Project Grant R44HL135965

ERYTHROMER: NANOSCALE BIOSYNTHETIC RED CELL SUBSTITUTE - RESEARCH SUMMARY/ABSTRACT ERYTHROMER (EM) IS A NOVEL BIOSYNTHETIC BLOOD SUBSTITUTE DEVELOPED TO ADDRESS THE CRITICALLY UNMET NEED FOR EMERGENCY TRANSFUSION IN SITUATIONS WHERE THE USE OF BANKED RED BLOOD CELLS (RBCS) ARE EITHER NOT AVAILABLE OR UNDESIRABLE. EM IS A SELF-ASSEMBLED LIPID-OLIGOMERIC HYBRID NANOPARTICLE WITH A HIGH PER PARTICLE PAYLOAD OF HEMOGLOBIN (HB) AND THE ALLOSTERIC MODIFIER, RSR13. EM IS SPECIFICALLY DESIGNED TO RECTIFY FAILURES OF PREVIOUS HEMOGLOBIN-BASED OXYGEN CARRIERS, WHICH DO NOT PRESERVE RBC PHYSIOLOGY. THE BIO-INSPIRED EM DESIGN SURMOUNTS PREVIOUS OBSTACLES BY EMULATING RBC FEATURES: LONG TERM STABILITY, PRECISE DYNAMICALLY-RESPONSIVE ALLOSTERIC EFFECTOR CONTROL OF HB OXYGEN AFFINITY, CONTROL OF HB INTERACTION WITH NITRIC OXIDE (NO), PREVENTING VASOSPASM, AND MITIGATION OF HEMOGLOBIN OXIDATION BY CONTAINMENT IN THE VASCULAR COMPARTMENT. EM IS DESIGNED FOR STERILE LYOPHILIZATION ENABLING EXTENDED SHELF LIFE AT AMBIENT CONDITIONS AND OFFERS COST-EFFECTIVE PRODUCTION AT SCALE. KALOCYTE HAS DEVELOPED A PRAGMATIC YET ROBUST STEP-WISE GOAL ORIENTED DEVELOPMENT PLAN FOR COMMERCIALIZATION INCLUDING METICULOUS EVALUATION OF PRECLINICAL SAFETY TO SUPPORT FIH DOSING. A SYSTEMATIC AND RIGOROUS IN VITRO, EX VIVO AND ANIMAL MODEL BASED PRE-CLINICAL PROOF-OF-CONCEPT STRATEGY PROVIDES STRONG EVIDENCE SUPPORTING THE PREMISE FOR AND FEASIBILITY OF THIS PROPOSAL. FURTHER, OUR COMMITMENT TO CHARACTERIZE A COMPREHENSIVE NON-GLP PHARMACOKINETIC AND EXPLORATORY TOXICOLOGY AS WELL AS AN FDA VETTED GLP TOXICOLOGY PLAN FOR EM IS ELUCIDATED. TO MEET THESE MILESTONES IN A TIMELY FASHION, NON-GLP DOSE DEPENDENT PHARMACOKINETIC STUDIES OF EM THAT PROBE TISSUE DISTRIBUTION, METABOLISM, AND ELIMINATION AND EXPLORATORY TOXICOLOGY STUDIES WILL BE CONDUCTED. SUCCESSFUL COMPLETION OF THESE EXPERIMENTAL STUDIES WILL INFORM ON PHARMACOKINETIC BEHAVIOR, POTENTIAL DOSE DEPENDENT SAFETY SIGNALS AND PRODUCT QUANTITY NEEDS, MOVING FORWARD INTO GLP TOXICOLOGY STUDIES AND EVENTUALLY FIH DOSING. THE DESCRIBED, COMPREHENSIVE DOSE DEPENDENT TOXICOLOGY STUDIES ARE TAILORED TO MEET FDA EXPECTATIONS THAT ALLOWS FOR DOSING OF EM IN A PHASE 1 CLINICAL TRIAL. THIS PROCESS REQUIRES, ESCALATING SINGLE DOSE TOXICOLOGY STUDY IN RABBITS EXPANDED TO 14 DAYS FOR POST DOSE RECOVERY. PARALLEL STUDIES INVESTIGATING CARDIAC ELECTROPHYSIOLOGY, PULMONARY HEMODYNAMICS, AND SYSTEMIC HEMODYNAMICS IN A DOG SAFETY PHARMACOLOGY STUDY WITH AN ADDED TOXICOKINETIC ARM. COMPLETION OF THESE IND- ENABLING STUDIES PROVIDES NECESSARY PRE-CLINICAL ANIMAL DATA QUALIFYING KALOCYTE TO SUBMIT AN IND PACKAGE FOR EM. EM HAS THE CAPABILITY TO DRAMATICALLY TRANSFORM CARE IN SITUATIONS WHERE THE ADVERSE EFFECTS OF STORED RBCS EXCEED BENEFIT AND MAY ENABLE NOVEL EFFICACIES. HOWEVER, THE MOST COMPELLING USE WILL BE IN SETTINGS WHERE STORED RBCS ARE UNAVAILABLE OR UNDESIRABLE. 1