IMPACT-TB*: A Phase II Trial Assessing the Capacity of Low Dose Imatinib to Induce Myelopoiesis and Enhance Host Anti-Microbial Immunity Against Tuberculosis. *Imatinib Mesylate per Oral As a Clinical Therapeutic for TB

Background: With existing anti-tubercular therapies, treatment success rates for multi- and extensively-drug resistant tuberculosis (MDR-TB, XDR-TB) are dismal, highlighting the urgent need for new drugs. Ratios of myeloid to lymphoid cells are important predictors of TB disease susceptibility and vaccine efficacy. Imatinib mesylate (Gleevec), a cancer drug used in humans for chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GISTs), is a potential "host- directed therapeutic (HDT)" for drug resistant TB infections and HIV/TB co-infections. Imatinib inhibits c-Abl tyrosine kinase (TK), which is dysregulated in CML, as well as related TKs (e.g. c-Kit). Imatinib facilitates clearance of Mycobacterium tuberculosis (Mtb), by disrupting the cellular mechanisms that Mtb uses for entry and survival in host cells. At doses 10-fold lower than those used for CML, imatinib also stimulates "emergency hematopoiesis," a host immune response to infection that mobilizes myeloid cell differentiation in the bone marrow and alters ratios of myeloid to lymphoid cells in the periphery towards protective levels, an effect suppressed by Mtb. Imatinib acts synergistically with antibiotics and is effective against antibiotic-resistant mycobacteria, and may be less likely to engender resistance compared to antibiotics. Preclinical data at low doses indicate efficacy of imatinib in a non-human primate (NHP) model of infection with TB or, alternatively, TB/SIV, which mimics poorly controlled TB or HIV/TB in humans.

Study Design, Endpoints, and statistical design: We describe the design of two NIH-sponsored Phase II clinical trials in humans (NCT03891901).

The first trial will comprise testing of 4 low doses of imatinib with or without antibiotics in 72 normal individuals in the United States. We will determine safety, immunological responses, and drug-drug interactions with standard of care antibiotics. The primary endpoints are to (i) identify the two best doses that induce myelopoiesis in humans, (ii) maximize bactericidal activity by immune cells ex vivo, and (iii) maximize safety. The trial is powered to detect a 2-fold increase in myelopoiesis across all imatinib doses relative to untreated individuals.

The second trial will assess the safety and microbiologic efficacy of two doses of imatinib administered over 3 months in conjunction with optimized background antibiotic regimens versus the optimized background regimen alone. The trial will include 180 individuals with TB or HIV/TB in South Africa (60 per arm). The primary endpoints are (i) the time to sputum culture conversion, (ii) lung function by PET-CT and spirometry, and (iii) immunological parameters associated with myelopoieisis. Secondary endpoints include transcriptomics, proteomics, and measures of pathogen-specific immune responses. The trial is powered to detect a 2-fold increase in myelopoiesis across all imatinib doses relative to untreated individuals. The trial is statistically powered to distinguish at either dose an improvement over baseline treatment in time to sputum conversion or lung function or both.

Major Inclusion/Exclusion Criteria: Phase II dosing trial: Normal volunteers, age 18 - 55 years. Phase II efficacy trial: Active antibiotic-sensitive tuberculosis with or without HIV. Pregnant women are excluded from both studies.

Trial Status: The dosing trial has FDA and NIAID approval to begin and is currently undergoing registration with DAIDS prior to starting enrollment.

Overall Goal: Data from these trials will provide a paradigm with which to further evaluate imatinib or other immunomodulatory HDTs as therapeutics for TB infection and HIV/TB co-infection. If successful, imatinib may shorten the time of treatment and limit development of antibiotic resistance, and may be useful against antibiotic resistant strains. This project is supported a grant from NIH/NIAID.