RADIKAL THERAPEUTICS, INC. — Department of Health and Human Services SBIR Phase II: 300

Description

DESCRIPTION provided by applicant Radikal Therapeutics RTX has invented a novel first in class bifunctional nitric oxide NO donor and redox catalyst R to treat septic shoc In rodent and ovine models of endotoxemia and gram negative bacillary septic shock therapeutic resuscitation with R improves outcome across clinically relevant endpoints including hemodynamics oxygenation and end organ injury In an LD murine model of endotoxemia post LPS administration of R or R dose dependently blocked renal lung and hepatic injury inhibited histologic damage in liver kidney lung and gut by and assured survival In an ovine model of Pseudomonal septic shock R resuscitation restored hemodynamics and oxygenation The proposed scope of work will construct a PD profile in a clinically relevant septic shock model design and implement methods to release and track the active pharmaceutical ingredient and develop bioanalytical methods of R and its metabolites Aim Establish the pharmacodynamic PD profile of R in an ovine model of sepsis RTX will carry out a placebo controlled randomized study wherein septic shock is produced in an LD model in mechanically ventilated male Merino sheep administered an inoculum of Pseudomonas aeruginosa via an IV route We will carry out studies in order to establish the dose response time window and safety of R in the septic sheep Task R and mg kg IV q h IV will be compared to vehicle control wherein the initial dose is delivered h post onset of bacteremia in order to establish the lowes dose providing optimal outcome andquot LDPOOandquot Plasma levels of R will be measured q h to relate drug concentration to efficacy Task We will determine the duration of the therapeutic time window by initiating R therapy or h at the LDPOO dose after the onset of bacteremia Hemodynamic oxygenation and ventilatory parameters will be assessed q h Serum and tissue will be examined h post onset of bacteremia for determination of response to R Aim Synthesize R Develop analytical methods for release and stability Define impurities and degradants and thereby define optimal storage conditions and dosing formulation R API material will be qualified prior to use in the ovine studies in order to assure identity and purity Analytical methods will be developed following ICH guidelines for this purpose and to establish storage conditions and stability of the R API and dosing solutions Aim Develop a bioanalytical methodology to quantitate R and its metabolites in plasma RTX will construct a pharmacodynamic profile relating plasma concentrations of R and its metabolites to pharmacologic activity A robust bioanalytical LC MS MS approach will be developed with an LOQ logs less than existing methods allowing for identification and quantitation of plasma R and its major metabolites at the low ng mL level We will qualify this approach for linearity precision and accuracy and define the conditions of plasma preparation and storage that optimize reliability of this methodology PUBLIC HEALTH RELEVANCE We are developing a novel drug intended as a therapeutic agent in critically ill patients with a diagnosis of septic shock We will test this agent in a clinically relevant large animal model of sepsis to confirm its optimal quantity and timing and carry out manufacturing and bioanalytical studies required for an IND application to the FDA to support clinical trials