UM1AI179699

Preclinical design and clinical translation of TB regimens (PREDICTR) consortium - project summary. The long duration and multidrug nature of tuberculosis (TB) treatment regimens pose obstacles to treatment completion for patients and providers, but also challenge research efforts to develop new and improved regimens. Without a validated early biomarker able to discriminate regimens with different curative potential, the field depends heavily on preclinical models. However, TB regimen development has been slow, often hindered and misled by poor preclinical-to-clinical translation.

Animal models and pharmacometric modeling played key roles in developing groundbreaking novel regimens capable of shortening treatment durations for drug-susceptible and multidrug-resistant TB to 4 and 6 months, respectively. However, these tools are still not utilized to their full potential. Recent successes in TB drug discovery have produced additional clinical and preclinical drug candidates, which have revealed a new challenge: with many possible combinations, how to prioritize multidrug regimens to test in resource-intensive clinical trials? The most efficient “critical path” of preclinical experiments and modeling to follow to identifying and optimizing the best regimens for advancement to clinical trials remains uncertain.

The proposed project will establish a comprehensive, collaborative, multidisciplinary consortium of scientific leaders, drug developers and other stakeholders to develop and pursue a preclinical and translational research agenda to identify novel regimens with the greatest potential for clinical success in adults and children with TB. The overarching hypothesis is that integration and analysis of specific preclinical and early clinical data using validated models and tools will enable data-driven clinical trial simulations that yield quantitative predictions of phase 2 and phase 3 trial endpoints useful to identify and rank regimens with the highest probability of clinical success in patients across the age and disease spectrum of pulmonary TB.

Initial efforts will be aimed at refining and validating preclinical in vivo (BALB/C and C3HEB/FEJ mouse) and in vitro models and translational tools by leveraging the largest data warehouse on TB drugs and regimens ever assembled, with data spanning from early preclinical stages to phase 3 clinical trials, for both back translation and forward prediction approaches to validation. The overall goal is to develop a fully data- and knowledge-driven approach to evaluate, prioritize and optimize novel drug regimens for clinical trials requiring only preclinical and early clinical trial data.

In addition to endpoints based on bacterial burden and relapse (in mice), the RS ratio, a new portable biomarker of bacterial “health”, will be evaluated as a complementary pharmacodynamic (PD) biomarker to increase efficiency and predictive accuracy of preclinical studies. The expected outcomes are novel methodologies of combining preclinical and early clinical data, a defined set of critical path experiments with predictive value, and a framework for model-informed decision-making based on quantitative predictions of clinical outcomes for emerging regimens prior to initiation of phase 2/3 trials. The predictions will be used to rank order candidate regimens for advancement to clinical trials.

San Francisco Regents Of The University Of California

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

San Francisco, California 94143 United States

Single Zip Code

Consortium for Design of TB Drug Regimens (UM1 Clinical Trial Not Allowed) (RFA-AI-22-059)

Amendment Since initial award the total obligations have increased 134% from $6,160,000 to $14,399,999.