Project Grant R01FD007839

DEVELOPMENT OF INTRAVENOUS VARESPLADIB, A PHOSPHOLIPASE A2 INHIBITOR, FOR THE TREATMENT OF SNAKEBITE ENVENOMING - 1 PROJECT SUMMARY 2 3 IN EXPERIMENTAL STUDIES, DIRECT INHIBITION OF THE SNAKE VENOM TOXIN SECRETORY PHOSPHOLIPASE A2 (SPLA2) RESULTS 4 IN SIGNIFICANT IMPROVEMENTS IN SPLA2-MEDIATED TOXICITIES, BUT THE BENEFITS OF SPLA2 INHIBITION IN HUMANS BITTEN 5 BY SNAKES REMAINS UNKNOWN. OPHIREX IS A PUBLIC BENEFIT CORPORATION WHOSE MISSION IS TO REDUCE DEATH AND 6 DISABILITY FROM SNAKEBITE ENVENOMING (SBE) THROUGH THE DEVELOPMENT OF VARESPLADIB, A HIGHLY POTENT INHIBITOR OF 7 SNAKE VENOM SPLA2. SNAKE VENOM SPLA2 AND SPLA2-LIKE PROTEINS ARE FOUND IN 95% OF MEDICALLY IMPORTANT 8 VENOMOUS SNAKES WORLDWIDE AND THOUGHT TO BE FOUND IN ALL VENOMOUS SNAKES NATIVE TO THE UNITED STATES. THESE 9 PROTEINS ARE KEY CONTRIBUTORS TO NEUROMUSCULAR PARALYSIS, COAGULOPATHY, CARDIOTOXICITY, RENAL TOXICITY, AND SKELETAL 10 MUSCLE INJURY. ANTIBODY THERAPIES ("ANTIVENOMS") HAVE LIMITED EFFICACY AGAINST SPLA2 BECAUSE OF THE GENERALLY 11 LOW ANTIGENICITY OF SPLA2 AND BECAUSE OF PHYSIOLOGIC BARRIERS TO THE ENTRY OF ANTIBODIES INTO IMPORTANT 12 COMPARTMENTS (E.G., MUSCLE, NEUROMOTOR JUNCTIONS). VARESPLADIB HAS BEEN FOUND TO RESCUE MICE AND PIGS FROM 13 LETHAL ENVENOMING FROM A VARIETY OF SPECIES OF SNAKE, EVEN WHEN GIVEN AT A POINT IN TIME WHEN ANTIVENOM IS NO 14 LONGER ABLE TO RESCUE THE ANIMALS. VARESPLADIB ALSO ACTS SYNERGISTICALLY WITH ANTIVENOM: IN PRECLINICAL STUDIES, 15 THE COMBINATION OF VARESPLADIB AND ANTIVENOM RESULTS IN GREATER INHIBITION OF SPLA2 AND GREATER PROTECTIVE 16 BENEFITS FROM A RANGE OF SPLA2-MEDIATED TOXICITIES THAN WOULD BE EXPECTED FROM SUMMING THE BENEFITS OF THE 17 TWO THERAPIES ON THEIR OWN. THE OVERARCHING GOAL OF THIS PROJECT IS TO CONDUCT RESEARCH TO SUPPORT REGULATORY 18 APPROVAL OF AN INTRAVENOUS FORMULATION OF VARESPLADIB FOR SBE. THIS WILL BE ACHIEVED THROUGH THE COMPLETION OF 19 A PHASE IIB DOUBLE-BLIND RANDOMIZED CONTROLLED TRIAL OF VARESPLADIB IN 110 PATIENTS BITTEN BY VENOMOUS SNAKES 20 AND RECEIVING CARE AT SITES IN THE U.S. AND INDIA. ALL PATIENTS WILL RECEIVE STANDARD OF CARE TREATMENT, INCLUDING 21 ANTIVENOM. PATIENTS WILL RECEIVE A CONTINUOUS INFUSION OF VARESPLADIB OR NORMAL SALINE FOR AT LEAST 6 HOURS. AFTER 22 6 HOURS OF WHENEVER THEY ARE CLINICALLY STABLE AND ABLE TO TOLERATE ORAL MEDICATION, PATIENTS WILL BE SWITCHED TO 23 ORAL TREATMENT WITH VARESPLADIB-METHYL OR PLACEBO. THE TOTAL DURATION OF TREATMENT WILL BE 7 DAYS. THE PRIMARY 24 OUTCOME WILL BE THE CHANGE FROM BASELINE TO THE AVERAGE AT 3 AND 6 HOURS OF THE SNAKEBITE SEVERITY SCORE, WHICH 25 ASSESSES KEY SNAKE VENOM TOXICITIES OF THE HEMATOLOGIC, NEUROLOGIC, RENAL, CARDIOVASCULAR, AND PULMONARY 26 SYSTEMS. THE PROPOSED WORK WILL ALSO UTILIZE TWO INNOVATIVE APPROACHES TO EXPANDING THE FINDINGS FROM THE TRIAL 27 TO OTHER IMPORTANT POPULATIONS: (1) PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELING WILL BE USED TO IDENTIFY AN 28 APPROPRIATE DOSING STRATEGY IN PEDIATRIC PATIENTS AND TO ENHANCE AVAILABLE PEDIATRIC SAFETY AND EFFICACY DATA; AND 29 (2) A SIMULATION MODEL WILL BE USED TO ESTIMATE THE CLINICAL EFFECT OF VARESPLADIB IN PATIENTS BITTEN BY SNAKE SPECIES 30 NOT WELL-REPRESENTED IN THE TRIAL. THE RESULTS OF THE PROPOSED WORK WILL BE USED TO SUPPORT REGULATORY APPROVAL 31 WITH THE POTENTIAL TO TRANSFORM THE PARADIGM FOR SNAKEBITE TREATMENT AND TO SAVE THOUSANDS OF LIVES EACH YEAR.