TY  - JOUR
AB  - BACKGROUND: The broad use of bedaquiline and pretomanid as the mainstay of new regimens to combat tuberculosis is a risk due to increasing bedaquiline resistance. We aimed to assess the safety, bactericidal activity, and pharmacokinetics of BTZ-043, a first-in-class DprE1 inhibitor with strong bactericidal activity in murine models. METHODS: This open-label, dose-expansion, randomised, controlled, phase 1b/2a trial was conducted in two specialised tuberculosis sites in Cape Town, South Africa. Adults aged 18-64 years with newly diagnosed pulmonary tuberculosis sensitive to rifampicin and isoniazid, who weighed at least 40 kg, had a positive sputum smear graded at least 1+, were HIV negative, and had no history of hypertension or other substantial comorbidities were admitted to hospital. In stage 1 (multiple-ascending dose phase 1b with an adaptive continual reassessment method), the starting dose of BTZ-043 was 250 mg, with planned dose increments of 250 mg up to 2000 mg, and cohorts of three participants were enrolled sequentially. In stage 2 (phase 2a dose-expansion stage), participants were randomly assigned (3:3:3:2) to receive one of three doses of oral BTZ-043 (decided after stage 1) or standard of care (isoniazid, rifampicin, pyrazinamide, and ethambutol) using sealed opaque envelopes. The BTZ-043 groups also received oral dolutegravir (a third of participants) or a probe drug cocktail (caffeine [probe for CYP1A2], tolbutamide [CYP2C9], dextromethorphan [CYP2D6], midazolam [CYP3A4], and digoxin [P-glycoprotein]; two-thirds of participants). Study staff and participants were not masked, but laboratory staff were masked to treatment assignment. The primary outcome was to assess the safety and tolerability of BTZ-43 over 14 days of dosing by evaluation of adverse events in the safety analysis population. Secondary outcomes were bactericidal activity, measured by time to positivity (TTP) and colony-forming unit (CFU) count; pharmacokinetics (stage 2; including the food effect on BTZ-043); and drug-drug interactions with CYP450 enzymes, P-glycoprotein, and dolutegravir. This study is registered with ClinicalTrials.gov, NCT04044001 (completed). FINDINGS: In stage 1, 61 patients were assessed for eligibility and 24 were enrolled into seven dose cohorts between Nov 13, 2019, and Aug 13, 2020. Dose escalations were performed safely up to 1750 mg of BTZ-043 with three participants per dose cohort (and two dose cohorts for the highest dose). In stage 2, 151 patients were assessed for eligibility and 54 were enrolled and randomly assigned between Feb 2, 2021, and Feb 9, 2022, to receive 250, 500, and 1000 mg of BTZ-043 or standard of care. 66 (85%) of 78 participants were male and 12 (15%) were female. The most frequently observed adverse events were nausea (12 [8%] of 154), headache (11 [7%]), dizziness (11 [7%]), and vomiting (eight [5%]). Most participants had adverse events of mild (46 [60%] of 77 participants) or moderate (22 [29%]) severity. Transient increases in alanine aminotransferase were observed in both stages, which declined again despite continued dosing and were classified as signs of adaptation of hepatic metabolism rather than hepatotoxicity. The worsening of pre-existing anaemia and QTcF interval prolongation in one individual each were rated as possibly related to the study drug. One patient died before the first scheduled dose of BTZ-043 500 mg due to a pulmonary embolism. In stage 1, bactericidal activity measured as CFU counts on solid media was highest at doses 750-1500 mg; in stage 2, all doses of BTZ-043 showed 14-day bactericidal activity, highest at 1000 mg on solid media (log10 CFU/mL per day -0·115 [95% CI -0·162 to -0·069]) and TTP estimates were highest at 500 mg in liquid media (log10 h per day 0·015 [0·010 to 0·019]). BTZ-043 pharmacokinetics showed increased exposure with high-fat food versus fasting (area under the curve [AUC]0-last geometric mean ratio 4·13 [90% CI 1·65 to 10·30] for BTZ-043; 2·99 [1·39 to 6·41] for BTZ-043total [BTZ-043 plus metabolite 2]; and 1·25 [0·66 to 2·39] for metabolite 1). When taken with a standard breakfast, BTZ-043total AUC showed a dose-proportional increase up to 33 200 ng/mL × h (range 12 500 to 48 200) at 1000 mg. The maximum concentration (Cmax) increased to 5060 ng/mL (2450 to 8020); and median half-life was 3·72 h (2·45 to 6·60). Probe drug evaluations showed bioequivalence (ie, 90% CI of the AUC0-infinity geometric mean ratio from administration to day 14 entirely within the range of 80 to 125%) for caffeine (100·0% [90% CI 86·3 to 115·9]), digoxin (113·4% [105·9 to 121·5]), and dolutegravir (106·1% [91·5 to 122·9]). Dextromethorphan (116·2% [104·6 to 129·1]), tolbutamide (252·7% [230·7 to 276·9]), and midazolam (77·0% [69·2 to 85·6]) did not meet the bioequivalence criterion. INTERPRETATION: Based on a small sample size, BTZ-043 is a promising antituberculosis drug candidate with favourable safety and good bactericidal activity. Larger follow-up studies are needed to detect any less frequent safety signals, further explore drug-drug interactions, identify the best dose, and evaluate efficacy in combination with other drugs. FUNDING: EDCTP2 programme; German Ministry for Education and Research; German Center for Infection Research; InfectControl; Bavarian Ministry for Science and the Arts; Swiss State Secretariat for Education, Research, and Innovation; and Nederlandse Organisatie voor Wetenschappelijk Onderzoek.
