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

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: 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.