Each year, approximately one-third of all hospitalized patients in the US (corresponding to about 12 million Americans) receive unfractionated heparin (UFH) to prevent clotting during surgical and invasive medical procedures, such as open-heart surgery and transcatheter heart valve replacement, and to prevent postoperative clotting issues, such as deep vein thrombosis, and major ischemic events, such as pulmonary embolism, heart attack, and stroke. UFH is a fast-acting, reversible, and inexpensive anticoagulant drug that indirectly inhibits several clotting factors, including thrombin and Xa. However, UFH is associated with serious acute side effects, including hypersensitivity reactions. The non-linear dose response to UFH and a high degree of patient-to-patient and batch-to-batch variability lead to medication errors related to improper dosing, and these errors are among the most common and serious in clinical practice. An estimated 1-5% of patients who receive UFH experience an immune response known as heparin-induced thrombocytopenia (HIT), which is considered life threatening or results in death in 20-30% of affected patients. Additionally, up to 26% of cardiac surgery patients experience "heparin resistance," where achieving therapeutic anticoagulation requires excessive doses of UFH. As with any anticoagulant, treatment with UFH carries the risk of excessive bleeding, which can be fatal. UFH is reversed by protamine, which is also associated with serious side effects, including anaphylaxis and toxicity. Accurate determination of the dosing ratio of protamine to UFH is challenging, putting patients at risk for protamine overdose. In the context of medical procedures that require precise (i.e., immediate and titratable) hemostatic control, such as transcatheter heart valve replacement, these shortcomings are particularly challenging. Thus, there is a recognized, unmet medical need for new anticoagulant/reversal agent combinations that are safe and fast acting with a predictable dose response to enable more precise hemostatic control during medical procedures. Helixomer, Inc. is developing a novel polynucleotide-based anticoagulant/antidote combination for intravenous anticoagulation. In vitro and in vivo data have demonstrated that Helixomer's anticoagulant drug, Hex01, and its antidote, Hex02, are highly specific and fast acting, with clear, predictable dose responses. Hex01 specifically binds to and directly inhibits thrombin, the enzyme responsible for fibrin deposition and clot formation. Hex02 base-pairs with and deactivates Hex01, reversing the anticoagulant effect by releasing thrombin. In this Direct-to-Phase II SBIR project, Helixomer will advance the preclinical development of Hex01 and Hex02 by i) validating bioanalytical assays for Hex01 and Hex02 in plasma to support preclinical development, ii) establishing scale-up manufacturing methods for Hex01, iii) determining a dosing strategy for Hex01 and Hex02 in a porcine large-animal model, and iv) defining safety and toxicity profiles for Hex01 and Hex02 and identifying the maximum tolerated dose through non-GLP dose range finding studies in rats and dogs. Successful completion of these critical preclinical studies will support subsequent pivotal GLP toxicology studies and IND submission.
Public Health Relevance Statement: PROJECT NARRATIVE Anticoagulant treatment can prevent thrombosis and major ischemic events, such as pulmonary embolism, heart attack, and stroke, but the anticoagulant/reversal agent pair most commonly used during surgical procedures, unfractionated heparin (UFH) and protamine, is associated with serious acute side effects, dosing errors, hemorrhage, and thrombosis. To meet the need for safer alternatives to UFH and protamine, Helixomer, Inc. is developing an innovative RNA-origami-based anticoagulant and a corresponding DNA-based reversal agent with predictable dose response profiles. In this Direct-to-Phase II project, Helixomer will validate essential bioanalytical methods for quantifying drug concentrations in plasma, determine dosing strategies in a large- animal model, determine the maximum tolerated dose, and assess the safety and toxicity of these novel drugs in preparation for a future first-in-human clinical trial.
