Modeling Treatment Response in Tuberculosis Early Bactericidal Activity Trials

@article{mcclean2026modeling,
  title = {{Modeling Treatment Response in Tuberculosis Early Bactericidal Activity Trials}},
  author = {Mairi C. W. McClean and Simon E. Koele and Julia Dreisbach and Susanne Mirold‐Mei and Fred Njeleka and Daniel Mapamba and Bariki Mtafya and Patrick P. J. Phillips and Veronique R. De Jager and Rodney Dawson and Kim Narunsky and Andreas H. Diacon and Elin M. Svensson and Norbert Heinrich and Francesco Paolo Casale and Michael Hoelscher},
  journal = {CPT: Pharmacometrics \& Systems Pharmacology},
  year = {2026},
  month = aug,
  doi = {10.1002/psp4.70311},
  url = {https://doi.org/10.1002/psp4.70311},
  note = {CC BY 4.0},
}

TY  - JOUR
TI  - Modeling Treatment Response in Tuberculosis Early Bactericidal Activity Trials
AU  - Mairi C. W. McClean
AU  - Simon E. Koele
AU  - Julia Dreisbach
AU  - Susanne Mirold‐Mei
AU  - Fred Njeleka
AU  - Daniel Mapamba
AU  - Bariki Mtafya
AU  - Patrick P. J. Phillips
AU  - Veronique R. De Jager
AU  - Rodney Dawson
AU  - Kim Narunsky
AU  - Andreas H. Diacon
AU  - Elin M. Svensson
AU  - Norbert Heinrich
AU  - Francesco Paolo Casale
AU  - Michael Hoelscher
PY  - 2026
DA  - 2026/08/07
JO  - CPT: Pharmacometrics & Systems Pharmacology
DO  - 10.1002/psp4.70311
UR  - https://doi.org/10.1002/psp4.70311
AB  - 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 modeling could provide insight into underlying biological processes. We generated TB‐MBLA (LifeArc) data from sputum samples from all 78 patients from the PanACEA BTZ‐043 Phase Ib/IIa trial and derived a summary measure of the joint distribution of the three TB‐MBLA, colony forming units (CFU), and time‐to‐positivity (TTP) biomarkers as the first principal component derived from a probabilistic principal component analysis (pPCA). With TB‐MBLA marker and the principal component 1 (PC1) values, 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 E max exposure–response between days 0–3 compared with CFU and TTP alone. We also successfully applied pPCA as a modeling 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. In this study, we present novel EBA data for the first‐in‐class antimycobacterial compound BTZ‐043 and contextualize the value of emerging bacteriological markers within the EBA trial framework.  Trial Registration: ClinicalTrials.gov identifier: NCT04044001
SN  - 2163-8306
ER  -