Modelling treatment response in tuberculosis early bactericidal activity trials

Culture-based monitoring of bacterial load is slow and susceptible to missing data, contributing to the length and cost of TB clinical trials. Non-culture-based alternatives, like the Tuberculosis Molecular Load Bacterial Assay (TB-MBLA), could represent a solution. Our objectives were to evaluate TB-MBLA as a biomarker in early bactericidal activity (EBA) studies and explore whether combining biomarkers with joint modelling could provide insight into underlying biological processes and reduce data loss. We generated TB-MBLA (LifeArc(R)) data from sputum samples from all 78 patients from the PanACEA BTZ-043 Phase Ib/IIa trial. In addition, we defined a joint biomarker as the first principal component derived from a probabilistic principal component analysis (pPCA) integrating TB-MBLA, colony forming units (CFU), and time-to-positivity (TTP) data. With TB-MBLA alone and the principal component 1 (PC1) marker we reevaluated the original stage IIa dose-response and stages Ib/IIa pharmacokinetics - pharmacodynamics (PK-PD) exposure-response analyses, applying linear and non-linear mixed models, respectively. For TB-MBLA, we could not detect an exposure-response effect in the PK-PD analysis, in contrast with CFU and TTP. When combining biomarkers, we observed a significant but less pronounced Emax exposure-response between days 0-3 compared with CFU and TTP alone. We also successfully applied pPCA as a modelling framework and show evidence that combining CFU and TTP in a joint latent component can improve detection of treatment effects compared with either biomarker alone. STUDY HIGHLIGHTSO_ST_ABSWhat is the current knowledge on the topic?C_ST_ABSBTZ-043 is a first-in-class antimycobacterial compound with promising applications in drug-sensitive pulmonary tuberculosis. TB EBA trials are typically conducted using sputum culture assays for dose-exposure-response modelling, but the technical challenges of these assays limit their effectiveness. What question did this study address?How does the novel RT-qPCR assay TB-MBLA perform as a dose-exposure response marker for novel antitubercular compound BTZ-043 and what are the effects of joint modelling approaches in EBA modelling tasks? What does this study add to our knowledge?We did not observe a significant exposure response for BTZ-043 in TB-MBLA over the 14-day treatment window. Joint modelling with pPCA can overcome the issues of missing and contaminated data that are canonical of culture data from TB treatment monitoring cohorts. How might this change drug discovery, development, and/or therapeutics?Designing EBA trials should consider the drug-bacterial subpopulation axis of the specific study drug to maximise efficiency. Latent variable modelling techniques can be an effective and efficient framework for modelling Mycobacterial tuberculosis load in EBA trials.