DESCRIPTION (provided by applicant): The current recommended 6-month treatment regimen for active tuberculosis (TB) is more than 40 years old and suffers from issues with drug toxicity and high rates of patient non-adherence, which combined have contributed to the emergence of drug resistant strains. For the first time in decades, the TB drug development pipeline is filled with several promising new agents that will soon be ready for phase 2 and phase 3 trials. However, testing the efficacy of these agents in clinical trials is a significant challenge because the conventional sputum-based, growth-based, microbiologic trial endpoints have notable technical and logistical weaknesses. For this proposal, entitled TB Surrogate Markers for Assessing Response to Treatment (TB SMART Study), our objective is to develop a blood-based, quantitative, host and pathogen-specific biomarker assay using a proven, high sensitivity, multiplexed electrochemiluminescence (ECL) platform that can, in combination with clinical data, supplant 2-month sputum culture, the current dichotomous Phase 2 trial endpoint. A non-sputum, non-growth based biomarker assay applied early in the course of a trial that could replace microbiologic intermediate endpoints, while retaining or improving upon their ability to predict outcomes, could transform the pace and scope of TB drug development, and of global TB control. It may additionally have utility for monitoring treatment of paucibacillary disease as is often seen in children, extra-pulmonary TB, and HIV/TB. To achieve this goal, we have assembled an investigative team of academics with expertise in TB drug development; industry partners with expertise in both unbiased and directed approaches to biomarker discovery; exosome scientists; and statisticians with expertise in bioinformatic approaches to prediction and surrogate marker identification. We will take advantage of specimens linked to clinical, radiographic, microbiologic, and PK/PD data from well-characterized patients with culture-confirmed pulmonary TB enrolled in four studies: three CDC-funded, TB Trials Consortium randomized, clinical trials, and one FDA-funded repository linked to Phase 3 TB trials. We will use available clinical trial data and sample sets to: 1) Identify blood-based, host and TB-specific biomarkers of treatment response using unbiased, targeted and exosome-enriched approaches 2) develop and qualify multi-parameter classifiers for predicting recognized microbiologic measures of bactericidal and sterilizing activity, using the host and pathogen biomarkers identified, and 3) develop, qualify and conduct validation studies of a finalist biomarker panel built on a multiplexed ECL platform. Upon completion of comprehensive qualification and validation studies proposed, we will be ready to release the multiplexed, ECL biomarker panel assay as "Qualified Kits" to be used and evaluated in prospective Phase 2 and 3 trials.

PUBLIC HEALTH RELEVANCE: For the first time in nearly half a century, a number of novel and newer agents for tuberculosis (TB) treatment are in development that may lead to shorter, safer, and more effective regimens. The objective of this R01 application is to develop a blood-based, highly sensitive and pathogen-specific, biomarker assay that can be used to monitor treatment response in TB patients enrolled in clinical trials assessing these new regimens. Our intention is for the assay to be used as a tool to rapidly assess efficacy of new drugs and new regimens, and thus significantly speed up drug development for TB.