Radikal Therapeutics (RTX) is developing a first-in-class cytoprotective small molecule agent (R-801) intended for the acute resuscitation of hemorrhagic shock (HS), the leading cause of death in trauma patients worldwide. Narrowly-directed therapies for HS have fared poorly in the clinic, suggesting that the pathogenesis of clinical HS is complex and arguing that a broader multi-faceted approach may be required. To this end, RTX is testing the utility of combining 2 classic approaches into a new single molecular entity. R-801 is a both: 1) a broad-spectrum catalytic antioxidant that removes intracellular redox stress, and 2) a selective pharmacological activator of the ischemic preconditioning (IPC) response. We hypothesize that this combination will provide at least additive and potentially synergistic reduction in HS-associated tissue injury and dysfunction. In rats subjected to lethal hemorrhage and resuscitation, R-801 administered 5 min before resuscitation reduced the fall in mean arterial pressure by 28% and attenuated the elevations in serum AST, creatinine, and pancreatic lipase by 72%, 62%, and 84%, respectively (p<0.002). Aim #1: Scale-up R-801 synthesis to multi-kg level production. In order to reduce manufacturing cost of goods and thereby strengthen our competitive position, RTX will carry out process research in order to minimize column chromatography steps in the manufacturing of R-801 and lessen manufacturing safety concerns related to the use of tetrazole catalysis. Aim #2: Establish the pharmacodynamics of R-801 in an ovine model of HS. In order to test the efficacy of R-801 in a large animal system, we have selected a classic HS model in sheep created by the rapid withdrawal of blood to achieve a fixed level of hypotensive MAP. We will utilize anesthetized female Merino sheep subjected to fixed-pressure hypotension for 90 min via a 10 min withdrawal of blood to an MAP of 40 mmHg. 5 min prior to reperfusion with shed blood, sheep will receive R-801 (0, 10, 30, and 100 mg/kg IV). A sham group will not undergo HS nor receive R-801. In addition to hemodynamic and respiratory measurements, terminal outcome endpoints at 24 h will include markers of tissue injury and inflammation. Each of the measures has been carefully selected so as to reveal a critical feature of organ injury. Aim #3: Transfer manufacturing technology to a GMP toll manufacturer to support Phase 1 clinical trials. In order to prepare R-801 drug product suitable for an IND submission, RTX will transfer its manufacturing methodology to a toll manufacturing firm, Regis Technologies (Morten Grove, IL), where a multi-kg GMP-grade batch will be produced to support clinical investigations. Aim #4: Prepare IND documentation to support an FDA-regulated study of the acute safety, tolerance, PK, metabolism, and excretion profile of an IV bolus infusion of R-801 in healthy human volunteers. In order to position RTX to carry out clinical first-in-man safety and PK investigations, we will submit to the FDA a full IND application in support of the Phase 1 safety and pharmacokinetic studies.
Thesaurus Terms: 3-Nitrotyrosine; Acute; Address; Animal Model; Animals; Antihypertensive Agents; Antioxidants; Attenuated; Base; Biochemical; Blood; Blood Flow; Blood Vessels; Bolus Infusion; Cadherin 5; Catalysis; Catalyst; Cause Of Death; Clinic; Clinical; Clinical Investigation; Clinically Relevant; Column Chromatography; Complex; Cost; Creatinine; Documentation; Dosage; Drug Kinetics; Effective Therapy; Efficacy Testing; Evaluation; Excretory Function; Falls; Female; First-In-Human; Functional Disorder; Hemodynamics; Hemorrhage; Hemorrhagic Shock; Histologic; Hour; Human Volunteers; Hypotension; Immunoreactivity; Infiltration; Inflammation; Injury; Innovation; Instrumentation; Intestines; Intravenous Bolus; Investigation; Ischemic Preconditioning; Kidney; Laceration; Lipase; Lipid Peroxidation; Liver Inflammation; Lung Inflammation; Manufacturer Name; Measurement; Measures; Medical; Metabolism; Methodology; Modeling; Molecular; Monitor; New Therapeutic Target; Novel; Novel Therapeutics; Organ; Orphan; Outcome; Oxidation-Reduction; Pancreas; Pathogenesis; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Phase I Clinical Trials; Physiological; Placebo Group; Plasma; Positioning Attribute; Pressure; Primary Endpoint; Process; Production; Rattus; Reperfusion Therapy; Research; Respiratory; Response; Resuscitation; Rodent; Safety; Scale Up; Serum; Sheep; Shock; Shotguns; Small Molecule; Stress; System; Technology; Testing; Tetrazoles; Therapeutic; Time; Tissues; Tnf Gene; Trauma; Trauma Patient; Vehicular Accident; Withdrawal;
