Cooperative Agreement U01FD007473

TGX-DDI (DDT-BMQ-000008) RING TRIAL: A CROSS-SITE VALIDATION STUDY OF AN IN VITRO TRANSCRIPTOMIC BIOMARKER FOR GENOTOXICITY TESTING - 1 PROJECT ABSTRACT/SUMMARY 2 GENOTOXICITY TESTING IS A CRUCIAL COMPONENT OF PRECLINICAL SAFETY EVALUATION FOR DRUGS AND 3 CHEMICALS. THE DEVELOPMENT OF BIOMARKERS THAT CAN ENHANCE EFFICIENCY AND TRANSLATIONAL 4 RELEVANCE DURING THE DRUG DEVELOPMENT PROCESS IS CRITICAL TO BOTH FDA AND NIH'S PUBLIC HEALTH 5 MISSION. WE HAVE DEVELOPED THE TGX-DDI TRANSCRIPTOMIC BIOMARKER, WHICH MEETS CRITICAL DRUG 6 DEVELOPMENT NEEDS BY PROVIDING AN EFFICIENT, REPRODUCIBLE APPROACH TO ASSESSING WHETHER A DRUG 7 CAUSES DNA DAMAGE THAT IS RELEVANT TO THE DEVELOPMENT OF CANCER IN VIVO. THE INTERPRETATION OF 8 POSITIVE IN VITRO GENOTOXICITY FINDINGS IN NEW DRUG TESTING IS A MAJOR CHALLENGE TO INDUSTRY AND 9 REGULATORY AGENCIES. THESE TESTS HAVE HIGH SENSITIVITY, BUT LOW SPECIFICITY, LEADING TO HIGH RATES OF 10 IRRELEVANT POSITIVE FINDINGS. IRRELEVANT POSITIVE RESULTS CAN TRIGGER EXPENSIVE, TIME-CONSUMING 11 FOLLOW-UP TESTS WITH UNCERTAIN OUTCOMES THAT INVOLVE ANIMAL USAGE AND CAN RESULT IN THE EXCLUSION 12 OF POTENTIALLY USEFUL DRUG CANDIDATES FROM FURTHER DEVELOPMENT. TGX-DDI IS A NOVEL, TRANSCRIPTOMIC 13 BIOMARKER MEASURING CHANGES IN THE EXPRESSION OF 64 GENES IN HUMAN CELLS CULTURE FOLLOWING 14 EXPOSURE TO TEST AGENTS RELATIVE TO SOLVENT CONTROLS. IN COMBINATION WITH A PUBLICLY ACCESSIBLE WEB 15 TOOL AVAILABLE VIA THE NATIONAL TOXICOLOGY PROGRAM, THIS APPROACH PROVIDES IMPORTANT EVIDENCE TO 16 CLASSIFY WHETHER A TESTED COMPOUND IS OR IS NOT DNA-DAMAGE INDUCING (DDI) WITH HIGH SPECIFICITY 17 FOR IN VIVO GENOTOXICITY. THE TGX-DDI BIOMARKER IS UNDER EVALUATION TO COMPLEMENT IN VITRO POSITIVE 18 CHROMOSOME DAMAGE TESTS AS PART OF THE FDA'S 21ST CENTURY CURES MANDATED DRUG DEVELOPMENT 19 TOOLS (DDT) QUALIFICATION PROCESS. IN SUPPORT OF THIS EVALUATION, THIS APPLICATION SEEKS FUNDING TO 20 EXECUTE A MULTI-SITE RING TRIAL TO EVALUATE THE REPRODUCIBILITY OF THE TGX-DDI BIOMARKER METHOD 21 UNDER COMPARABLE CONDITIONS AT MULTIPLE LABORATORIES. A TOTAL OF 17 BLINDED COMPOUNDS WILL BE 22 TESTED AT FOUR DIFFERENT LABORATORY SITES USING COMMON STANDARD OPERATING PROCEDURES, A COMMON 23 CELL LINE, AND A COMMON TRANSCRIPTOMIC PLATFORM (NANOSTRING). THE STUDY WILL BE DEEMED A 24 SUCCESSFUL DEMONSTRATION OF CROSS-LABORATORY PERFORMANCE IF EACH LABORATORY SUCCESSFULLY 25 EXECUTES THE DEFINED PROTOCOLS AND ARRIVES AT THE SAME, CORRECT CALL (DDI OR NON-DDI) FOR EACH OF 26 THE COMPOUNDS. THE RESULTS OF THIS STUDY WILL BE INCORPORATED INTO THE FINAL DATA PACKAGE TO BE 27 SUBMITTED TO THE FDA DDT QUALIFICATION PROGRAM AND WILL HOPEFULLY LEAD TO THE OFFICIAL QUALIFICATION 28 OF THE TGX-DDI BIOMARKER. ONCE QUALIFIED, THIS MARKER WILL PROVIDE CRITICAL WEIGHT OF EVIDENCE TO 29 SUPPORT THE CURRENT GENOTOXICITY TESTING BATTERY AND WILL THUS ENHANCE THE ACCURACY AND EFFICIENCY 30 OF DRUG DEVELOPMENT. THIS REPRESENTS A MAJOR STEP TOWARDS MODERNIZING OUR APPROACH TO RISK 31 ASSESSMENT BY USING NEW TOOLS AND ANALYTICAL PIPELINES LIKE THE ONES DESCRIBED HERE.