Project Terms: Affect; Anaphylactic Reaction; Anaphylactic Shock; Anaphylaxis; Anticoagulant Agents; Anticoagulant Drugs; blood thinner; thrombopoiesis inhibitor; Anticoagulants; Anticoagulation; Theriacs; Antidotes; Biological Assay; Assay; Bioassay; Biologic Assays; Blood; Blood Reticuloendothelial System; Blood Coagulation Factor; Coagulation Factors; clotting factor; Cardiovascular system; Cardiovascular; Cardiovascular Body System; Cardiovascular Organ System; Heart Vascular; circulatory system; Clinical Trials; Cessation of life; Death; Dialysis procedure; Dialysis; dialysis therapy; DNA; Deoxyribonucleic Acid; Single-Stranded DNA; ssDNA; Canis familiaris; Canine Species; Dogs; Dogs Mammals; canine; domestic dog; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Endotoxins; Enzyme-Linked Immunosorbent Assay; ELISA; enzyme linked immunoassay; Enzymes; Enzyme Gene; Euthanasia; Mercy Killing; Extracorporeal Membrane Oxygenation; Fibrin; Future; Cardiac Surgery procedures; Cardiac Surgery; Cardiac Surgical Procedures; Heart Surgical Procedures; heart surgery; Hemorrhage; Bleeding; blood loss; Hemostatic Agents; Hemostatics; Heparin; Heparinic Acid; Hospitalization; Hospital Admission; Human; Modern Man; Hypersensitivity; Allergy; In Vitro; Ischemia; Kinetics; Lead; Pb element; heavy metal Pb; heavy metal lead; Medication Errors; medication administration errors; Methods; Mus; Mice; Mice Mammals; Murine; Myocardial Infarction; Cardiac infarction; Myocardial Infarct; cardiac infarct; coronary attack; coronary infarct; coronary infarction; heart attack; heart infarct; heart infarction; Overdose; Patients; Plasma; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Polynucleotides; Postoperative Period; Post-Operative; Postoperative; Production; Protamines; Pulmonary Embolism; Rattus; Common Rat Strains; Rat; Rats Mammals; Risk; RNA; Non-Polyadenylated RNA; RNA Gene Products; Ribonucleic Acid; Safety; Saline; Saline Solution; Stroke; Apoplexy; Brain Vascular Accident; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Stroke; brain attack; cerebral vascular accident; cerebrovascular accident; stroked; strokes; Family suidae; Pigs; Suidae; Swine; porcine; suid; Thrombin; Thrombase; fibrinogenase; Thrombosis; thrombotic disease; thrombotic disorder; Time; Tissues; Body Tissues; Toxicology; Genetic Transcription; Gene Transcription; RNA Expression; Transcription; Work; Deep-Venous Thrombosis; Deep Vein Thrombosis; analytical method; Procedures; cardiac valve replacement; heart valve replacement; Acute; Clinical; Phase; biologic; Biological; Medical; Immunological response; host response; immune system response; immunoresponse; Immune response; Therapeutic; fluid; liquid; Liquid substance; Shapes; Deposition; Deposit; Intravenous; Life; Hour; Event; Reaction; Operative Surgical Procedures; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; meetings; meeting; American; experience; immunotoxicity; toxic reaction in immunology; aptamer; Animal Model; Animal Models and Related Studies; model of animal; Base Pairing; Toxic effect; Toxicities; novel; Appearance; Maximum Tolerated Dose; Maximal Tolerated Dose; Maximally Tolerated Dose; response; assay development; Molecular Interaction; Binding; preventing; prevent; Coagulation Process; Clotting; Coagulation; Address; Dose; Affinity; Data; Detection; in vivo; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Preparation; preparations; Development; developmental; nano; preclinical study; pre-clinical study; Biodistribution; innovate; innovative; innovation; resistant; Resistance; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; full scale manufacturing; large scale manufacturing; mass production; large scale production; clinical practice; commercial scale manufacturing; manufacturing ramp-up; scale up batch; scale up production; upscale manufacturing; manufacturing scale-up; Industry Standard; pre-clinical development; preclinical development; patient variation; variability between patients; variation between patients; patient variability; first in man; first-in-human; heparin-induced thrombocytopenia; side effect; safety assessment; detection assay; pig model; piglet model; swine model; porcine model; manufacture
