Isabella Van Der Feltz 6, Erlandy Basson 1,2, Norbert Heinrich 1,2,3, Brian H. Aldana 5, Catarina Cova-Miserok 1,2, Lilian Tina Minja 7, Fairoez Ryklief 8, Kidola Jeremiah 9, Louis Botha 10, Francesca Saluzzo 11, Wandini Lutchmun 1,2, Derek J. Sloan 12,13, Jodie A. Schildkraut 13, Timothy D. McHugh 14, Leticia Wildner 14, Patrick P.J. Phillips 5, Elin M. Svensson 6,15, Julia Dreisbach 1,2, Michael Hoelscher 1,2,3,4
1 Institute of Infectious Diseases and Tropical Medicine, LMU University Hospital, LMU Munich (Munich, Germany), 2 German Center for Infection Research (DZIF), Munich Partner Site (Munich, Germany), 3 Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology, Infection and Pandemic Research (Munich, Germany), 4 Unit Global Health, Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU) (Neuherberg, Germany), 5 UCSF Center for Tuberculosis, University of California San Francisco (San Francisco, United States ), 6 Department of Pharmacy, Pharmacology and Toxicology, Radboud University Medical Center (Nijmegen, The Netherlands), 7 NIMR National Institute for Medical Research (NIMR) Mbeya (Mbeya, Tanzania ), 8 TASK Brooklyn (Cape Town, South Africa ), 9 NIMR National Institute for Medical Research (NIMR) Mwanza (Mwanza, Tanzania), 10 TASK Eden (George, South Africa ), 11 Vita Salute San Raffaele University (Milan, Italy), 12 University of St Andrews (St Andrews, United Kingdom), 13 Department of Pulmonary Diseases, Radboud University Medical Center (Nijmegen, The Netherlands), 14 UCL Centre for Clinical Microbiology, University College London (London, United Kingdom), 15 Department of Pharmacy, Uppsala University (Uppsala , Sweden)
Objectives
BTZ-043, a drug candidate currently under investigation for treatment of tuberculosis (TB), inhibits cell wall synthesis of mycobacteria by blocking the enzyme DprE1 [1]. BTZ-043 is safe and well-tolerated when administered for 14 days [2]. An exposure-response was identified for the first two days on treatment [3].The DECISION study evaluated safety, tolerability, BTZ-043 pharmacokinetics (PK) and pharmacodynamics (PD) in participants with pulmonary TB, with primary objective to describe BTZ-043 PK using a population model. The primary efficacy objective was to establish an exposure-response model (PD) for BTZ-043, with response measured as the decline in bacterial load over time.
Methods
DECISION was an open-label randomized, controlled dose-ranging multi-center phase IIb trial in 92 adult participants with newly diagnosed, drug-sensitive pulmonary TB from four sites in Tanzania and South Africa. These participants were randomized into one of four arms and received BTZ-043 in doses of 0mg (control), 500mg, 1000mg or 1500mg once daily in combination with bedaquiline and delamanid for 16 weeks. Participants in the control arm received moxifloxacin instead of BTZ-043. An adequate adherence population was defined as not having missed more than 14 missed doses during the experimental phase of treatment, and based on this criterium 83 participants were included in the analysis.
Participants underwent intensive PK sampling on day 28 and sparse sampling on day 56 of the study. Intensive sampling timepoints were 0 hrs (predose), 15 min, 30 min, and 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0 hrs postdose (pre-dose the following day). Sparse sampling timepoints were 0, 1.0, 2.0, 4.0 and 6.0 hrs. Plasma concentration of BTZ-043total, BTZ-043 and metabolite M1 were determined by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) combination assay.
Duplicate sputum samples were collected weekly from treatment initiation until week 16. PD response was assessed by serial measures of bacterial load in sputum samples, quantified by time to positivity (TTP) in Mycobacterial Growth Incubator Tubes (MGIT). A population PK model of BTZ-043 and its main metabolites M1 and M2 was developed in NONMEM, starting from an available model [3]. Subsequently, an exposure-response model was developed in NONMEM, using the log10 transformed TTP data and the individual exposure metrics from the PK model. Bilinear and linear models were explored. An upper limit of quantification of 25 days was used [4, 5].
