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Non\u2010culture\u2010based alternatives, like the Tuberculosis Molecular Load Bacterial Assay (TB\u2010MBLA), could represent a solution. Our objectives were to evaluate TB\u2010MBLA 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\u2010MBLA (LifeArc) data from sputum samples from all 78 patients from the PanACEA BTZ\u2010043 Phase Ib\/IIa trial and derived a summary measure of the joint distribution of the three TB\u2010MBLA, colony forming units (CFU), and time\u2010to\u2010positivity (TTP) biomarkers as the first principal component derived from a probabilistic principal component analysis (pPCA). With TB\u2010MBLA marker and the principal component 1 (PC1) values, we reevaluated the original stage IIa dose\u2013response and stages Ib\/IIa pharmacokinetics\u2014pharmacodynamics (PK\u2010PD) exposure\u2010response analyses, applying linear and non\u2010linear mixed models, respectively. For TB\u2010MBLA, we could not detect an exposure\u2010response effect in the PK\u2010PD analysis, in contrast with CFU and TTP. When combining biomarkers, we observed a significant but less pronounced\n                    <jats:italic>E<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    exposure\u2013response between days 0\u20133 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\u2010in\u2010class antimycobacterial compound BTZ\u2010043 and contextualize the value of emerging bacteriological markers within the EBA trial framework.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Trial Registration:<\/jats:bold>\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link>\n                    identifier: NCT04044001\n                  <\/jats:p>","DOI":"10.1002\/psp4.70311","type":"journal-article","created":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T03:44:47Z","timestamp":1786160687000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Modeling Treatment Response in Tuberculosis Early Bactericidal Activity Trials"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-2972-0877","authenticated-orcid":false,"given":"Mairi C. W.","family":"McClean","sequence":"first","affiliation":[{"name":"Institute of Infectious Diseases and Tropical Medicine, LMU University Hospital  Munich Germany"},{"name":"Institute of AI for Health, Helmholtz Center Munich\u2014German Research Center for Environmental Health  Neuherberg Germany"},{"name":"Institute for Medical Information Processing, Biometry, and Epidemiology (IBE), Pettenkofer School of Public Health LMU Medizin, Ludwig\u2010Maximilians\u2010Universit\u00e4t M\u00fcnchen  Munich Germany"},{"name":"Helmholtz Pioneer Campus Helmholtz Zentrum M\u00fcnchen\u2014German Research Center for Environmental Health  Neuherberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7011-667X","authenticated-orcid":false,"given":"Simon E.","family":"Koele","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Pharmacology, and Toxicology Radboud Institute for Medical Innovation, Radboud University Medical Center  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6625-9857","authenticated-orcid":false,"given":"Julia","family":"Dreisbach","sequence":"additional","affiliation":[{"name":"Institute of Infectious Diseases and Tropical Medicine, LMU University Hospital  Munich Germany"},{"name":"German Center for Infection Research (DZIF), Munich Partner Site  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Mirold\u2010Mei","sequence":"additional","affiliation":[{"name":"Institute of Infectious Diseases and Tropical Medicine, LMU University Hospital  Munich Germany"},{"name":"German Center for Infection Research (DZIF), Munich Partner Site  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8528-5038","authenticated-orcid":false,"given":"Fred","family":"Njeleka","sequence":"additional","affiliation":[{"name":"National Institute for Medical Research\u2010Mbeya Medical Research Center  Mbeya Tanzania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5642-488X","authenticated-orcid":false,"given":"Daniel","family":"Mapamba","sequence":"additional","affiliation":[{"name":"National Institute for Medical Research\u2010Mbeya Medical Research Center  Mbeya Tanzania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3772-8671","authenticated-orcid":false,"given":"Bariki","family":"Mtafya","sequence":"additional","affiliation":[{"name":"National Institute for Medical Research\u2010Mbeya Medical Research Center  Mbeya Tanzania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6336-7024","authenticated-orcid":false,"given":"Patrick P. J.","family":"Phillips","sequence":"additional","affiliation":[{"name":"UCSF Center for Tuberculosis University of California San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6389-5575","authenticated-orcid":false,"given":"Veronique R.","family":"De Jager","sequence":"additional","affiliation":[{"name":"TASK Applied Science Clinical Research Center  Cape Town South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9804-1588","authenticated-orcid":false,"given":"Rodney","family":"Dawson","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Cape Town Lung Institute  Cape Town South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7939-3710","authenticated-orcid":false,"given":"Kim","family":"Narunsky","sequence":"additional","affiliation":[{"name":"Department of 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Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469\u20100691.2011.03626.x"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1128\/jcm.01225\u201012"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl\u20102019\u2010214238"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tube.2013.12.002"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00652\u201019"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1128\/jb.182.22.6358\u20106365.2000"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd940"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20101\u20104939\u20107037\u20107_5"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3791\/60460\u2010v"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/jacamr\/dlaf127"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmi.2024.06.016"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lanmic.2024.07.015"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkaf076"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201410\u20101801OC"},{"key":"e_1_2_10_16_1","unstructured":"\u201cC\u2010Path \u201d[Internet] [cited 2026 Jul 28] TB PACTS https:\/\/c\u2010path.org\/tools\u2010platforms\/tb\u2010pacts\/."},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1101\/2024.05.06.24306879"},{"key":"e_1_2_10_18_1","unstructured":"LifeArc \u201cTB\u2010MBLA User Manual \u201d[lab manual online] Edinburgh (Scotland). LifeArc;2024 https:\/\/www.lifearc.org\/wp\u2010content\/uploads\/2024\/10\/TB\u2010MBLA\u2010User\u2010Manual.pdf."},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/1467\u20109868.00196"},{"key":"e_1_2_10_20_1","unstructured":"A.Tran \u201callentran\/pca\u2010magic \u201d(2025) accessed January 16 2026 https:\/\/github.com\/allentran\/pca\u2010magic."},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201700069"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.12793\/tcp.2017.25.4.157"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.104.5.737"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.69"},{"key":"e_1_2_10_25_1","unstructured":"K.Stinson \u201cUse of TB\u2010MBLA in Clinical Trials \u201dConference presentation presented at: The Union World Conference on Lung Health Copenhagen November 20 2025."},{"key":"e_1_2_10_26_1","doi-asserted-by":"crossref","unstructured":"S. T.Tabor A. D.Friesen M. J.Reichlen et\u00a0al. \u201cMind the Gap: Understanding Discordance Between Culture\u2010 and a Non\u2010Culture\u2010Based Measure of Bacterial Burden in Murine Tuberculosis Treatment Models \u201dpreprint bioRxiv December 18 2025 2025.12.18.695164 https:\/\/doi.org\/10.64898\/2025.12.18.695164.","DOI":"10.64898\/2025.12.18.695164"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010025\u201056146\u20109"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2023.106775"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1128\/aac.02310\u201021"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dku415"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010024\u201074318\u20103"}],"container-title":["CPT: Pharmacometrics &amp; Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.70311","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/psp4.70311","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.70311","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T04:11:33Z","timestamp":1787199093000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.70311"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8]]},"references-count":30,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1002\/psp4.70311"],"URL":"https:\/\/doi.org\/10.1002\/psp4.70311","archive":["Portico"],"relation":{},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"value":"2163-8306","type":"print"},{"value":"2163-8306","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8]]},"assertion":[{"value":"2026-01-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70311"}}