in-human; Formulation; functional outcomes; Generations; Glycoprotein Ib; Goals; Hemorrhage; Hemostatic function; improved; improved outcome; in vitro activity; in vivo; Inflammation; innovation; Ischemia; Ischemic Stroke; Lead; Ligands; Measures; Mechanics; Methods; Morbidity - disease rate; mortality; Myocardial Infarction; Names; novel strategies; oligomycin sensitivity-conferring protein; Oligonucleotides; Operative Surgical Procedures; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phase I Clinical Trials; Physiological; Platelet Activation; Platelet aggregation; platelet function; Platelet Glycoprotein GPIb-IX Complex; Platelet Glycoproteins; Play; Population; pre-clinical; preclinical development; prevent; Process; Production; Proteins; receptor; Regimen; Resistance; restenosis; Risk; RNA; Role; Safety; scaffold; Series; Stroke; stroke model; stroke patient; stroke therapy; Therapeutic; Thrombectomy; Thrombelastography; Thrombin; Thrombosis; Thrombus; Time; Toxic effect; Toxicogenetics; Toxicology; Translating; Validation; von Willebrand Factor