Results
Drug concentrations were analyzed in 1209 samples from 68 participants. Percentages of concentrations below the limit of quantification (BLOQ) were 5.29% for BTZ-043total, 11.1% for BTZ-043 and 1.07% for M1. M2 concentrations were calculated by subtracting BTZ-043 from BTZ-043total concentrations. The population PK model was developed based on 1075 BTZ-043, 1196 M1 and 795 M2 concentrations. BLOQ concentrations were ignored.
BTZ-043, M1 and M2 PK were well-described by the available PK model. The final adapted model included allometric scaling based on weight and effect of BTZ-043 dose on bioavailability, which was 28% (95% confidence interval 13% – 46%) higher for the 500mg dose compared to the 1000mg and 1500mg doses. With this model, BTZ-043total and BTZ-043 AUC0-24h and Cmax were derived for use in the exposure-response analysis.The efficacy data consisted of 2986 TTP observations (1227 quantitative) from 83 participants. DECISION TTP data was well described by a linear model (one slope) with a scaling effect on baseline representing difference before and after start of treatment. The estimated effect of BTZ-043total AUC0-24h was a 39.6% steeper slope for the median AUC0-24h of 44100 ng/mL*h compared to no BTZ-043, but the 95% confidence interval was wide (5.05% –103%). The 1500mg dose had a median BTZ-043total AUC0-24h of 72400 ng/mL*h, which was associated with a 65.1% steeper slope compared to no BTZ-043. The model also included an effect of X-ray AI severity score, which was negative on TTP slope, indicating that individuals with higher pulmonary lung involvement have a slower decrease in bacterial load during treatment.
Conclusions
In conclusion, the results from the PKPD modelling indicates that BTZ-043 adds efficacy on top of a backbone-regimen of bedaquiline and delamanid in persons with pulmonary TB. As no maximal effect was observed, the highest BTZ-043 dose of 1500mg is expected to be the most effective.
References:
References
1. Kloss F, Krchnak V, Krchnakova A, Schieferdecker S, Dreisbach J, Krone V, et al. In Vivo Dearomatization of the Potent Antituberculosis Agent BTZ043 via Meisenheimer Complex Formation. Angew Chem Int Ed Engl. 2017;56(8):2187-91. https://doi.org/10.1002/anie.201609737.
2. Heinrich N, de Jager V, Dreisbach J, Gross-Demel P, Schultz S, Gerbach S, et al. Safety, bactericidal activity, and pharmacokinetics of the antituberculosis drug candidate BTZ-043 in South Africa (PanACEA-BTZ-043–02): an open-label, dose-expansion, randomised, controlled, phase 1b/2a trial. The Lancet Microbe. 2025;6(2):. https://doi.org/10.1016/j.lanmic.2024.07.015.
3. Koele SE, Heinrich N, De Jager VR, Dreisbach J, Phillips PPJ, Gross-Demel P, et al. Population pharmacokinetics and exposure-response relationship of the antituberculosis drug BTZ-043. J Antimicrob Chemother. 2025;80(5):1315-23. https://doi.org/10.1093/jac/dkaf076.
4. Dufault SM, Davies GR, Svensson EM, Sloan DJ, McCallum AD, Patel A, et al. Analysis of time-to-positivity data in tuberculosis treatment studies: Identifying a new limit of quantification. medRxiv. 2024https://doi.org/10.1101/2024.05.06.24306879.
5. Minja LT, van der Feltz I, Manyama C, Mpagama S, Mhimbira F, Noreña I, et al. Delpazolid in combination with bedaquiline, delamanid, and moxifloxacin for pulmonary tuberculosis (PanACEA-DECODE-01): a prospective, randomised, open-label, phase 2b, dose-finding trial. Lancet Infect Dis. 2025;25(11):1219-29. https://doi.org/10.1016/s1473-3099(25)00289-0.
Reference: PAGE 34 (2026) Abstr 12222 [www.page-meeting.org/?abstract=12222]
Poster: Drug/Disease Modelling - Infection