AU  - Heinrich, N.*
AU  - de Jager, V.*
AU  - Dreisbach, J.*
AU  - Gross-Demel, P.*
AU  - Schultz, S.*
AU  - Gerbach, S.*
AU  - Kloss, F.*
AU  - Dawson, R.*
AU  - Narunsky, K.*
AU  - Matt, L.*
AU  - Wildner, L.*
AU  - McHugh, T.D.*
AU  - Fuhr, U.*
AU  - Aldana, B.H.*
AU  - Mouhdad, C.*
AU  - Brake, L.T.*
AU  - Boeree, M.J.*
AU  - Aarnoutse, R.E.*
AU  - Svensson, E.M.*
AU  - Gong, X.*
AU  - P J Phillips, P.*
AU  - Diacon, A.H.*
AU  - Hoelscher, M.
C1  - 73009
C2  - 56887
TI  - 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.
JO  - Lancet Microbe
VL  - 6
IS  - 2
PY  - 2025
SN  - 2666-5247
ER  - 

TY  - JOUR
AB  - Background: Chronic obstructive pulmonary disease (COPD) is associated with airway inflammation and bacterial dysbiosis. The relationship between the airway microbiome and bronchial gene expression in COPD is poorly understood. We aimed to identify differences in the airway microbiome from bronchial brushings in patients with COPD and healthy individuals and to investigate whether any distinguishing bacteria are related to bronchial gene expression. Methods: For this 16S rRNA gene sequencing and host transcriptomic analysis, individuals aged 45–75 years with mild-to-moderate COPD either receiving or not receiving inhaled corticosteroids and healthy individuals in the same age group were recruited as part of the Emphysema versus Airways Disease (EvA) consortium from nine centres in the UK, Germany, Italy, Poland, and Hungary. Individuals underwent clinical characterisation, spirometry, CT scans, and bronchoscopy. From bronchoscopic bronchial brush samples, we obtained the microbial profiles using 16S rRNA gene sequencing and gene expression using the RNA-Seq technique. We analysed bacterial genera relative abundance and the associations between genus abundance and clinical characteristics or between genus abundance and host lung transcriptional signals in patients with COPD versus healthy individuals, and in patients with COPD with versus without inhaled corticosteroids treatment. Findings: Between February, 2009, and March, 2012, we obtained brush samples from 574 individuals. We used 546 of 574 samples for analysis, including 207 from healthy individuals and 339 from patients with COPD (192 with inhaled corticosteroids and 147 without). The bacterial genera that most strongly distinguished patients with COPD from healthy individuals were Prevotella (median relative abundance 33·5%, IQR 14·5–49·4, in patients with COPD vs 47·7%, 31·1–60·7, in healthy individuals; p<0·0001), Streptococcus (8·6%, 3·8–15·8, vs 5·3%, 3·0–10·1; p<0·0001), and Moraxella (0·05%, 0·02–0·14, vs 0·02%, 0–0·07; p<0·0001). Prevotella abundance was inversely related to COPD severity in terms of symptoms and positively related to lung function and exercise capacity. 446 samples had assessable RNA-seq data, 257 from patients with COPD (136 with inhaled corticosteroids and 121 without) and 189 from healthy individuals. No significant associations were observed between lung transcriptional signals from bronchial brushings and abundance of bacterial genera in patients with COPD without inhaled corticosteroids treatment and in healthy individuals. In patients with COPD treated with inhaled corticosteroids, Prevotella abundance was positively associated with expression of epithelial genes involved in tight junction promotion and Moraxella abundance was associated with expression of the IL-17 and TNF inflammatory pathways. Interpretation: With increasing severity of COPD, the airway microbiome is associated with decreased abundance of Prevotella and increased abundance of Moraxella in concert with downregulation of genes promoting epithelial defence and upregulation of pro-inflammatory genes associated with inhaled corticosteroids use. Our work provides further insight in understanding the relationship between microbiome alteration and host inflammatory response, which might lead to novel therapeutic strategies for COPD. Funding: EU Seventh Framework Programme, National Institute for Health Research.
AU  - Ramsheh, M.Y.*
AU  - Haldar, K.*
AU  - Esteve-Codina, A.*
AU  - Purser, L.F.*
AU  - Richardson, M.*
AU  - Müller-Quernheim, J.*
AU  - Greulich, T.*
AU  - Nowinski, A.*
AU  - Barta, I.*
AU  - Stendardo, M.*
AU  - Boschetto, P.*
AU  - Korzybski, D.*
AU  - Prasse, A.*
AU  - Parr, D.G.*
AU  - Hohlfeld, J.M.*
AU  - Döme, B.*
AU  - Welte, T.*
AU  - Heath, S.*
AU  - Gut, I.*
AU  - Morrissey, J.A.*
AU  - Ziegler-Heitbrock, L.
AU  - Barer, M.R.*
AU  - Singh, D.*
AU  - Brightling, C.E.*
C1  - 62471
C2  - 50821
SP  - e300-e310
TI  - Lung microbiome composition and bronchial epithelial gene expression in patients with COPD versus healthy individuals: A bacterial 16S rRNA gene sequencing and host transcriptomic analysis.
JO  - Lancet Microbe
VL  - 2
IS  - 7
PY  - 2021
SN  - 2666-5247
ER  -